J. Chris Carey
Ronald S. Gibbs
Danforth's Obstetrics and Gynecology, 10th Edition. Lippincott Williams & Wilkins. 2008
Preterm Labor
Preterm birth is a leading cause of neonatal morbidity and mortality. Over the past several decades, there has been a marked increase in survival of very low –birth-weight infants. This increase in survival has been attributed to increased use of corticosteroids, regionalization of perinatal care, improved methods of mechanical ventilation, availability of exogenous surfactant, and improved nutritional therapy. However, the reduction in mortality has not been accompanied by a reduction in neonatal morbidity or long-term handicaps. It is estimated that 50% of all major neurologic handicaps in children result from premature births.
Despite widespread awareness of the problem and use of therapies believed to be beneficial to prevent preterm births, the rate of preterm delivery has increased in the
Mechanisms of Labor Onset
Labor occurs when the uterus converts from a state of containment to an environment that attempts to expel the fetus. In humans, the average gestational period is 280 days ±14 days. Therefore, term labor is defined as labor that occurs between 37 and 42 weeks gestation. Preterm labor is defined as labor that occurs between 20 and 37 weeks gestation. In theory, pathologic activation of the normal parturition process results in preterm labor and delivery.
In both term and preterm labor, following an unknown stimulus, the mechanisms that produce labor override those that maintain the pregnancy. Activation of the parturition process results in membrane activation, cervical ripening, and an increase in myometrial responsiveness to endogenous and exogenous signals. Subsequently, labor progresses along a common pathway that results in uterine contractions that are sufficient to cause progressive cervical dilation to allow for expulsion of the fetus. A number of inciting events have been implicated in premature births. These events include decidual hemorrhage (abruption), mechanical factors (overdistension of the uterus, cervical incompetence), hormonal changes (fetal or maternal stress), or subclinical/clinical infection. Infection is associated with as many as one third of preterm deliveries, particularly those occurring at the earliest gestational ages. The role of infection in preterm labor will be reviewed separately in this chapter.
Figure 11.1 Overview of spontaneous preterm birth.
Animal models have helped in understanding labor. Important findings in animal labor models include an increase in oxytocin receptors present in the myometrium, gap junctions developing between myometrial cells, an increased response to agents capable of producing contractions in the uterus, and physical and biochemical changes of the cervix resulting in a softened consistency. Uterine smooth muscle contractility is produced by the actin-myosin interaction, following myosin light chain phosphorylation, which is controlled by myosin light chain kinase. Myosin light chain kinase is activated by calcium as a calmodulin-calcium complex. Cyclic adenosine monophosphate (cAMP) also regulates kinase by inhibiting phosphorylation. Many factors are involved in this control. Some of the proposed theories of labor will be discussed in the following sections.
Hormonal
Alteration in systemic or local levels of steroid hormones is an initiating factor of labor in some animals. The role of hormonal changes in initiating human labor is less clear. The withdrawal of the uterine inhibitor hormone progesterone has been shown to play a major role in many animals (e.g., sheep, rats, rabbits). In sheep, progesterone withdrawal seems to be caused by an increased responsiveness of fetal adrenal cells to adrenocorticotropic hormone (ACTH), resulting in increased production of cortisol. Through several steps, cortisol redirects placental steroid biosynthesis and decreases progesterone secretion. The decreased circulating progesterone in the sheep leads to increased myometrial gap junction formation, an increase in prostaglandin formation, and increased response of the uterus to agents capable of producing contractions. In this sheep model, fetal ACTH secretion controls the onset of labor.
However, major differences exist, between sheep hormonal status and that of primates, including humans. In humans, there is not a great increase in cortisol from the fetal adrenal gland before labor, nor has a dramatic decrease in progesterone been consistently demonstrated. Yet, progesterone is important in human pregnancy, and numerous studies have examined the role of the progesterone-to-estrogen ratio before the onset of labor. In 1974, investigators demonstrated a significant fall in serum progesterone levels and a rise in estrogen levels in many women before labor. This finding has not been reproduced consistently. Estriol may be a signal from the fetus indicating that it is mature and ready for delivery. Production of estriol increases during the last month of pregnancy. In the large amounts produced, estriol is as active as estradiol in stimulating uterine growth. There are reports of an elevation in the estradiol/progesterone ratio at the end of pregnancy.
The antiprogesterones-RU-486 (mifepristone) and ZK-98299 (onapristone)-in humans and other primates can enhance the responsiveness of the uterus and induce cervical change within 12 to 48 hours, again suggesting a role for progesterone in preventing labor onset.
Administration of progesterone has been demonstrated to prevent preterm birth in humans. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network progesterone trial demonstrated that women at high risk for preterm birth who were treated with progesterone were significantly less likely to deliver preterm than those treated with placebo. In that trial, women with a previous preterm birth were treated with weekly injections of 250 mg of 17-alpha-hydroxyprogesterone caproate or placebo from 17 to 20 weeks until 36 weeks or delivery. They reported that 111/306 (36.3%) of women treated with progesterone delivered at less that 37 weeks compared with 84/153 (54.9%) treated with placebo (relative risk [RR] 0.66; 95% confidence interval [CI] 0.54 to 0.81). Significantly fewer women treated with progesterone also delivered at <35>
As of this writing, the optimal route and dose of progesterone have not been established. Published studies have used intramuscular injections of 17-alpha-hydroxyprogesterone caproate, progesterone suppositories, oral progesterone, and intramuscular progesterone tablets. The Food and Drug Administration (FDA) has not approved any progesterone preparation for the prevention of preterm birth, and the injectable formulations must be compounded prior to use. Compounded formulations are not overseen by the FDA, and accuracy of dosing and sterility are in the hands of the compounding pharmacy.
