Obstetrics & Gynecology:
ACOG Practice Bulletin No. 31: Assessment of Risk Factors for Preterm Birth
Preterm birth is the second leading cause of neonatal mortality in the United States (1) (second only to birth defects), and preterm labor is the cause of most preterm births (2). Neonatal intensive care has improved the survival rate for babies at the cusp of viability, but it also has increased the proportion of survivors with disabilities (3). The incidence of multiple births also has increased along with the associated risk of preterm delivery (4). Interventions to delay preterm delivery in these settings have not shown conclusive effectiveness. Because the morbidity of babies born after 34–35 weeks of gestation has diminished, most efforts to identify preterm deliveries have focused on deliveries before this age. This document describes the various methods proposed for predicting preterm birth and the evidence for their roles in clinical practice.
Preterm labor is defined as regular contractions associated with cervical change before the completion of 37 weeks of gestation. Spontaneous preterm birth includes preterm labor, preterm spontaneous rupture of membranes, and cervical incompetence; it does not include indicated preterm delivery for maternal or fetal conditions (5). Preterm delivery accounted for 11.8% of births in the United States in 1999; this figure has increased steadily from 9.4% in 1981 (6).
The pathophysiologic events that trigger preterm parturition are largely unknown but may include decidual hemorrhage (abruption), mechanical factors (uterine overdistention or cervical incompetence), and hormonal changes (perhaps mediated by fetal or maternal stress) (7–9). In addition, several bacterial infections have been associated with preterm labor. Commonly identified organisms are Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Peptostreptococcus, and Bacteroides species (10). Because these bacteria usually are of low virulence, it is unclear whether they are truly etiologic or are associated with an acute inflammatory response of another etiology.
Value of Predicting Risk
The ability to predict whether a woman is at risk of preterm delivery has value only if an intervention is available that is likely to improve the outcome. The opportunity to administer maternal corticosteroid therapy is an important intervention recommended by the National Institutes of Health because it is strongly associated with decreased morbidity and mortality (11–13). In addition, maternal tocolytic therapy may prolong pregnancy for up to 48 hours in some women, during which time corticosteroids can be administered (14). Because tocolytic and steroid therapy may result in untoward maternal and fetal consequences, use of these therapies should be limited to women with true preterm labor at high risk for spontaneous preterm birth. Finally, in women being managed at hospitals without appropriate neonatal resources, identifying women at risk allows for appropriate maternal transport to a tertiary care center. Conversely, identifying those women at low risk for preterm delivery would avert the use of unnecessary interventions.
Risk factors for preterm birth include demographic characteristics, behavioral factors, and aspects of obstetric history. Demographic characteristics that carry a high risk for preterm birth include nonwhite race (African American relative risk [RR]=3.3), age younger than 17 years or older than 35 years (RR=1.47–1.95), low socioeconomic status (RR=1.83–2.65), and low prepreg‐nancy weight (odds ratio=2.72) (15,16). Maternal history of preterm birth, particularly in the second trimester, has a strong statistical association with the risk of preterm delivery (17); this risk appears to be associated with prior spontaneous preterm birth with or without rupture of membranes and increases the relative risk sixfold to eightfold. Risk also increases with vaginal bleeding in more than one trimester (18). Controversy exists as to whether an excessively physically stressful job can lead to early delivery; one study has shown an increase in spontaneous preterm birth associated with long periods of standing (>40 hours per week) (19). Smoking increases the risk of preterm birth (20) and low birth weight, and some evidence suggests it increases the risk for spontaneous abortion (21). Despite the identification of a number of risk factors, attempts to determine the risk of preterm delivery based on historic and epidemio‐logic risk scoring systems (22–24) have been unable to reliably identify women who will give birth preterm.
Biologic Markers for Predicting Preterm Birth
Home Uterine Activity Monitoring
Tocodynamometry has long been used for hospital‐based evaluation of uterine contractions. Home uterine activity monitoring (HUAM) has been proposed as a method for predicting preterm birth in high‐risk women. It consists of a combination of telemetric recordings of uterine contractions with the use of a tocodynamometer and daily telephone calls from a health care practitioner to offer patient support and advice. Uterine activity beyond an arbitrary cutoff triggers notification of the patient's health care practitioner. This approach was based on the observation that some women who subsequently give birth before term have an increase in uterine activity earlier in pregnancy than women who give birth at term (25) and that these prodromal uterine contractions otherwise may not be recognized by the patient.
Activation of the fetal hypothalamic pituitary‐adrenal axis precedes some spontaneous preterm births. Adrenal production of dehydroepiandrosterone results in increased placental estrogen synthesis. Observational studies have shown that maternal levels of serum estradiol and salivary estriol increase before the onset of spontaneous term and preterm labor (26). These findings prompted the design of a test to predict preterm delivery by measuring salivary estriol; however, maternal estriol levels show diurnal variation, peaking at night (27). Also, estriol levels may be suppressed by betamethasone administration (28).
