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Berkman ND, Thorp JM Jr, Hartmann KE, et al. Management of Preterm Labor. Rockville (MD): Agency for Healthcare Research and Quality (US); 2000 Dec. (Evidence Reports/Technology Assessments, No. 18.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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2Methodology

This chapter documents the procedures that the Research Triangle Institute-University of North Carolina at Chapel Hill Evidence-based Practice Center (RTI-UNC EPC) used to develop a comprehensive evidence report for the AHRQ that describes and contrasts the approaches currently used in the management of preterm labor. To set the framework for the review, we present first the key questions and their underlying causal pathways followed by a detailed description of the literature search, which includes documenting the inclusion and exclusion criteria for literature acquisition, selecting relevant MeSH terms, listing databases searched, retrieving the gray literature, and specifying the eligibility criteria for study inclusion. Once we determined which studies met the inclusion/exclusion criteria and were eligible for inclusion, we abstracted data onto data extraction forms and then transferred critical information to evidence tables; these forms are also described in this chapter.

The methodology chapter also discusses quality issues (i.e., the RTI-UNC EPC's quality control procedures with regard to determining the eligibility for inclusion, carrying out data abstraction, and developing the quality rating for individual studies). An evidence report requires an extensive search for all types of literature. Because some published works are of higher methodologic quality than others, the RTI-UNC EPC developed quality rating forms specific to each body of literature studied in relation to managing preterm labor. This chapter describes the development of the rating system and its use in the analysis. Last, the RTI-UNC EPC's procedures for conducting a supplemental meta-analysis and the peer review process are discussed.

Key Questions and Causal Pathways

We address four key questions in this report. All questions were put into final form with input from the TEAG (Appendix A). After consultation with the TEAG, we determined that two additional questions concerning the enhancement of fetal lung development with corticosteroids and the cost-effectiveness of using antibiotic and tocolytic pharmacotherapies were inappropriate for further study through this report. The decision concerning corticosteroids was based on our conclusion that we would have little to add to the knowledge in the field. In relation to cost-effectiveness studies, we did not find a body of literature to review.

First, we discuss the key clinical questions and then we present the causal pathways (Figures 1-4) for each of the questions.

Figure 1. Causal pathway: Biologic markers.

Figure

Figure 1. Causal pathway: Biologic markers.

Figure 2. Causual pathway: Tocolytics.

Figure

Figure 2. Causual pathway: Tocolytics.

Figure 3. Causual pathway: Antibiotics.

Figure

Figure 3. Causual pathway: Antibiotics.

Figure 4. Causual pathway: Home uterine activity monitoring.

Figure

Figure 4. Causual pathway: Home uterine activity monitoring.

Final Key Questions

The first question concerns the effectiveness of using three biologic markers in assessing the risk of preterm delivery: fFN found in cervicovaginal secretions, EVUSD of the cervix, and E3. The second and third questions relate to pharmacotherapies for arresting the condition: tocolytics to stop uterine contractions, and antibiotics for treating possible underlying infections. The tocolytic review separates studies based on whether the aim was treatment during the episode of preterm labor and uterine activity (first-line use) or promotion of continued quiescence of the uterus (maintenance use). By contrast, although various antibiotics are used in treating preterm labor, they are discussed as one group. The fourth question concerns using home uterine activity monitoring for detecting early labor uterine contractions.

Our specific key questions are as follows:

1.

What are the appropriate criteria for the 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?

2.

What is the efficacy and/or effectiveness of tocolytics in managing preterm labor?

3.

What is the efficacy and/or effectiveness of antibiotics in managing preterm labor?

4.

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?

In the context of managing preterm labor, the efficacy or effectiveness of treatment refers to three major categories of outcomes: delivery, maternal morbidities, and infant health. From a clinical perspective, the outcomes of greatest concern are infant morbidities and mortality associated with preterm birth; however, because these are rare events and difficult to quantify except in large samples, and because prolonging the pregnancy is believed to be correlated with improved infant outcomes, studies also include birth outcomes as intermediate or proxy measures of efficacy.

Our search included both efficacy results from RCTs and effectiveness outcomes from observational research to ensure the greatest breadth of understanding of the research in this area. Efficacy results are obtained from studies where health care is delivered under relatively ideal conditions, such as controlling for confounding interventions. In contrast, effectiveness results are gathered under more normal conditions. The potential harms associated with treatment are presented in relation to tocolytic therapy. Our review of the literature concerning diagnostic testing includes only cohort studies because those were the only ones available. Our review of the use of home uterine activity monitoring includes only English language efficacy studies, because our search was limited based on time and resource considerations.

Corticosteroids

In 1994, researchers from the United States and other countries participated in a Consensus Development Conference sponsored by the National Institute of Child Health and Human Development (NICHHD) to discuss the perinatal outcomes associated with the use of corticosteroids. The panel assessed relevant studies; most of the outcomes, both maternal and neonatal, reflected data collected in RCTs. The resulting consensus statement and clinical recommendations provide the definitive scientific approach to antenatal corticosteroid therapy. 2

Similar to the AHRQ evidence reports, the NICHHD panel reviewed the literature and evaluated findings using a grading system. The ratings developed for the NICHHD project were based on those constructed by the Canadian Task Force on the Periodic Health Examination (now, Canadian Task Force on Preventive Health Services), as adapted by the U.S. Preventive Services Task Force. The ratings largely capture the nature of the study designs and the strength of the recommendations that can be based on the literature.

The expert panel concluded that antenatal corticosteroid therapy is recommended for most women at risk of preterm birth. The advantages of this therapy include substantial reductions in neonatal morbidity and mortality, with specific effects on respiratory distress syndrome and intraventricular hemorrhage in preterm infants. The benefits identified appear to be greatest 24 hours post-therapy, and the treatment window extends from 24 to 34 weeks' gestation. 2 In addition, several followup studies that tracked children up to 12 years of age failed to find adverse effects in children exposed prenatally to corticosteroids. 2 The expert panel also concluded that corticosteroid therapy provides a cost-effective solution that improves perinatal outcomes and reduces the need for more expensive neonatal interventions for premature infants.

If the biologic markers described in this evidence report can accurately assess the risk of preterm birth in women with preterm labor symptoms, then one would assume that more targeted use of steroids might follow. Targeting antenatal corticosteroid therapy would avoid under and over treatment and would achieve one of the consensus conference's goals.