Oxytocin
It is well known that oxytocin produces uterine activity when administered to pregnant women. The role of endogenous oxytocin as an initiator of term or preterm labor is less well defined. Some reasons to suspect that oxytocin is a universal initiator of labor are its ability to induce labor when given exogenously and the increase in blood levels that accompanies labor in most species. Because of the pulsatile manner of oxytocin release and the difficulty in measuring the hormone, its precise role in humans has been difficult to ascertain. Compared with nonlaboring patients, oxytocin levels appear to be significantly increased during the first stage of labor and increase to a greater amount during the second stage of labor. Oxytocin levels are higher in umbilical artery blood than in umbilical vein or maternal blood. This finding suggests that the fetus is a source of oxytocin production and release during labor. It is clear that the uterus becomes more sensitive to oxytocin in the days preceding labor. The number of myometrial cell membrane oxytocin receptors greatly increases as pregnancy advances, with a further increase during labor itself. In humans as well as in other species, the concentration of oxytocin receptors is a major reason for increased contractility of the uterus. The increase in oxytocin receptors is the result of increased estrogen levels.
Prostaglandins
Another important part of the parturition model is the synthesis and release of prostaglandins E2 and F2. This is supported by an increase in prostaglandins or metabolites in the amniotic fluid, endometrium, decidua, myometrium, and blood at the time of labor; the administration of prostaglandins inducing labor; and inhibitors to prostaglandin synthesis delaying labor. It is likely that the prostaglandins have a role in parturition originating from the decidua and myometrium. Oxytocin has the ability to stimulate prostaglandin release through the decidual receptors. In addition, infection of the membranes can release prostaglandins and may be an initiating factor in many cases of preterm labor.
Bacterial by-products may be directly responsible for the stimulation of prostaglandin release in the following ways. Bacterial phospholipase releases the precursor arachidonic acid from the amnion, leading to increased prostaglandin synthesis. Gram-negative organisms also may be able to produce prostaglandins through endotoxin stimulation of the decidua or membranes. Gram-positive organisms also may have prostaglandin-stimulating abilities through peptidoglycans. Phospholipase A2 is contained within the lysosome of the fetal membranes. As phospholipase A2 is released from the lysosome, prostaglandin may be synthesized, resulting in uterine contractions.
Cytokines
Cytokines are proteins secreted by the immune system in response to infection. There is recent interest in the role of cytokines and growth factors (e.g., epidermal growth factor, insulinlike growth factors 1 and 2) as potential initiators of labor. The cytokines interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF) stimulate the amnion and decidua to produce prostaglandins and increase at time of labor, while transforming growth factor-β (TGF-β ) inhibits prostaglandin production by other cytokines and may have antiprogestin properties. Finally, several different cytokines have been found in the amniotic fluid of patients with preterm labor.
Other Factors
Endothelins are potent vasoconstrictors in the sarafotoxinlike family. Some isoforms of endothelins are potent uterotonics. Although endothelin does not appear to increase at time of labor, uterine sensitivity and endothelin-receptor numbers do increase in the pregnant uterus. There is some decrease of endothelin-1 in the amniotic fluid of patients in labor, but this may be a consequence rather than an initiator of labor. Nitric oxide, produced from l-arginine by the enzyme nitric oxide synthase (NOS), mediates relaxation of vascular smooth muscle. It has been shown in various animal tissues, including human, that the NOS enzyme is decreased in myometrial tissue at term. Thus, nitric oxide may have a role in maintaining a quiescent uterus.
It can be hypothesized that parturition is a development of an estrogen environment. This estrogen environment promotes changes in the maternal pituitary with increased oxytocin synthesis and release. Estrogen may also be acting directly on the placenta and cervix. As the antiestrogen progesterone level decreases, estrogen can act to increase oxytocin receptors, prostaglandin production, and gap junction number and size. As the cervix ripens, the underlying membranes and decidua become exposed to the vaginal bacteria, triggering an inflammatory response with release of cytokines and prostaglandins. At this point, the paracrine events take dominance over the endocrine effects. Some conditions, such as infection, can overwhelm the endocrine phase of parturition.
Infection as a Cause of Preterm Birth
Preterm birth has been linked with symptomatic nongenital infections such as acute pyelonephritis and pneumonia. A large body of evidence suggests that subclinical infection may be an important cause of premature labor, especially labors resulting in very early delivery.
The hypothesis linking subclinical infection and premature birth may be summarized as follows. Microbes or their products such as endotoxin enter the uterine cavity during pregnancy, most commonly ascending from the lower genital tract. Blood-borne infection from a nongenital focus occurs less commonly. Microbes or their products then interact, most likely with the decidua or possibly with the membranes, producing prostaglandins or directly leading to uterine muscle contraction. This interaction is most likely mediated through a cytokine cascade. As a result, there is cervical dilation, entry of more microbes into the uterus, and continuation of “the vicious cycle” resulting in premature birth.
The first piece of evidence linking subclinical infection to preterm birth is that the prevalence of histologic chorioamnionitis is increased among preterm births. In membranes from preterm deliveries, there is a consistent and very strong association between positive membrane cultures and the likelihood of membrane infiltration. For example, when the birth weight is greater than 3,000 g, the percentage of placentae showing histologic chorioamnionitis is less than 20%; when the birth weight is below 1,500 g, the percentage is 60% to 70%. Most cases of histologic chorioamnionitis are caused by infection.
| TABLE 11.1 Prenatal Infections as a Cause of Preterm Birth: Association and Treatment Recommendations | ||||||||||||||||||||||||
| ||||||||||||||||||||||||
Second, clinically recognized infections are increased in mothers and neonates after preterm birth. Sepsis and meningitis are increased 3- to 10-fold in preterm infants. Less widely recognized is the increase in maternal infection after preterm birth. These observations suggest that subclinical infection underlies preterm birth and that the infection became clinically evident during or shortly after birth.