Bacterial vaginosis (BV) is a common alteration of the normal vaginal flora and has been found in 10–25% of patients in general gynecologic and obstetric clinics and in up to 64% of patients in clinics for sexually transmitted diseases (29). Fifty percent of women with BV are asymptomatic (30). Bacterial vaginosis also has been found more frequently in African‐American women (22%) than in white women (8%) (10,31). The presence of BV has been associated with preterm delivery independent of other known risk factors (32,33).
Fetal Fibronectin Screening
Fetal fibronectin (fFN) is a basement membrane protein produced by the fetal membranes that functions as an adhesion binder of the placenta and membranes to the decidua (34,35). It is normally present in cervical secretions until 16–20 weeks of gestation. Numerous trials have shown both an association with the presence of fFN and preterm birth (5,34,36) and a decrease in the risk of preterm birth when the test result for the presence of this protein is negative. The basis for the association of fFN and preterm birth is unclear. It has been hypothesized that fFN is a marker for the disruption of the chorioamnion and underlying decidua due to inflammation with or without infection (34). A positive midtrimester fFN test result has been associated with subsequently diagnosed maternal and fetal infection (37).
Transvaginal cervical ultrasonography has been shown to be a reliable and reproducible way to assess the length of the cervix (38). A prospective blinded trial showed an association between cervical length and preterm delivery (39). This study established the normal distribution of cervical length in pregnancy after 22 weeks of gestation. It also looked at various cervical measurements as criteria for the prediction of preterm delivery.
Clinical Considerations and Recommendations
▸ Does the use of HUAM predict preterm birth?
The usefulness of HUAM as a screening test depends on both its ability to detect women at higher risk for preterm birth as well as the effectiveness of any intervention to then prevent preterm birth. At least 13 randomized controlled trials examining the efficacy of HUAM have published results (40–52). The studies vary in design, criteria for inclusion of patients, and measurements of endpoints and outcomes. These differences make comparisons difficult. Furthermore, many of these studies had limitations with their research design, including sample size (power) or numbers of patients, that preclude reaching conclusions about the usefulness of HUAM. Results vary, with some trials reporting no difference and some reporting a difference in outcome in monitored and unmonitored women. The largest study involved 2,422 women at risk and showed no improvement in outcome (41).
Earlier studies that showed a reduction in the incidence of preterm birth with HUAM have been criticized for their flawed design (53,54); some studies have been identified as having biases and errors sufficient to warrant dismissing the results (55). The U.S. Preventive Services Task Force performed an independent review and concluded the device was not effective (56). Although the U.S. Food and Drug Administration has approved a HUAM device for women with a prior preterm birth, there is no demonstrated role for HUAM in the prevention of preterm birth. Data are insufficient to support a benefit from HUAM in preventing preterm birth (13,57,58); therefore, this system of care is not recommended.
▸ Does salivary estriol determination predict preterm birth?
There have been two prospective trials evaluating whether salivary estriol levels can predict preterm delivery (59,60); they showed that salivary estriol was more predictive than traditional risk assessment. However, the results of the second trial showed a relatively poor sensitivity of 71%, specificity of 77%, and a false‐positive rate of 23% (using delivery before 37 weeks of gestation as the outcome measure) (60). Because the test carries a high percentage of false‐positive results, its use could add significantly to the cost of prenatal care, particularly if used in a low‐risk population. Although the hormonal pathway etiology for some cases of preterm birth is intriguing, trials with salivary estriol testing to predict preterm birth have failed to establish its usefulness for anything more than investigational purposes at present.
▸ Do screening and treatment for BV affect the likelihood of preterm birth?
Trials of screening and treatment for BV in pregnant women to reduce the incidence of preterm delivery have been conducted in mixed populations with varying results. Some small studies found screening and treatment of women at risk for preterm birth reduced the risk of preterm birth (61,62), but other studies have not confirmed these findings (63,64).
A recent meta‐analysis reviewed five trials involving 1,504 women (65). The analysis included trials of women without risk factors for preterm birth as well as studies that screened general obstetric populations. Treatments used in these trials included amoxicillin, clindamycin, and metronidazole. Although investigators found antibiotic therapy effective at eradicating BV, the difference in the rate of preterm birth between the two groups was not statistically significant. However, looking at the subgroup of women with a previous preterm birth, the difference was significant, with an odds ratio of 0.37 (95% confidence interval, 0.23–0.60). This meta‐analysis did not include results from the most recent and largest double‐blind, randomized controlled trial. This trial of 1,953 women found no difference in the rates of preterm birth between the treatment and placebo groups, and no subgroup demonstrated a statistically significant difference in preterm birth rates (64).
Although some trials have shown an association with the presence of BV and preterm birth, most large trials designed to determine whether treatment of BV can prevent preterm birth have failed. Currently, there are insufficient data to suggest screening and treating women at either low or high risk will reduce the overall rate of preterm birth (66). There is speculation that BV could be either a marker or a cause of choriodecidual inflammation without intraamniotic infection (24). However, research testing this hypothesis by serial fFN screening in women with BV was unable to confirm an association (67).
▸ Does screening for fFN predict preterm birth?