After reviewing the NICHHD Consensus Development Conference findings to assess their methodologic soundness, we searched for subsequent peer-reviewed literature concerning the effect of treating pregnant women with preterm labor with corticosteroids to enhance fetal lung maturity. In our review of the literature published since the NICHHD findings were released, we did not uncover any more recent studies evaluating treatment efficacy, effectiveness, or cost-effectiveness; all subsequent publications were review articles and meta-analyses. Based on these results, we elected not to revisit this topic in further detail.

Cost-effectiveness of Treatment

One of the issues originally proposed for this review concerned the question of the cost-effectiveness of using biologic markers or antibiotic or tocolytic pharmacotherapies in treating women with preterm labor. Although, in principle, we agree that this is a potentially worthy topic, as shown in the literature review section of this chapter, we also determined that the body of literature specifically covering these questions was insufficient for an evidence-based study. Only one study relating to this topic was uncovered. Thus, with the concordance of our TEAG, we did not investigate this issue in this report.

Causal Pathways

As indicated in the illustrations of the causal pathways (Figures 1, 2, 3, and 4), the diagnosis and treatment of a woman in preterm labor requires several steps and possibly the combination of several management modalities. Owing to the complexity of the problem, the potential breadth of its etiology, and our focus on the management of preterm labor, we begin our causal pathways with presentation of the patient with signs and symptoms of preterm labor. For example, these might include contractions, dilation, and/or effacement.

At this point, the clinician faces two challenges. The first challenge is to decide how to diagnose the preterm labor itself, which may include assessing the likelihood of preterm birth using biologic markers. The second is to determine whether the preterm labor stems from a treatable cause (e.g., an infection) that might be addressed through managing the condition or whether it cannot be attributed to a likely treatable cause and so should be limited to managing the symptoms (e.g., through the use of tocolytics).

We have devised causal pathways for each of the diagnostic, treatment, and monitoring modalities we examined. The causal pathway for biologic markers (Figure 1) indicates that their purpose is to predict which patients presenting with signs and symptoms of preterm labor are likely to continue to preterm birth. In other words, their value lies in their ability to add predictive value (either positive or negative) to the clinician's diagnostic abilities. If the biologic markers have strong positive predictive value, they would indicate which women are likely to give birth preterm. The converse is equally valuable-if the biologic markers have strong negative predictive value, they may be able to predict which women are likely not to give birth preterm and, therefore, enable women and their clinicians to avoid unnecessary treatment.

Figures 2 and 3 present two pharmacotherapy treatment scenarios. Figure 2 presents the hypothesized causal pathway for using tocolytics in managing uterine contractions associated with an episode of preterm labor. Figure 3 depicts the pathway for using antibiotics for treating infections relating to the condition. In both of these causal pathways, adjunctive bed rest, hydration, and/or routine inpatient monitoring may be occurring. In addition, when use of antibiotics is the issue, then concurrent use of tocolytics may be occurring and vice versa (concurrent use of antibiotics when use of tocolytics is the issue). Biologic markers might be used for diagnostic purposes with any of these modalities or combination of modalities.

These causal pathways can become quite complicated as the possible options and outcomes multiply. In our presentation, the treatment pathways are somewhat simplified because they do not reflect the possibility that clinicians might use more than one type of tocolytic when the first agent that is tried fails or the possibility that different practitioners might invoke the pharmacologic agents at different times in the course of an initial or subsequent preterm labor episode. Similarly, the "diagnosis" part of the causal pathway does not reflect the fact that different practitioners use different clinical criteria for diagnosing preterm labor, including different tests or using the tests in a different order if biologic testing is selected.

The causal pathway for home uterine activity monitoring (Figure 4) presents a relationship showing early detection allowing for intervention and, hence, leading to a greater opportunity for successful treatment. The system is held out not as a method of preventing adverse outcomes, but rather as a way of indicating when, if at all, at-risk women are symptomatic and, therefore, in need of treatment.

Literature Search

This portion of Chapter 2 describes our literature search strategy and results. Included are inclusion/exclusion criteria with regard to population, medical condition, interventions, and setting, quality grading forms containing the criteria for evaluating the quality of the evidence from the studies reviewed, databases searched and search terms used, and additional sources contacted for gray literature and works in progress. Documented here are the steps used to refine the literature search to the final number of articles ultimately reviewed and included in each evidence table.

Inclusion and Exclusion Criteria for the Literature Search

The criteria listed in Table 2 provide the basis for the systematic search strategy. They map to the key questions with regard to the population being studied, the treatment setting for patients with preterm labor, and the publication language. As seen in the table, for the management of preterm labor, we have identified the population of interest as humans and pregnant women of any age, race/ethnicity, demographic, or health status characteristic. Women must be exhibiting signs and symptoms of preterm labor. Studies are included based on therapies or interventions examined, including testing with biologic markers, antibiotic or tocolytic treatment, or monitoring with home uterine activity monitoring. All inpatient and outpatient settings are considered, including patients' homes. Other filters involve the time period of interest and study publication languages. In cooperation with the TEAG and the need to limit our analysis, studies focusing solely on women with preterm premature rupture of membranes, medically indicated preterm birth, or multiple gestations were excluded. As noted in the table, the inclusion/exclusion criteria used in the home uterine activity monitoring review is somewhat more restrictive than those used for the other analyses.

Table 2. Management of preterm labor: inclusion/exclusion criteria.

Table

Table 2. Management of preterm labor: inclusion/exclusion criteria.

Search Terms

The literature review specialist in cooperation with the study director and the scientific director developed the MeSH search terms used in the analysis. Searches in the National Library of Medicine (NLM) databases (e.g., MEDLINE) were limited by the subject heading: explode premature labor. This phrase is defined in the NLM databases as the onset of labor before term but after the fetus has become viable, usually sometime during estimated gestational ages of 29 through 38 weeks. Both preterm labor and premature delivery default to this subject heading. Preterm premature rupture of membrane, which is excluded from this analysis, is not included under this heading.

To ensure inclusion of relevant study designs, we searched within the MeSH tree under epidemiologic study characteristics, which are defined as types and formulations of studies used in epidemiologic and clinical research. Relevant MeSH key words included under this general topic and searched concurrently through the "exploded" term are clinical trials (Phase I-IV, controlled clinical trials, multicenter studies, and randomized controlled trials), analytic studies, epidemiologic studies, retrospective studies, prospective studies, longitudinal studies, followup studies, feasibility studies, pilot studies, sampling studies, intervention studies, cross-over studies, cohort studies, case control studies, and cross-sectional studies.

In addition, we searched the intersection of the terms premature labor and diagnosis to capture review articles. Bibliographies in review articles were examined as a double check to our electronic literature search to ensure that all relevant articles were included in the study. We searched for economic and cost analyses using the search terms costs and cost analysis and cost-benefit analysis.