Third, there are associations of preterm birth with various maternal lower genital infections or microbes (Table 11.1). Although Ureaplasma urealyticum in the lower genital tract had been associated with LBW infants in earlier studies, a large National Institutes of Health (NIH) study reported no associations of U. urealyticum in the vagina with any adverse pregnancy outcome (preterm birth, PPROM, LBW, or birth weight U. urealyticum in the lower genital tract is not associated with LBW/preterm pregnancies, even though this organism is one of the most common isolates from the amniotic fluid of women in preterm labor. Lower genital infection with Chlamydia trachomatis has also not been consistently associated with adverse pregnancy outcome. However, women with active chlamydial infection and with a positive serum antichlamydial immunoglobulin M (IgM) have an increased risk of preterm delivery. Although a consistent association has not been observed between maternal group B streptococci (GBS) colonization and premature birth in several small studies, a large investigation of approximately 13,000 women showed that pregnant women with heavy GBS colonization had a small but significant increase in risk for LBW (odds ratio [OR] 1.2; 95% CI 1.01 to 1.50). There were no significant increases in other adverse outcomes, including preterm birth, among heavily colonized women. Women with light colonization were not at an increased risk for any adverse outcomes. There is increasing evidence of an association between Trichomonas vaginalis and premature birth. Although small, earlier studies had conflicting results, the large Vaginal Infections and Prematurity Study found that the presence of T. vaginalis in the vagina at midpregnancy was significantly associated with preterm LBW (7.1% of women with T. vaginalis vs. 4.5% without T. vaginalis; OR 1.6; 95% CI 1.3 to 1.9). The MFMU Network bacterial vaginosis/T. vaginalis trial showed an association between carriage of T. vaginalis and preterm birth. Considerable data have linked lower genital tract anaerobes with preterm labor. Further, bacterial vaginosis, in which there is a predominance of anaerobes, has been consistently associated with approximately a two- to threefold increase in spontaneous preterm delivery. Among other infections, untreated pyelonephritis has been associated with a risk of preterm delivery of approximately 30%, and asymptomatic bacteriuria is associated with a 60% higher rate of LBW (95% CI 1.4 to 1.9) and a 90% higher rate of preterm delivery (95% CI 1.3 to 2.9).
Fourth, positive cultures of the amniotic fluid/membranes/decidua are found in some patients in premature labor. The range of positive amniotic fluid cultures obtained by amniocentesis from asymptomatic women in premature labor is 3% to 24%. When more sensitive testing for detection of bacteria (polymerase chain reaction) is carried out in amniotic fluid from women in preterm labor, bacteria are detected in 30% to 50%. The most likely route of upper genital tract infection in preterm labor is an ascending path through the vagina and cervix. Similarities in organisms isolated from the amniotic fluid and the lower genital tract support this pathogenic route. It is also possible that bacteria may enter the uterine cavity hematogenously through spread via the placenta, by contamination at the time of instrumentation such as during amniocentesis or chorionic villus sampling, or even by spread from the abdominal cavity via the fallopian tubes. Other sources of organisms for hematogenous spread include bacteremia from periodontal disease or procedures. Among women in spontaneous preterm labor with intact membranes, genital mycoplasmas, anaerobic organisms, and Gardnerella vaginalis (the so-called bacterial vaginosis organisms) are the organisms most commonly found in the amniotic fluid. Sexually transmitted organisms such as Neisseria gonorrhoeae and C. trachomatis are rarely found in the amniotic fluid, and GBS and Escherichia coli are found occasionally. Patients in preterm labor at early gestational ages have the highest likelihood of having a positive culture of the amniotic fluid. It may be speculated that intrauterine infection occurs early in pregnancy (or even has preceded the pregnancy) and may remain without clinical detection for months.
Fifth, biochemical “markers” of infection are often present among women in premature labor. In infection-induced premature labor, the primary site of infection is probably not the amniotic fluid but the decidua or membranes. More sensitive markers of infection potentially include amniotic fluid glucose concentrations, serum white blood cell counts, C-reactive protein, and amniotic or serum cytokines. Unfortunately, relatively few are clinically useful. Among patients in preterm labor, a low amniotic fluid glucose (<14>
Sixth, bacteria or their products induce preterm birth in animal models. Animal models have provided direct evidence that infection triggers preterm birth in the rabbit, monkey, and mouse.
The evidence linking infection to preterm birth has led to many trials of antibiotic therapy to prevent preterm birth. Antibiotic treatment trials may be classified as one of four designs:
- Those conducted prenatally in patients at high risk for preterm delivery
- Those directed toward a specific organism or condition
- Those conducted in women in preterm labor with intact membranes, as adjuncts to tocolytic therapy
- Those conducted in women with PPROM.