A meta‐analysis of 27 studies showed consistent moderate success using fFN screening to predict preterm birth (68). Using delivery at less than 34 weeks of gestation as the outcome, sensitivity was 61% and specificity was 83% (68). A study that analyzed the relationship between fFN, short cervix, BV, and designated traditional risk factors for spontaneous preterm birth showed the highest association of preterm birth with positive fFN test result, followed by a cervical length less than 25 mm and a history of preterm birth (69). The negative predictive value of the fFN test to identify symptomatic women who are actually at low risk for imminent preterm delivery ranges from 69% to 92% before 37 weeks of gestation, with a greater than 95% likelihood of not delivering within 14 days of a negative test result (13,70,71).
Although a negative test result appears to be useful in ruling out preterm delivery that is imminent (ie, within 2 weeks) (13,72,73), the clinical implications of a positive test result have not been evaluated fully because no obstetric intervention has been shown to decrease the risk of preterm delivery. The test should not be routinely used to screen low‐risk, asymptomatic women, because the incidence of preterm birth in this population is low and the test, therefore, has limited usefulness (68).
If the test is to be used in specific high‐risk groups, the following criteria should be met: intact amniotic membranes, minimal cervical dilatation (<3 cm), and sampling performed no earlier than 24 weeks and 0 days of gestation and no later than 34 weeks and 6 days of gestation (74). If the test is to be clinically useful, the results must be available from a laboratory within a time frame that allows for clinical decision making (ideally within 24 hours).
▸ Does cervical ultrasonography predict preterm birth?
Numerous studies have confirmed the association of cervical shortening with preterm delivery, but they have varied widely in their predictive value (13,75–77). A review of 35 studies using cervical length (determined by ultrasonography) to predict preterm delivery found sensitivities ranging from 68% to 100%, with specificities from 44% to 79% (78).
A prospective trial of more than 2,900 women evaluated by serial transvaginal ultrasonography at 24 weeks of gestation and again at 28 weeks of gestation showed the RR of preterm delivery increased as the cervical length decreased. Specifically, at 28 weeks of gestation, when cervical lengths were 40 mm or less, RR was 2.80; at 35 mm or less, RR was 3.52; at 30 mm or less, RR was 5.39; at 26 mm or less, RR was 9.57; at 22 mm or less, RR was 13.88; and at 13 mm or less, RR was 24.94 (39).
Despite the usefulness of cervical length determination by ultrasonography as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome (79). Until effective treatment options are identified, cervical length measurement has limited clinical application.
▸ Should fFN and cervical ultrasonography be used together to better identify those at highest risk?
In a multicenter trial, investigators found a short cervix (defined as <25 mm), particularly if associated with a positive fFN test result, to be a strong predictor of preterm birth (80). A more recent trial by the National Institute of Child Health and Human Development looked at the sequential use of both methods to try to stratify risk groups as well as discern etiologies of preterm birth (69) (see Table 1). The presence of either a cervix less than 25 mm in length at less than 35 weeks of gestation or a positive fFN test result was strongly associated with preterm birth, especially in women with a history of preterm birth. These data were particularly useful in decreasing the assessed risk of preterm birth in women with classic risk factors and negative results of one or both tests. The success of interventions once a short cervix is identified or positive fFN test result is determined remains uncertain (13).
Summary of Recommendations
The following recommendation is based on good and consistent scientific evidence (Level A):
▸ There are no current data to support the use of salivary estriol, HUAM, or BV screening as strategies to identify or prevent preterm birth.
The following recommendations are based on limited or inconsistent scientific evidence (Level B):
▸ Screening for risk of preterm labor by means other than historic risk factors is not beneficial in the general obstetric population.
▸ Ultrasonography to determine cervical length, fFN testing, or a combination of both may be useful in determining women at high risk for preterm labor. However, their clinical usefulness may rest primarily with their negative predictive value given the lack of proven treatment options to prevent preterm birth.
▸ Fetal fibronectin testing may be useful in women with symptoms of preterm labor to identify those with negative values and a reduced risk of preterm birth, thereby avoiding unnecessary intervention.
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The MEDLINE database, the Cochrane Library, and ACOG's own internal resources and documents were used to conduct a literature search to locate relevant articles published between January 1985 and May 2000. The search was restricted to articles published in the English language. Priority was given to articles reporting results of original research, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Guidelines published by organizations or institutions such as the National Institutes of Health and the American College of Obstetricians and Gynecologists were reviewed, and additional studies were located by reviewing bibliographies of identified articles. When reliable research was not available, expert opinions from obstetrician‐gynecologists were used.
Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force:
I Evidence obtained from at least one properly designed randomized controlled trial.
II‐1 Evidence obtained from well‐designed controlled trials without randomization.
II‐2 Evidence obtained from well‐designed cohort or case‐control analytic studies, preferably from more than one center or research group.
II‐3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
Based on the highest level of evidence found in the data, recommendations are provided and graded according to the following categories:
Level A—Recommendations are based on good and consistent scientific evidence.
Level B—Recommendations are based on limited or inconsistent scientific evidence.
Level C—Recommendations are based primarily on consensus and expert opinion.
© 2001 by The American College of Obstetricians and Gynecologists.