We also searched for specific therapies. First, we searched on the relevant diagnostic tests within the term biologic markers, where the scope is defined as measurable and quantifiable biologic parameters that serve as indexes for health- and physiology-related assessments. Specific biologic markers included in the study are salivary estriol (estriol, saliva), endovaginal ultrasound, and fetal fibronectin (fibronectins). Second, we searched exploded antibiotics, which include ampicillin, amoxicillin, metronidazole, erythromycin, ceftizoxime, ampicillin-salbactam. Finally, we exploded tocolytic agents, which include ritodrine, terbutaline, isoxsuprine, magnesium sulfate, nifedipine, nicardipine, indomethacin, fenoterol, ethanol, nylidrin, and salbutamol.

Our primary literature search was conducted through MEDLINE. The MEDLINE database is widely recognized as the premier source for bibliographic coverage of biomedical literature. MEDLINE encompasses information from Index Medicus, Index to Dental Literature, andInternational Nursing, as well as other sources of coverage in the area of communication disorders, population biology, and reproductive biology.

In addition, we searched EMBASE (the electronic version of Excerpta Medica) because it provides a more complete coverage of the literature published in Europe, Latin America, and Asia. Apart from being a database that AHRQ has specified as being of interest, the EMBASE search is important because, historically, drugs have been approved for clinical application earlier in Europe than in the United States. Clinical findings regarding a drug's efficacy may have been published in Australia or Canada before reaching the U.S. market. We used a similar search strategy and terms for EMBASE as were employed for MEDLINE.

Additional databases searched include: (1) the Cochrane Collaboration database to examine relevant meta-analyses and systematic reviews closely related to our topic; (2) the related York database of the National Health Science Center for Reviews and Dissemination; (3)International Pharmaceutical Abstracts, a database devoted exclusively to pharmaceuticals and produced by the American Health-System Pharmacist Association; (4) the Health Economic Evaluations Database for literature concerning cost and economic analyses; (5)Genderwatch, a search engine that covers international journals, magazines, newsletters, regional publications, special reports, and conference proceedings devoted to women's and gender issues; and (6) the Population Index, a reference tool that focuses on the world's population literature. Of all these databases, Genderwatch and the Population Index uncovered no matches with our topics.

Gray Literature Search

In its first task order (Pharmacotherapies of Alcohol Dependence), the RTI-UNC EPC outlined a search strategy for uncovering the so-called "gray literature" (i.e., potentially useful literature and documents that are to be found in outlets other than peer-reviewed journals). For this evidence report on the management of preterm labor, the RTI-UNC EPC has pursued a similar strategy.

Ideally, gray literature searches include reviews of government documents and monographs; industry reports and studies; unpublished studies and works in progress; proceedings and technical bulletins; and FDA Medical Officer's Reviews of original or extended (change of label) New Drug Approval applications, including advisory committee minutes for drugs, and similar reviews of Pre-Market Approval applications for devices. In reality, constraints on time and resources necessitate strategic reductions in the scope of the gray literature search.

We made two important decisions in restricting our gray literature work. Our earliest strategic decision, in consultation with the task order officer, was not to conduct gray literature searches for home uterine activity monitoring devices because of time and resource limitations. We did search for and review Pre-Market Approval documents archived at the FDA Web site (http://www.fda.gov) for home uterine activity monitoring devices, the E3 test, and the fFN test. We identified and reviewed research information offered by the manufacturer of the E3 test SalEst ® (http://www.biex.com), and fFN test (http://www.adeza.com). Both manufacturers provided information such as clinical monographs; however, with the exception of one brief four-person case study that appeared to have been written expressly for the manufacturer, all research to which they referred is available already as journal articles or abstracts.

Our second significant strategic decision was sharply to restrict our search for gray literature on antibiotics, for several reasons that reflect an initial investment of study resources. First, thousands of antibiotics are marketed in the United States alone. For example, just one of the earliest antibiotics, erythromycin, is marketed for human use by almost 20 different pharmaceutical firms; most of them market more than one version (oral and intravenous and/or intramuscular). Multiplying all possible antibiotics by all firms marketing them would create a search the size of which no EPC could undertake.

Second, and more important, in no case is an antibiotic specifically labeled for use in the treatment of preterm labor. Only two antibiotics are approved currently by the FDA for the treatment of bacterial vaginosis in pregnancy, metronidazole and clindamycin (Anti-Infective Drugs Advisory Committee Meeting, 64th Meeting, Issue: Guidance documents on developing antimicrobial drugs: General considerations and individual indications. Wednesday, July 29, 1998.) The RTI-UNC EPC's experience with the gray literature search for alcohol suggests that pharmaceutical firms do not engage in research into off-label uses unless they are preparing an application for a new or changed labeling approval, and they will not otherwise comment on off-label uses for their drugs. Thus, although antibiotics are prescribed routinely in the management of preterm labor, all such prescriptions are "off label."

Additionally, most antibiotics in use, except for the latest generation of cephalosporins, could not have been investigated in pregnant human subjects because the FDA explicitly prohibited the use of "women of childbearing potential" from clinical trials beginning in 1977, and an informal practice of exclusion had been the rule before then. Only in 1993, did the FDA issue a new guideline emphasizing the need for drug research using women as subjects, and the question of conducting drug research in pregnant women is still exceedingly controversial. Most antibiotics, like most drugs, are labeled Pregnancy Category C (harms to fetal development are shown in animal studies but no adequate, well-controlled human studies exist); an antibiotic example includes clarithromycin, which also must carry a Boxed Warning strongly advising against use during pregnancy. Other common antibiotics, such as the aminoglycosides, including streptomycin, fall under Pregnancy Category D (there is evidence of harm to the fetus from human studies, and patients should be advised of the potential hazards). (See, for example, Public Hearing, Content and Format of Labeling for Human Prescription Drugs, Part 15 - Pregnancy Labeling Categories, Friday, September 12, 1997, Bethesda, MD, which we have reviewed as a part of the gray literature search.)

In other words, no pharmaceutical company could have tested its new antibiotic in a sample of pregnant women, even had it wished to do so. Thus, it is neither reasonable nor efficient to devote scarce resources to such a search. The one exception may be in the case of the latest generation of cephalosporins, which are classed in Pregnancy Category B (no evidence of harm from animal studies, but no adequate, well-controlled human studies have been conducted, and the drug should be used only if clearly indicated). Anecdotally, manufacturers have sometimes expressed off-the-record interest in research into cephalosporin use during pregnancy, but we have found no evidence that any manufacturer has petitioned the FDA recently for a change in labeling for use in pregnant women.