Table 11.2 summarizes current practices for use of antibiotics to prevent preterm birth. The discordant results in antibiotic trials raise the question as to why antibiotics have not consistently prevented preterm birth or neonatal morbidity associated with preterm birth. One explanation is that infection is simply not a significant cause of preterm labor, but this seems unlikely in view of all the other evidence. Another explanation is that studies have had too low a power. However, large meta-analyses, the MFMU Network trials, and the ORACLE trial appear to exclude this possibility. Further, because preterm labor has multiple causes, a true effect of antibiotics may be diluted by those cases of preterm labor not caused by infection. It may also be that only a subset of pregnant women (e.g., perhaps genetically predisposed women) with high cytokine response are at risk for preterm labor after subclinical infection. Another explanation is that the antibiotics studied in most of the trials were simply the wrong ones (e.g., not including antibiotics with better anaerobic activity), the antibiotics were given too late, or the antibiotic dose or timing were incorrect. Because infection is more likely to cause very early preterm birth (T. vaginalis trial found that women with T. vaginalis who were treated with metronidazole were more likely to deliver preterm than those treated with placebo. The PREMET trial also found that women with a positive fetal fibronectin were more likely to deliver preterm if they were treated with metronidazole than placebo. It is possible that metronidazole therapy changes the vaginal flora in women who do not have bacterial vaginosis in such a way as to increase the risk of preterm birth.
| TABLE 11.2 Use of Antibiotics to Prevent Preterm Birth in Women with Preterm Labor and Premature Rupture of the Membranes | |||
|
Epidemiology of Preterm Labor
In 2004, 12.5% of women in the
Figure 11.2 Causes of LBW births in public and private patients. (
Several major and minor risk factors are associated with development of preterm labor and PROM (Tables 11.3, 11.4). One of the most obvious and important risk factors for prematurity is a prior history of preterm delivery. To better quantify this relationship, Mercer and associates performed a subgroup analysis of data collected during a large population-based observational study evaluating risk factors for preterm delivery. In this study, gravid women with any prior spontaneous preterm birth had a 2.5-fold increased risk of spontaneous preterm delivery in the current pregnancy. This risk increased to 10.6-fold if the spontaneous preterm birth occurred prior to 28 weeks gestation. Interestingly, women with a history of loss between 13 and 22 weeks gestation had rates of prematurity that were similar to women who did not have this history (10.1% vs. 8.8%; P =.69).
Another major risk factor for preterm labor and birth is multiple gestation. The rate of multiple gestations has increased dramatically over the past 15 years. The increase in twins and higher-order multiples is largely a reflection of increased use of ovulation induction and assisted reproductive technologies. Fifty percent of twins deliver prematurely, with a mean gestational age at delivery of approximately 35 weeks. As expected, the percent of preterm deliveries increases in proportion to the number of fetuses. Triplets and quadruplets deliver on average at 32 weeks and 30 weeks, respectively. Until researchers develop techniques to perform artificial reproductive technologies that minimize the risk of having high-order multiples, then these women will continue to be at significant risk for delivering prematurely and suffering the consequences of preterm birth.
| TABLE 11.3 Major Preterm Labor Risk Factors | ||||||||||||||||||
| ||||||||||||||||||
| TABLE 11.4 Minor Preterm Labor Risk Factors | ||||||||||||||||||
| ||||||||||||||||||
Blacks are 1.6 to 2.5 times more likely to deliver prematurely than white women of similar age and socioeconomic status. Although blacks have higher rates of prematurity, the rates of neonatal morbidity are lower in black neonates when compared with whites born at similar gestational ages. This suggests that the gestational period may be shorter in black women. Low socioeconomic status is also strongly associated with prematurity. It is not clear whether this is related to environment, genetic predisposition, infection, or access to medical care.
Table 11.4 also lists a number of “minor” risk factors for preterm labor and delivery. Several of these will be discussed in more detail later in this chapter. In general, the minor risk factors can be broken into two categories: those that are potentially modifiable and those that are not. Many of the minor risk factors are common in pregnancy. Individually, their contribution to prematurity is small; however, the risk is compounded by the addition of other risk factors. The impact of work on preterm birth remains controversial. Prolonged, physically demanding work does appear to independently increase the risk of prematurity and is potentially modifiable.
Prediction of Women at Risk for Preterm Labor
Over the past 2 decades, many researchers have focused on identification of women who are at risk for preterm delivery. Theoretically, identification of asymptomatic women at risk for preterm delivery would allow obstetricians to effectively intervene to prevent preterm delivery or to decrease neonatal morbidity and mortality in preterm neonates. In an
- receive a complete course of antenatal corticosteroids prior to delivery
- if necessary, receive tocolytic agents to maximize the probability that antenatal corticosteroids will be given
- be transported to a level III perinatal center.
Another potential benefit of screening is to identify women at low risk for preterm delivery and thereby avoid administration of potentially dangerous medications or therapies to these women.
Table 11.5 is a review of “ideal” criteria for a screening test. An ideal screening test should have high sensitivity and positive predictive value as well as high specificity and high negative predictive value. Most screening tests do not meet these requirements and trade off sensitivity for specificity. Depending on the clinical scenario where screening tests are used and the consequences of treatment or no treatment, one must decide which test characteristic to stress. For example, one could argue that given the high morbidity associated with preterm birth, the ideal screening test should have a high sensitivity to allow treatment of the majority of women “at risk” and accept a lower specificity rate. On the other hand, one could argue, as the ACOG did, that avoidance of treatment with potentially hazardous drugs is beneficial in women with symptoms who are at “low risk” for delivery, thus stressing the importance of the test's specificity and negative predictive value. The following will review available screening tests.
| TABLE 11.5 Criteria for Screening Tests | |
|
Risk Scoring Systems
Risk scoring systems were promoted heavily in the 1980s to identify women at risk for preterm delivery. The risk scoring systems weigh major and minor risk factors for preterm birth as well as current pregnancy complications (Tables 11.3, 11.4). The scoring systems work best in multiparous patients and worst in privately insured nulliparas with singleton gestations. Overall, the sensitivity of the screening tool ranges from 3% to 30% and the positive predictive values from 0% to 20%, depending on the population studied. While easy to use to identify women who may have modifiable risk factors for preterm delivery, the scoring systems do not reliably identify women at risk. They should not be used alone to institute interventions that may or may not be warranted.
Contraction Monitoring
Contraction monitoring has also been advocated to identify women at risk for preterm birth. Main and associates, in an inner-city clinic in Philadelphia, had low-risk women between 28 and 32 weeks' gestation wear tocometers while waiting in the clinic to be seen. Women with six or more uterine contractions per hour were more likely to deliver prematurely than women who did not. Using this cutoff, the sensitivity was 75% and the specificity was 79%. As technology became more advanced, this concept was developed further and home uterine activity monitoring (HUAM) became possible. HUAM, as initially promoted, was a combination of telemetric recording of uterine activity and daily contact with perinatal nurses trained to identify signs and symptoms of early preterm labor. The following assumptions were used to establish a role for HUAM:
- Women with preterm uterine activity are more likely to deliver prematurely than women who deliver at term.
- Women at risk for preterm labor may be unaware of their contractions, thus they present too faralong in established labor for treatment to be effective.
- Effective treatment for preterm labor is available.
At least 13 randomized clinical trials have evaluated the role of HUAM. These trials differ dramatically depending on the inclusion and exclusion criteria, the use of adjunctive tocolytic agents, and the primary end points. Despite being “randomized clinical trials” many of the reports were so severely flawed that they were not included into several meta-analyses on the subject. After review of all of the evidence, both the ACOG (HUAM: not recommended) and the U.S. Preventive Services (HUAM: devise not effective) discouraged the use of this expensive and unproven therapy. Additional research may be warranted in specific at-risk subgroups.
Screening for Bacterial Vaginosis
Bacterial vaginosis is a common alteration of normal vaginal flora affecting 10% to 25% of normal women. The majority of infections are asymptomatic. The presence of bacterial vaginosis has been clearly associated with preterm births in both prospective cohort studies and case-control studies. As a result, investigators and clinicians have attempted to eradicate bacterial vaginosis in an effort to reduce the incidence of preterm delivery. The largest randomized controlled trial to date was conducted by the MFMU Network. In this double-blinded, randomized clinical trial, women with bacterial vaginosis were randomized to receive metronidazole 2 g orally for two consecutive days or placebo. Women were rescreened and retreated, if indicated, at 24 to 29 weeks gestation, according to the original treatment assignment. Figure 11.3 summarizes the principal findings of the trial. Overall, there was no reduction in preterm deliveries. This result was confirmed in women who had prior preterm delivery. In one recent meta-analysis that included 15 trials of treatment for bacterial vaginosis, the authors concluded that treatment of bacterial vaginosis with clindamycin or metronidazole did not reduce the risk of preterm birth or PPROM. In a statement by the ACOG, the organization does not endorse routine, universal screening for bacterial vaginosis. However, another analysis in women with prior preterm delivery found that treatment of bacterial vaginosis for 7 days or more with oral metronidazole decreased recurrent preterm birth. This area remains controversial (Table 11.1).
Fetal Fibronectin
Fetal fibronectin has been widely promoted as a tool to identify women at risk for preterm delivery. Fetal fibronectin, a basement membrane protein, is a normal constituent of the extracellular matrix of the maternal-fetal interface. It is present in normal human pregnancies prior to 20 weeks gestation and near term. Its presence between 20 and 34 weeks gestation strongly has been associated with preterm birth, but more important, its absence has been associated with low risk of preterm delivery.
Figure 11.3 Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. (Rx, prescription; PTD, preterm delivery; PTL, preterm labor; PPROM, preterm premature rupture of the membranes; RR, relative risk; CI, confidence interval.) (Carey J, Klebanoff M, Hauth J, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National
Leitich and coworkers performed a comprehensive meta-analysis on the efficacy of fetal fibronectin in identifying women at risk for preterm delivery. They included 27 articles using fetal fibronectin in a variety of settings. Similar to other investigators, they noted that the test's usefulness was a result of its high specificity and was limited by the low sensitivity in identifying women who would go on to deliver prior to 34 weeks gestation. The sensitivity of the test decreased further in identifying women who would deliver prior to 37 weeks but increased when it was used serially.
In order to maximize fetal fibronectin, its use should be restricted to women with intact membranes, cervical dilation less than 3 cm, and gestational age between 24 and 34 completed weeks gestation, and results should be available within 24 hours. False-positive fetal fibronectins may be obtained in women with recent intercourse or vaginal examinations or in the presence of bacterial vaginosis and vaginal bleeding.
In general, the sensitivity of fetal fibronectin increases in symptomatic women, women with a cervical length of less than 2.5 mm, women with a history of prior preterm delivery, and women with bacterial vaginosis. The negative predictive value in women with preterm contractions ranges from 69% to 92% before 37 weeks gestation. Importantly, a negative fetal fibronectin has a 95% likelihood that delivery will not occur within 14 days of sampling.
Will fetal fibronectin change management and improve outcomes? Fetal fibronectin results have been shown to alter clinical management in certain settings and may be cost-effective. Physicians may use the test to determine who will receive tocolytic therapy and antenatal corticosteroids as well as who is appropriate for a maternal transport. Clearly, this test has potential, yet further work is required to determine what interventions are appropriate and whether the test improves outcomes. An ACOG summary states that “fetal fibronectin 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.”
Cervical Evaluation
It long has been noted that premature dilation or effacement of the maternal cervix is associated with preterm birth. There has been a great deal of research interest in precisely measuring the uterine cervix with ultrasound to identify women at risk for preterm birth. Several techniques for measuring the cervix have been advocated. In general, it is believed that vaginal measurements are superior to abdominal measurements. Furthermore, several measurements should be obtained and averaged given the variability in cervical lengths for a given individual at a single monitoring session. In order to improve inter-interpreter variability, individuals who are performing the ultrasound should undergo formal training and participate in continuing quality assurance.