Additional strategic decisions concerned tocolytics. The gray literature search on tocolytics appears to reveal that discrepancies arise not from differences between published and unpublished literature but from differing emphases on and interpretations of outcomes and, perhaps, differing ideological approaches to the treatment of women in preterm labor.

This task order includes an evaluation of the tocolytic drug atosiban, an oxytocin-receptor antagonist, approval for which was denied by the FDA's Advisory Committee for Reproductive Health Drugs on April 20, 1998. Despite the failure of the R.W. Johnson Pharmaceutical Research Institute (Johnson & Johnson) to gain approval for atosiban, we have nonetheless located an unpublished manuscript describing the multicenter RCT of atosiban (forthcoming in the American Journal of Obstetrics and Gynecology). We have also obtained and reviewed the minutes of the 1998 Reproductive Health Drugs Advisory Committee meeting. From these minutes, it seems clear that the committee's failure to approve atosiban resulted not from its doubts about the drug's efficacy to halt labor as the endpoint, but rather from its concern as to whether the endpoint of interest ought to be improved perinatal outcome. The Advisory Committee was not satisfied that the manufacturer had collected data addressing such concerns, but it was not in agreement about the kind of perinatal outcomes trial it wanted to see. The manufacturer, Johnson & Johnson, maintains that it proceeded correctly in the initial application. Thus, for the present in the United States, there will be no further efforts to seek approval for atosiban, although it is expected to be approved very soon in 15 European Nations, and the scientific basis for its approval will be published shortly on the European Agency for the Evaluation of Medicinal Products Web site (personal communication, between Sue Tolleson-Rinehart and Johnson & Johnson official, September 23, 1999).

Ritodrine and terbutaline are both beta-mimetic agents. Terbutaline is approved only for treatment of asthma, but it has become the most frequently used tocolytic in the United States. Ritodrine, under the brand name Yutopar ® , was the only drug to receive FDA approval as a tocolytic. The drug, approved in 1980, was available in both oral and intravenous forms until a 1992 meeting of the Fertility and Maternal Drug Advisory Committee, resulting in an FDA request for more testing of high doses of oral ritodrine for tocolytic maintenance. In response, the manufacturer removed oral ritodrine from the market. Controversy still revolves around the clinical information presented to the Drug Advisory Committee at that time from the Canadian Ritodrine Trial; the results of the trial and criticisms of it are in the published literature. 96

Ritodrine in intravenous form remained available as a tocolytic treatment until its two manufacturers, Abbott and AstraZeneca, stopped manufacture. Abbott discontinued the intravenous form before December 1997; AstraZeneca stopped manufacturing it on September 1, 1998, but the last expiration date of previously shipped product was August 1999, meaning that ritodrine could have remained in use until that time. Terbutaline has been employed in an off-label use for tocolysis for the same period and in fact, has surpassed ritodrine in use. In a Fertility and Maternal Drug Advisory Committee meeting in 1993, committee members recommended that the FDA solicit a specific application for change of label to include tocolysis for intravenous terbutaline; also discussed was the possibility of a literature-only application because the literature on terbutaline as a tocolytic was already voluminous.

At roughly the same time, the use of terbutaline in a subcutaneous infusion pump delivery system was increasing. Its advocates (including pregnant women) have generally argued that the terbutaline infusion pump effectively maintains tocolysis at much lower doses than is possible with other delivery systems and that it permits pregnant women to continue tocolysis maintenance at home, rather than in the hospital.

In 1996, the National Women's Health Network presented a Citizen's Petition to the FDA, requesting prohibitory action on the terbutaline subcutaneous infusion pump allegedly because of two maternal deaths that could be attributed to terbutaline use (Docket No. 96P-0258/CP1). On November 13, 1997, Associate Commissioner for Health Affairs Stuart Nightingale issued a "Dear Colleague" letter that said, in part:

Based on information available to the Agency, as well as a review of the published literature, it is clear that the demonstrated value of tocolytics in general is limited to an initial, brief period of treatment, probably no more than 48-72 hours. No benefit from prolonged treatment has been documented. In addition, the safety of long-term subcutaneous administration of terbutaline sulfate, especially on an outpatient basis, has not been adequately addressed.

Published reports on the safety of this use are seriously hampered by methodologic inadequacies. It appears that women receiving continuous subcutaneous terbutaline sulfate infusions experience side-effects and complications similar to those experienced by women receiving terbutaline and other beta-sympathomimetics intravenously. Complications include chest pain, tachycardia, dyspnea, and pulmonary edema. At least one maternal death occurred during outpatient use of a continuous infusion of terbutaline sulfate by subcutaneous pump. The impact of long-term use on maternal glucose metabolism and the risks of prolonged exposure of the fetus are largely unknown.

The "Dear Colleague" letter provoked considerable response from clinicians, researchers, and patient advocates; it apparently induced Matria, Inc., the marketer of the terbutaline pump system, to bring suit against the National Women's Health Network. Advocacy also included a petition from obstetricians to the FDA (Docket No. 98P-0218/CP) to approve subcutaneous terbutaline as a tocolytic treatment. The RTI-UNC EPC has no evidence to date that the FDA has responded to the substance of the petition.

This review for tocolytics suggests that its gray literature actually refers to or summarizes the published literature for policy purposes, rather than presenting unpublished literature. The remaining tocolytic in this evidence report, magnesium sulfate, is not subject to FDA approval as a drug.

As we discussed at the beginning of this section on gray literature, we also examined government documents and manufacturers' information associated with approval and use of assays for E3 and fFN. The first fFN assay was approved on September 21, 1995; a subsequent "Rapid System" by the same manufacturer was approved on August 14, 1998. An E3 assay was approved on April 29, 1998. The available information suggests that most (if not all) of the data relied on by the manufacturers now can be found in published articles and abstracts. Similarly, Pre-Market Approval information for ultrasound devices, including a portable device designed by General Electric expressly for use in obstetrics and gynecology, is straightforward and presents no unusual data. It may be worth noting, however, that the FDA suggests in its guidelines for labeling home uterine activity monitoring devices that they include the following precaution: "No widely accepted controlled studies have been conducted that show that this device is effective at the early detection of preterm labor other than in patients with a previous preterm delivery."

Finally, our efforts to identify unpublished work or other work in progress produced only the atosiban manuscript cited earlier in this chapter.