Several large prospective cohort studies have been performed that have been useful in establishing cervical nomograms for low-risk and high-risk women. In general, as the cervix becomes progressively shorter or dilates, the risk of preterm delivery increases. Cervical length is also correlated with gestational age (i.e., as gestation advances, the cervix matures and shortens). Different cutoff values have been tested. The sensitivity and positive predictive value depend on the prevalence of preterm birth in the population and the gestational age at testing and delivery. A cervical length of <30>
The proponents of cervical ultrasound evaluation stress the benefit in obtaining more precise measurements with vaginal ultrasound than digital evaluation and the improved ability to detect subtle changes. Furthermore, vaginal ultrasound allows one to avoid vaginal examinations. To date, only two published randomized clinical trials have evaluated the use of cervical cerclage in women with premature shortening of the cervix with no evidence of preterm labor. In the first, the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT), women with the following histories were approached:
- A history consistent with cervical incompetence
- PPROM prior to 32 weeks gestation
- History of cold-knife conization
- Diethylstilbestrol exposure
- Uterine anomaly.
Consenting women who met the inclusion criteria and who had a cervical length less than 2.5 cm prior to 27 weeks were randomized to receive a McDonald cerclage and bed rest or bed rest alone. Placement of a cervical cerclage resulted in a significant decrease in preterm delivery prior to 34 weeks gestation (0 of 19 in the cerclage group vs. 7 of 16 in the expectant management group; P = .002). The decrease in preterm delivery prior to 34 weeks gestation also was associated with a decrease in composite adverse neonatal outcome (1 of 19 vs. 8 of 16; P = .005). In contrast, Rust and colleagues randomized women with a shortened cervix detected on routine ultrasound evaluation between 16 and 24 weeks gestation were randomized to receive a cerclage (n = 31) or expectant management (n = 30). The groups were well balanced at randomization for potential confounders. Overall, there was no difference in gestational
age at delivery (33.5 ±6.3 weeks in the cerclage group vs. 34.7 ±4.7 weeks in the expectant management group; P = .4) or the perinatal death rate (12.9% in the cerclage group vs. 10.0% in the expectant management group; P = .9).
At this time, there does not appear to be sufficient evidence to recommend routine ultrasound screening of the uterine cervix, as no treatment has been definitively established that will improve neonatal outcome.
Summary of Screening Tests Used to Identify Women at Risk for Preterm Labor
Several screening tests are available to identify women at risk for preterm delivery. All fail to meet the goals of an “ideal screening test,”since no therapy has been proven to be effective in preventing preterm labor and delivery. As a result, these tests should be considered experimental and used as part of randomized clinical trials with sufficient power to evaluate treatments for prevention of preterm birth.
Preterm Labor Defined
Preterm labor is defined as labor occurring prior to 37 weeks gestation. Clinically, it is difficult to distinguish women with true preterm labor from women who are experiencing preterm uterine contractions. In order to improve the accuracy of the diagnosis, Creasy has proposed using the following criteria: uterine contractions (>4 contractions per 20 minutes) and cervical dilation (>2 cm in a nullipara and >3 cm in a multipara) and cervical effacement (>80%) or uterine contractions and cervical change. Cervical change is the most well-accepted clinical criteria, yet it is the criteria most vulnerable to bias. For example, what constitutes minimal cervical change and over what time period does cervical change need to occur to be acute and warrant intervention? While this definition is more stringent than that proposed by the ACOG and others, over 50% of women who fulfill Creasy's criteria will deliver at term with or without treatment. An alternate approach is to await cervical change during a prescribed period of observation. Utter and colleagues defined minimal cervical change as dilation of the cervix by at least 1 cm and effacement of at least 1 cm in women less than 3 cm dilated on admission. Is it appropriate to wait for cervical change, and will waiting until labor becomes more established affect treatment success? In a retrospective case-control study, Utter and associates compared the outcomes of pregnancies in women treated with ritodrine on admission who had uterine contractions and “minimal”cervical change with women who were observed and treated only when cervical change as defined above was determined. There were no differences in any maternal or neonatal outcomes, including the number of days to delivery and “success”rates with tocolysis. Similarly, Guinn and colleagues randomized women with uterine contractions who were >2 cm to one of three therapies: observation alone, subcutaneous terbutaline, or intravenous hydration. Overall, there were no differences in any outcome measures between groups. Approximately 15% of women assigned to each of the groups went on to make cervical change during observation and were treated with parenteral tocolysis. In all cases, parenteral tocolysis was successful in delaying delivery for a minimum of 48 hours to allow treatment with antenatal corticosteroids. This approach avoided administration of tocolytic agents to 85% of women with no increase in morbidity or preterm delivery rates. An alternative strategy to awaiting cervical change is to use the rapid fetal fibronectin test and treat only women with a positive test. However, this strategy remains under investigation.