Literature Retrieval Process

Basic Approach to Article Selection

Once articles were identified through the electronic database search or review article bibliographies, we examined abstracts of the articles to determine whether studies did, in fact, meet our criteria. Two reviewers (one clinician and one methodologist) reviewed abstracts independently for inclusion or exclusion. If both reviewers agreed, an article was retained (or excluded). If the two reviewers disagreed (one indicating eligible and the other judging ineligible), the scientific director made the final decision.

To ensure that all appropriate articles were included and no significant ones were missed, the scientific director rereviewed a 20 percent sample of abstracts determined to be eligible for inclusion as well as all those determined to be ineligible. Generally speaking, for all abstracts, we erred on the side of inclusion rather than exclusion. When abstracts were not available from the electronic search or when there was a question of relevance, the project director or scientific director subjected the full articles to additional scrutiny. In the end, we excluded a study once the full article was examined if, upon this closer scrutiny, we found that it did not conform to the inclusion/exclusion criteria.

For the article review stage, each abstraction form used by a reviewer included an eligibility checklist, or screen, so that if specific criteria were not met, the reviewer was directed not to proceed with the article review. Items that reviewers looked for included whether preterm birth was a study outcome, whether our minimum sample size was met, and whether subjects had signs and symptoms of preterm labor. The eligibility checklist used to review the biologic marker, tocolytic, and antibiotic literatures is presented in Figure 5. The comparable screen used in review of the home uterine activity monitoring literature contained an additional item prompting the reviewer to discontinue the abstraction if the article was not reporting on an RCT.

Figure 5. Article eligibility screen

Screen (If any response is "No," then stop. If any response is "Can't Tell," bring it to the attention of the research coordinator.)

Preterm birth an outcome? Image ftrs_square.jpg Yes Image ftrs_square.jpg No Image ftrs_square.jpg Can't Tell
40 or more subjects at completion? Image ftrs_square.jpg Yes Image ftrs_square.jpg No Image ftrs_square.jpg Can't Tell
Intervention used as part of treating subjects with signs/symptoms of preterm labor (not a preventive intervention used among asymptomatic patients)? Image ftrs_square.jpg Yes Image ftrs_square.jpg No Image ftrs_square.jpg Can't Tell

Productivity and Results of the Literature Search and Retrieval Process

We compiled the results from the electronic literature searches into the ProCite bibliographic database and removed duplicate records. The bibliographic software allowed us to record articles that were to be included in the evidence tables and those that were to be excluded with the reason for their exclusion. Table 3 summarizes our search results, showing that 797 studies were retrieved and reviewed for inclusion in the report. Of these, only 195 were included in the analysis after inappropriate articles were excluded.

Table 3. Search results by topic.

Table

Table 3. Search results by topic.

Tables 4 through 9 provide details of the literature search in each topic area. Presented are the results of the bibliographic databases searched and bibliographies in review articles examined followed by the number of resulting articles excluded with the reason for exclusion. Articles were excluded for primarily three reasons: (1) subjects did not have signs and symptoms of preterm labor, (2) the article was a literature review, or (3) the sample size was too small (fewer than 40).

Table 4. Biologic markers search strategy.

Table

Table 4. Biologic markers search strategy.

Table 5. Tocolytic search strategy.

Table

Table 5. Tocolytic search strategy.

Table 6. Harms related to tocolytic use search strategy.

Table

Table 6. Harms related to tocolytic use search strategy.

Table 7. Antibiotic search strategy.

Table

Table 7. Antibiotic search strategy.

Table 8. Home uterine activity monitoring search strategy.

Table

Table 8. Home uterine activity monitoring search strategy.

Table 9. Costs and cost analyses search strategy.

Table

Table 9. Costs and cost analyses search strategy.

As can be seen in these tables, we had sufficient evidence to warrant proceeding with a review of studies concerning all topics except the cost-effectiveness of using biologic markers or pharmacotherapies in preterm labor (a total of one article concerning the three interventions) (Table 9). Also, we did not find any literature on the biologic marker E3 that met our inclusion criteria; therefore, we did not proceed further with these topics during this review.

Data Abstraction Process

Data Extraction Form

The project director and scientific director worked with core project staff to develop data extraction forms to use for entry of relevant information from the eligible publications. The data extraction form was developed in an iterative fashion with extensive communication between the methodologists and researchers. We began by outlining common variables across types of studies, including study design features and outcomes. We then created more specialized forms to serve as the most efficient and effective vehicles to extract the necessary information from each of the five bodies of literature included in this review: (1) biologic markers, (2) tocolytic benefits, (3) tocolytic harms, (4) antibiotics, and (5) home uterine activity monitoring.

Included across all studies were the following:

  • Description of 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, and maternal and fetal indications for birth.
  • Definition of preterm labor.
  • Description of the test, treatment, or intervention.
  • Description of adjunct therapies.
  • Description of outcomes measured such as prolongation of pregnancy, gestational age at delivery, maternal morbidities, and infant birth weight.
  • Description of secondary analyses performed.

These variables were incorporated into the data extraction forms whose basic structure taken from forms developed for the evidence report on pharmacotherapies for alcohol dependence. The draft forms underwent extensive reviews, including pretesting on several randomly selected articles. After the pretest, we revised the forms to increase their utility and efficiency. The final forms can be found in Appendix B.

The tocolytic and antibiotic data extraction forms were quite similar in design. The tocolytic form had one additional question to capture the definition of tocolysis used in the analysis; therefore, only the tocolytic form is included in Appendix B. We made minor modifications to the form design to accommodate the home uterine activity monitoring literature and made more extensive modifications for the biologic marker form. Rather than mostly capturing the efficacy of treatment based on outcomes of RCTs, the biologic marker literature focuses on the effectiveness of the intervention with outcomes presented generally in terms of predictive values (positive and negative) and sensitivity and specificity. Both the home uterine activity monitoring and biologic marker extraction forms also are found in Appendix B.

Abstractors and Training

The RTI-UNC EPC used abstractors with two types of backgrounds for the data extraction process: individuals with content or clinical expertise and those with strong methodologic skills. Several obstetricians, one pediatrician with training in women's health, and a nurse midwife served as clinican abstractors; all had prior research experience. The methods abstractors were doctoral students in the UNC School of Public Health or the UNC Department of Economics who have 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 in conducting clinical research in the topic area (the scientific director).

To collect high-quality data, we put necessary instructions directly on the data extraction forms. Based on prior work of the RTI-UNC EPC, we found that any separately distributed written instructions were less reliable sources of help for abstractors than the extraction form itself. In addition, all abstractors attended two formal training sessions. At the first session, we explained the process and goals of the abstraction. Following the training, the abstractors were sent home with an article to review. We then reconvened the group and, through a review of the test article, ensured that the reviewers understood what was expected from their work. For example, we instructed abstractors that when inconsistencies arose between results stated in the text of an article and those presented in tabular form, they were to take data from the text. They also were told to extract precisely what was contained in the article and to reserve opinions concerning the contents to the comments section at the end of the form.

At the completion of abstractor training, the data abstraction process began. The project director, scientific director, and UNC research coordinator monitored progress. Problems or questions that abstractors encountered were routed through the research coordinator to the appropriate senior staff member.

Tocolytic Harms Abstraction

Extraction Form

The literature search on side effects or harms of tocolytic use, confined to literature in the English language was conducted using MEDLINE and EMBASE. In addition, we included all abstracted efficacy and effectiveness articles that had been flagged as containing harms information. To ensure a comprehensive review of potential harms and because study results were to be analyzed in aggregate, we did not limit this search by the stringent criteria used for the benefits studies. For example, we retained articles concerning women with ruptured membranes in the analysis because the side effects of tocolytic treatment would be the same as for women with intact membranes.

Because of time and resource constraints, we extracted data using only a simple, rather than dual, abstractive. A certified nurse midwife entered data into a spreadsheet and transferred them into an analytic data set for analysis.

Our harms extraction form (Appendix B) covered the following types of information:

  • Types of maternal and neonatal side effects.
  • Sample size of each arm of the study and total sample size.
  • Frequency of side effects in each group.
  • Methodology for harms data collection.

We did not abstract the harms of antibiotic therapy because they are generally well known to clinicians. Pregnancy commonly does not alter the potential complications of antibiotic therapy for mother or baby. One minor exception is tetracycline and its propensity to stain fetal teeth and bone. A potentially serious harm that has not been assessed adequately is the development of resistance to antimicrobials from widespread exposure of pregnant women to antibiotics, which could make treatment of neonatal sepsis more difficult.

Analysis Methodology

Harms results are presented through graphic representation rather than as evidence table entries. This methodology provides a means of comparing the number and percentage of participants experiencing adverse reactions to treatment or placebo. For clarity in the analysis, we grouped the harms into two categories: maternal harms and fetal/newborn harms. We aggregated individual descriptors into clinically sensible categories within each of these broad categories. The aggregation process may lead to some "double counting" of harms. For example, if an article described 15 percent of the subjects as having chest pain and 10 percent as having arrhythmia, then 25 percent of the patients would be assessed as having serious cardiovascular harms. From the studies, one cannot determine whether the patients with the various types of harms are the same or different patients. We did not allow greater than 100 percent of subjects to have harms within a category. Double counting of harms would result when one patient experienced both chest pain and arrhythmia; therefore, the graphs comparing studies should be viewed as somewhat more valuable for demonstrating the relative rates of harms among the therapeutic categories, rather than the absolute rates. (See results in Chapter 3.)

We performed a sensitivity analysis to examine whether such possible double counting would affect the patterns of harms demonstrated in the graphs. A low estimate of harm rates could be attained by selecting the side effect with the highest percentage within each category rather than by adding the harms within categories. In this low-estimate sensitivity analysis, if 25percent of patients had chest pain and 10 percent arrhythmia, then serious maternal cardiac harms would be reported as 25 percent. When we performed this analysis, we found the same overall pattern of harms.

The analysis of fetal/newborn harms and the evaluation of efficacy in other sections of this report overlap to some extent. Rates of fetal demise, sepsis, or intraventricular hemorrhage (IVH) could be considered as either a therapeutic effect or a harm associated with use of the pharmacologic treatment. This information, then, may also be found in the evidence tables.

The aggregation of individual harm variables into categories is presented in Table 10. This categorization, of course, is somewhat arbitrary, but it does reflect a significant advance over the level of categorization in the source articles, which often provided no categorization at all. The placebo category refers to placebo pharmacologic therapy within the context of an RCT. Almost all placebo groups also received standard supportive care such as hospitalization, bed rest, and intravenous hydration.

Table 10. Categories of maternal and fetal/newborn harms related to tocolytictreatment.

Table

Table 10. Categories of maternal and fetal/newborn harms related to tocolytictreatment.

Quality Control, Adjudication, and Reliability

Quality control for determining the eligibility for abstraction was described earlier in the section "Basic Approach to Article Selection." In short, all titles and abstracts were subject to dual review, and the scientific director adjudicated discrepancies. Each article was abstracted by two independent abstractors-one a clinician (content reviewer) and the other a methodologist. Abstractors were blinded to the authors' names, the institution that produced the work, and the journal title; however, in some instances, given the distinct formatting of certain journals, reviewers may have recognized journal titles.

Through prior work of the RTI-UNC EPC, we learned that using a third party for adjudicating differences between reviewers in a system of dual abstraction can be very time consuming. We decided for this project that the more efficient and effective process was for the two abstractors to discuss and reconcile differences between themselves and record their review on one reconciled extraction form. Information contained on the reconciled forms were spot checked by the project manager and the RTI research coordinator. In contrast, abstractors did not reconcile their opinion of the quality of the article as expressed through their responses on the quality rating form. We recorded a grade from each reviewer in the evidence tables.

Because the abstractors adjudicated their own work and completed a joint extraction form, we decided that a statistical check on the interrater reliability of their original data collection was not appropriate. In the past, the RTI-UNC EPC has used kappa statistics to evaluate agreement between reviews. Because our method of reconciliation produced 100percent agreement between reviewers (i.e., essentially perfect interrelater reliability), kappa statistics were neither useful nor appropriate.

Quality Rating Development and Analysis

Quality of the evidence can be judged on two levels: (1) at the level of the individual article and (2) in summary over the spectrum of articles addressing each of the key therapies or interventions. This portion of Chapter 2 describes our approaches to the development of quality ratings on both levels.

Quality of Individual Articles

The RTI-UNC EPC approach to assessing the quality of the individual articles considers the various concerns important to the scientific method of conducting research, including the internal and external validity of each study. It encompasses, among other factors, study design, measurement issues, statistical analyses, and the appropriateness of the conclusions being drawn.

The forms used to collect information on the quality of the literature were the same for the antibiotics and tocolytic literature (Figure 6). We made a few changes in the forms to accommodate differences in the biologic markers literature (Figure 7) and the home uterine activity monitoring studies (Figure 8). For example, the biologic marker form asks whether the authors provide calculations of sensitivity and specificity, likelihood ratios, or odds ratios. This information would not be relevant for the pharmacotherapy literature.