Treatment of Preterm Labor
Once the diagnosis of preterm labor is made, what treatments are available and do they work? Several agents have been used as tocolytic agents to suppress uterine activity in hopes that prolongation of pregnancy would improve neonatal outcomes (Table 11.6). The vast majority of placebo-controlled clinical trials were published during the 1970s and 1980s. Most of the placebo-controlled trials were small, and the concurrent use of antenatal corticosteroids was low. Overall, women who received any tocolytic agent had a mean time to delivery of approximately 48 hours. Therefore, it is not surprising that tocolytic therapy has not been associated with improvements in neonatal outcomes. Despite this finding, tocolytic agents are widely prescribed throughout the world. The justification for the continued use of unproven drugs is the supposition that had the drugs been administered along with antenatal corticosteroids, the 48 hours gained in utero would be beneficial to the neonate and result in improved outcomes. This theory remains untested. However, given the current “standard of care” in the
| TABLE 11.6 Overview of Tocolytic Agents | |
|
| TABLE 11.7 Absolute Contraindications to Tocolytic Therapy | |
|
β-Adrenergic Agonists
β-Mimetics are the most widely prescribed and best-studied tocolytic agents. The two most commonly used β-mimetic agents in the
The maternal side-effect profile with β-agonists is of particular concern. None of the β-agonists used for tocolysis are completely β-2 selective. Therefore, mothers can experience side effects from both β-2- and β-1sensitive tissues. The negative β-2 effects include maternal hypotension, decreased urinary output, increased glucose secretion, hypokalemia, and pulmonary edema. The negative β-1 effects include tachycardia, palpitations, constipation, decreased gastric emptying, hypokalemia (decrease 0.6 to 1.5 mEq below pretreatment levels), agitation, and jitteriness. The most severe maternal adverse effects include cardiac arrhythmias, myocardial infarction, pulmonary edema, postpartum cardiomyopathy, and death. These risks can be minimized by judicious use of fluids, close monitoring of intake and output, and avoidance of other tocolytic agents.
| TABLE 11.8 Relative Contraindications to Tocolytic Therapy | |
|
β-Mimetics rapidly cross the placenta. The fetal response is similar to the adult. Cardiovascular effects include tachycardia, increased cardiac output and redistribution of blood flow, increased thickness of the intraventricular septum, neonatal supraventricular tachycardia, myocardial ischemia, myocardial necrosis, hydrops, and hypoglycemia. Long-term follow-up studies demonstrated no overall difference in children exposed to β-mimetics versus control groups that received placebo. However, evidence suggests that β-mimetics may increase the incidence of intraventricular hemorrhage in preterm neonates. This finding has been noted in a couple of case-control studies performed in large neonatal databases. This finding was not previously noted in the randomized placebo-controlled trials of β-mimetics. Further studies are necessary to evaluate this potential adverse effect of β-mimetics.
Are β-mimetics efficacious? The largest placebo-controlled trial of β-mimetics was performed in
At this time, advocates for the use of β-mimetics believe that the benefit-to-risk ratio is favorable and that prolonging pregnancy may increase the proportion of women who complete a course of antenatal corticosteroids prior to delivery. As newer agents with less potential for maternal and fetal adverse effects become available, the use of β-mimetics will continue to decrease in the acute setting.
Magnesium Sulfate
In recent years, magnesium sulfate has become the tocolytic of choice in many labor and delivery units. The use of magnesium sulfate as a tocolytic was adopted despite the absence of data of its effectiveness and safety in well-designed, placebo-controlled trials. Several randomized trials have shown that magnesium sulfate is no more effective than placebo as a tocolytic, and a meta-analysis concluded that “magnesium sulphate is ineffective at delaying birth or preventing preterm birth, and its use is associated with an increased mortality for the infant”.
Magnesium sulfate is the most widely prescribed tocolytic agent used in the
Magnesium sulfate primarily is cleared by the kidneys and rapidly is excreted in the pregnant woman with normal renal function. It generally is accepted that blood levels of 6 to 8 mg/dL of magnesium sulfate are optimal for tocolysis. However, there is a great deal of variation in the biologic response to this agent, including the level that is required to achieve uterine quiescence and the level associated with toxicity. For example, in one study, investigators used a case-control study design and compared women who did and did not respond to magnesium sulfate tocolysis. Overall, there were no significant differences in serum levels of magnesium sulfate in the women who did and did not respond to tocolysis. This finding is similar to that of a randomized controlled trial comparing a high-dose magnesium protocol (8-g load, then 2 to 4 g per hour) to a low-dose magnesium protocol (4-g load, then 2 to 4 g per hour). The high-dose protocol did achieve tocolysis more rapidly than the low-dose protocol. However, there was a corresponding increase in maternal side effects with the high-dose protocol. Overall, there was no difference between the protocols with respect to prolongation of pregnancy or a reduction in neonatal morbidity. Finally, many physicians believe that it is necessary to wean patients from magnesium sulfate tocolysis. This practice was evaluated in a randomized trial comparing a weaning protocol with immediate withdrawal of magnesium sulfate. Not surprisingly, weaning prolonged labor and delivery stays by approximately 8 hours. Overall, there was no difference in time gained in utero or differences in neonatal outcomes between the two groups. Women who were weaned had significantly higher rates of recurrent labor in the current admission and in the future.
Maternal side effects are common with magnesium sulfate and are presented in Table 11.9. As blood levels of magnesium increase, so does the potential for severe toxicity. Maternal deaths have occurred with magnesium sulfate as a result of respiratory depression and cardiac arrest. In general, these events should be preventable by following the patient's clinical status carefully. This monitoring should include hourly assessments of intake and output, the level of deep tendon reflexes, and oxygen saturation using a pulse oximeter. Careful labeling of all medications as well as strict adherence to concentration should reduce the likelihood of an inadvertent bolus of large amounts of magnesium sulfate. In cases of extreme magnesium toxicity, administration of calcium gluconate may be useful to try and reverse the effects of magnesium sulfate.
| TABLE 11.9 Maternal Side Effects Related to Magnesium Sulfate | |
|
Magnesium sulfate also has significant fetal and neonatal effects. Magnesium sulfate crosses the placenta and accumulates in the fetus. As a result, it can affect fetal biophysical parameters (primarily fetal breathing activity) and decrease fetal heart rate variability. Neonates born with cord levels of magnesium sulfate greater than 4 mg per 100 mL may show signs of depression, including decreased muscle tone, drowsiness, poor respiratory effort, and low Apgar scores. A case of neonatal osteoporosis with associated fractures has been reported in a woman undergoing long-term tocolysis with magnesium sulfate.