Figure 6. Quality of articles form: Categories and points for grading literature Preterm labor: Antibiotics and tocolytics literature

Category 1: Problem or question studied
Category 2: Sampling
Category 3: Measurement
Category 4: Internal validity
Category 5: External validity
Category 6: Construct validity
Category 7: Statistical conclusions
Category 8: Justification for conclusions
NoYes
1.Is the defnition used for the diagnosis of preterm labor clearly stated?02
NoYes
2.Is the recruitment strategy clearly described?01
NoYes
3.Is there random allocation of treatment?02
NoYes
4.Are baseline levels of cervical dilation and effacement assessed?01
NoYes
5.Are patients with ruptured membranes excluded or assessed in a stratified analysis?01
NoYes
6.Are medically indicated or iatrogenic pregnancies excluded or assessed in a stratified analysis (e.g., preeclampsia, severe fetal defects, placenta previa)?01
Unknown or
>20%
<20%
7.Is the dropout rate of patients invited into the study less than 20%?01
8.What outcomes are measured?NoYes
1.

Proportion of patients with preterm delivery at a defined period (e.g., 32, 34, or 37 weeks).

01
2.

Maternal outcomes (e.g., length of hospital stay, chorioamnionitis, endometritis).

01
3.

Neonatal outcomes (e.g., APGAR, need for intensive care unit, length of stay, respiratory distress syndrome, birth weight, intraventricular hemorrhage).

01
NoYes
9.Are the outcome measurements clinically relevant?010.5
NoYesNA
10.Are potential confounding variables taken into account in the outcome analysis (e.g., age, race, type of preterm labor, parity)?01 Image ftrs_check.jpg
NoYesNA
11.Are cointerventions (e.g., bed rest, hydration, or use of antibiotics when tocolytics are the study question, or vice versa) measured or reported on?01 Image ftrs_check.jpg
NoYesNA
12.Are the treating clinicians masked to treatment administered?01 Image ftrs_check.jpg
NoYesNA
13.Are the patients masked to treatment received?01 Image ftrs_check.jpg
NoYes
14.Do the study conclusions apply to pregnant women in the United States or to important subgroups of the U.S. population?01
NoYes
15.Is the clinical setting specified clearly?01
NoYes
16.Are the criteria used to assign gestational age clearly stated?01
NoYesNA
17.If the study is negative, is a power analysis performed?01 Image ftrs_check.jpg
NoYesSome
18.Are statistically significant (or insignificant) findings clinically significant?010.5
NoYesSome
19.Are statistical tests used appropriate to the data?010.5
NoYes
20.Are the conclusions warranted from the data and/or design of the study?02

Figure 7. Quality of articles form: Categories and points for grading biologic marker literature

Category 1: Problem or question studied
Category 2: Sampling
Category 3: Measurement
Category 4: Internal Validity
Category 5: External validity
Category 6: Construct validity
Category 7: Statistical conclusions
Category 8: Justification for conclusions
NoYes
1.Is the description of the test procedure provided?01
NoYes
2.Are the relevant outcomes clearly defined?01
NoYes
3.Is a reference standard for the test clearly referenced?01
NoYes
4.Is the recruitment strategy clearly described?01
5.Are inclusion/exclusion criteria clearly stated?01
6.Are baseline levels of cervical dilation and/or effacement assessed?01
7.Are patients with ruptured membranes excluded or assessed in a stratified analysis?01
8.Are medically indicated or iatrogenic deliveries excluded or assessed in a stratified analysis (e.g., preeclampsia, severe fetal defects, placenta previa)?01
Unknown or
>20%
<20%
9.Is the dropout rate of patients invited into the study less than 20%?01
10.What outcomes are measured?NoYes
1.

Proportion of patients with preterm delivery at a defined period (e.g., 32, 34, or 37 weeks).

01
2.

Maternal outcomes (e.g., length of hospital stay, chorioamnionitis, endometritis).

01
3.

Neonatal outcomes (e.g., APGAR, need for intensive care unit, length of stay, respiratory distress syndrome, birth weight, intraventricular hemorrhage).

01
NoYesSome
11.Are the outcome measurements clinically relevant?010.5
NoYesNA
12.Are potential confounding variables taken into account in the outcome analysis (e.g., age, race, type of preterm labor, parity)?01 Image ftrs_check.jpg
NoYesNA
13.Are cointerventions (e.g., bed rest, hydration, tocolytic use) measured or reported on?01 Image ftrs_check.jpg
NoYesNA
14.Are the treating clinicians masked to test result?01 Image ftrs_check.jpg
NoYesNA
15.Are the patients masked to test result?01 Image ftrs_check.jpg
NoYes
16.Is the clinical setting specified clearly?01
NoYes
17.Are the criteria used to assign gestational age clearly stated?01
NoYesNA
18.Is a power analysis performed?01 Image ftrs_check.jpg
NoYesSome
19.Are statistically significant (or insignificant) findings clinically significant?010.5
NoYesSome
20.Are statistical tests used appropriate to the data?010.5
NoYes
21.Do the authors provide either sensitivity/specificity, likelihood ratios or odds ratios?01
NoYes
22.Are the conclusions warranted from the data and/or design of the study?02

Figure 8. Quality of articles form: Categories and points for grading literature home uterine activity monitoring

Category 1: Problem or question studied
Category 2: Sampling
Category 3: Measurement
Category 4: Internal validity
Category 5: Construct validity
Category 6: Statistical conclusions
Category 7: Justification for conclusions
NoYes
1.Is the definition used for the diagnosis of preterm labor clearly stated?01
2.Is the intervention being tested clearly described?01
NoYes
3.Is the recruitment strategy described?01
NoYes
4.Are the inclusion criteria for the study stated?01
NoYes
5.Is the randomization scheme described?01
NoYes
6.Are baseline levels of cervical dilation and effacement presented?01
Unknown or
>20%
<20%
7.Is the dropout rate of patients invited into the study less than 20%?01
NoYes
8.Are all patients who dropped out of the study accounted for?01
NoYes
9.Are the outcomes clearly described?01
NoYesSome
10.Are the outcome measurements clinically relevant?010.5
NoYesNA
11.Are potential confounding variables taken into account in the outcome analysis (e.g., age, race, labor, parity)?01 Image ftrs_check.jpg
NoYesNA
12.Are any cointerventions reported on?01 Image ftrs_check.jpg
NoYesNA
13.Are the treating clinicians masked to intervention group?01 Image ftrs_check.jpg
NoYesNA
14.Are the patients masked to treatment received?01 Image ftrs_check.jpg
NoYes
15.Are the criteria used to assign gestational age stated?01
NoYesNA
16.Was a power analysis performed?01 Image ftrs_check.jpg
NoYesSome
17.Are statistical tests used appropriate to the data?010.5
NoYesSome
18.Are statistical tests clearly described?010.5
NoYes
19.Are levels of significance and or confidence intervals given?01
NoYes
20.Was an intent-to-treat analysis performed?01
NoYes
21.Are the conclusions warranted from the data?01
22.Are the conclusions warranted from the study design?01

To assess the internal validity of a study (i.e., the likelihood that the design and conduct of the study minimize systematic error or bias) the following factors were evaluated from each study across all study types:

  • Description of the recruitment strategy.
  • Masking of the treating clinician and patient.
  • Inclusion of baseline measurements including cervical dilation, effacement, and estimated gestational age.
  • Definition of outcome measures, attrition rates, and confounding variables.

Statistical considerations included assessing the adequacy of the methods used and whether the authors did a power calculation. The rating scale also addressed the clinical relevancy of the statistical findings.

With regard to diagnostic and outcome measures, the abstractors evaluated whether the standard for a test was clearly referenced. In addition, the quality rating instrument assessed whether studies included the three major categories of outcomes (i.e., those for delivery, mothers, and infants).

External validity (i.e., whether the findings of the study can be generalized to populations that did not participate in the study) also was considered for quality rating. We included in our evaluation whether the clinical setting was specified clearly and whether conclusions apply to pregnant women in the United States.

The quality rating instrument was based on a point scale that was transformed into a percentage score, with the higher percentage score denoting a better study. Each abstractor completed the quality rating for each article reviewed. The individual scores provided in the evidence tables for each article were derived by calculating the following ratio: the points from the responses circled by the abstractor (numerator) divided by the total number of points that could have been awarded (denominator). When the items were determined to not be applicable, "NA," then the total number of points for that item was removed from both the numerator and denominator. Quality rating scores for each article were not averaged across the two abstractors (i.e., clinician and methodologist), so that patterns across studies could be observed.

Grading of the Evidence

According to a report developed by Lohr and Carey,97 several systems have been proposed in the past 10 to 15 years for "grading the quality or strength" on a given clinical topic or pathway; however, little or no consensus exists about which specific system is best, and thus little guidance was given about which approach to use for our review.

The RTI-UNC EPC developed a grading scheme that considers the strength and the quality of the evidence based on the work of the RTI-UNC EPC in the Evidence Report on the Pharmacotherapy for Alcohol Dependence98 and a report by the U.S. Preventive Services Task Force (1996).99 Our determination of the strength of the evidence includes an evaluation of the consistency of study findings over all studies, the quality rating scores for individual pieces of research, the magnitude of important outcomes, and, when available, the results of our meta-analyses. Because we include both randomized and cohort studies in the review, we also record whether the evidence is appropriate for evaluating the efficacy or the effectiveness of the findings. The letter grade given to a body of literature is not necessarily higher because it contains a greater number of RCTs; rather, it rests on the quality of the studies themselves. We did not assign scores for each of the variables considered for the ratings; instead, we based our quality assessment on an adjudicated rating that was initially provided by the project director, scientific director, and clinical methodologist as follows:

Grading of the Evidence

Good (A):The data 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 in preterm labor.
Fair (B):The data are sufficient for evaluating the quality of the findings. The data indicate inconsistencies in the findings between the key drug or intervention and alternative treatment or placebo for treating women in 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 in preterm labor.
Incomplete evidence (I):The data are insufficient for assessing the quality of the key drug or intervention for treating women in preterm labor based on limited sample size or poor methodology.
Efficacy (1):The evidence was obtained from well-designed RCTs.
Effectiveness (2):The evidence was obtained from well-designed cohort or case control analytic studies.

Development of the Evidence Tables

We created our evidence tables from the format used in the RTI-UNC EPC's Evidence Report on Pharmacotherapy for Alcohol Dependence. Based on this example, we separated the presentation of study information into two tables-one for study design and the other for outcomes. The content of these two tables are presented in Table 11. All the evidence tables are contained in Volume 2.

Table 11. Content of study design and outcomes evidence tables.

Table

Table 11. Content of study design and outcomes evidence tables.

The information contained in the tables is self-explanatory; however, numerous abbreviations, which can be found in Appendix C, were used to conserve space.

The content of the study design table is consistent across study topics. All tables include a statement of the research objective, the definition of preterm labor used by the authors, patient inclusion/exclusion criteria, and a description of the experimental intervention. When available, we include the total number of participants at the beginning and at the end of the study as well as the number of participants in each arm of the study at its conclusion.

Information unique to particular studies includes a definition of tocolysis in the tocolytics table and the exclusion of compliance assessment information in the biologic markers tables (as this would be irrelevant in relation to a diagnostic test). The home uterine activity monitoring study design table (Evidence Table 13) includes a list of the outcome measures that are described in greater detail in the outcomes table.

The outcomes tables across types of studies include data on delivery, maternal, and infant outcomes. The presentation is the same in the tables describing tocolytic and antibiotics outcomes (Evidence Tables 3 through 12). The home uterine activity monitoring outcome table provides information on recurrent preterm labor and includes comments and limitations of the study. In the pharmacotherapy studies table, information about the treatment for recurrent labor is included under intervention. We did not include comments and limitations for other study types because authors typically did not provide such information.

The presentation of outcomes in the biologic marker outcome tables is somewhat different from the other study types (Evidence Tables 1 and 2) because they describe the results of diagnostic tests and delivery outcomes and are presented in terms of sensitivity, specificity, positive predictive value and negative predictive value.

Peer Review Process

Among the more important activities involved in producing a credible evidence report is conducting an unbiased and broadly based review of the draft report. Such a review, here termed "peer review," should provide an array of scientists, methodologists, users, and laypersons adequate opportunity to comment on the report and to identify problems of fact, interpretation, or presentation. Appendix A describes the selection process for peer review and lists the names of the peer reviewers.

Supplemental Analysis

In addition to the systematic review of the literature discussed above, we conducted meta-analyses focusing on treatment effects of each class of first-line tocolytics and maintenance tocolytics, 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. We restricted the literature for the meta-analyses to studies included in our evidence tables, RCTs, and to data concerning women with intact membranes. Chapter 4 presents a thorough discussion of the analyses, including selection criteria, methodology, and study findings.

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