Controversy exists over the long-term effects of magnesium sulfate. A number of cohort and case-control studies have suggested that magnesium sulfate exposure at birth may reduce rates of cerebral palsy in preterm infants. The MagNet trial was the first trial published that formally evaluated this hypothesis. This trial randomized women with preterm labor and intact membranes to receive magnesium sulfate or other tocolytics if <4 n =" 46)" n =" 47)" st="on">
Calcium Channel Blockers
Calcium channel blockers or calcium antagonists are nonspecific smooth muscle relaxants. They prevent the influx of extracellular calcium ions into the myometrial cell. The effects are not specific to the uterus.
Nifedipine has been used as a tocolytic agent. Numerous protocols for nifedipine exist. In general, 10 mg nifedipine is administered orally. If contractions persist, the dose can be repeated every 20 minutes for a total of 30 mg in 1 hour. Maternal hypotension is relatively common. If hypotension develops, additional doses of nifedipine must be held. Once contractions decrease, the patient may receive 10 mg every 6 hours of nifedipine orally or receive 30 to 60 mg of the sustained-release nifedipine per day. Nicardipine, a potent uterine relaxant, may be administered as a 40-mg loading dose followed in 2 hours by a 20-mg dose to a maximum dose of 80 mg if uterine contractions do not abate. This can be followed by sustained-release nicardipine 45 mg every 12 hours.
Calcium channel blockers produce vasodilation and decrease peripheral vascular resistance. Maternal hypotension defined as either a 25% decrease in mean arterial pressure or symptomatic hypotension is relatively common. Many patients experience transient facial flushing or develop nausea and headache. Maternal side effects appear to be less common than in women treated with the β-sympathomimetics, but severe complications have been reported. For example, there has been a case of maternal myocardial infarction associated with high-dose nifedipine therapy following ritodrine treatment in women in preterm labor. The authors have had a similar case using a low dose of nifedipine following magnesium sulfate tocolysis. Nifedipine potentiates the toxicity of magnesium sulfate by causing neuromuscular blockade. There have been reports of profound hypotension, neuromuscular blockade, and maternal death resulting from the combination of magnesium sulfate therapy and calcium channel blockers. This complication may not be as frequent as initially believed. However, there are no protocols that establish the safety of using these medications together. Therefore, they should not be used concurrently.
In general, calcium channel blockers appear to be well tolerated by the fetus and neonate. There has been one case of neonatal heart block associated with their use. Concerns remain that calcium channel blockers may have adverse effects on the fetal and placental circulation resulting in growth restriction, acidosis, and stillbirth.
No randomized trial has been published that compares calcium channel blockers with placebo for tocolysis. Several meta-analyses have been conducted comparing nifedipine with other tocolytics. A Cochrane review found that calcium channel blockers (mainly nifedipine) were superior to β-mimetics (mainly ritodrine) as a tocolytic. A meta-analysis concluded that “Although calcium antagonists have not been evaluated against placebo, comparative trials with beta-agonists have shown more favorable neonatal outcomes and better prolongation of gestation”. There is no clear first-line tocolytic agent.”
Prostaglandin Synthetase Inhibitors
Prostaglandins are integrally involved in cervical ripening and labor. Therefore, it would make sense that inhibiting prostaglandin synthesis should prevent preterm labor and delivery. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase, thus preventing the conversion of arachidonic acid to prostaglandin. The effects are not limited to the uterus. Indomethacin is the most widely studied prostaglandin synthetase inhibitor used for treatment of women in preterm labor.
The authors' protocol for indomethacin tocolysis involves the administration of a 100-mg loading dose given as a suppository per rectum. If regular uterine contractions persist 1 to 2 hours after the initial 100-mg suppository, an additional 50 to 100 mg may be given. Oral therapy is then instituted at 50 mg every 6 hours for 48 hours while betamethasone is dispensed. The absorption of indomethacin is excellent from both the rectal and oral routes. Therefore, if rectal suppositories are not available, the oral formulation can be effectively substituted. Fetal echocardiography is not considered necessary when administering indomethacin as outlined above. Fetal contraindications to the use of indomethacin include growth restriction, renal anomalies, chorioamnionitis, oligohydramnios, ductal dependent cardiac lesions, and twin-twin transfusion syndrome.
Indomethacin is very well tolerated in the gravida in comparison to other tocolytic agents. Serious maternal side effects are rare when the agent is used in a brief course of tocolysis. As with any NSAID, mild gastrointestinal upset may occur. More serious potential complications include gastrointestinal bleeding, alterations in coagulation, thrombocytopenia, and asthma in aspirin-sensitive patients.
Prolonged treatment can lead to renal injury, especially when nephrotoxic drugs such as aminoglycosides are employed. Drugs of this class are antipyretic agents and may obscure a clinically significant fever. Maternal contraindications to indomethacin include renal or hepatic disease, active peptic ulcer disease, poorly controlled hypertension, asthma, and coagulation disorders.
In contrast to the generally favorable maternal side-effect profile, the potential for fetal and neonatal complications of indomethacin tocolysis is worrisome. In actuality, serious complications are rare when limiting treatment to short courses and adhering to established protocols.
The principal side effects of indomethacin tocolysis have been constriction of the ductus arteriosus, oligohydramnios, and neonatal pulmonary hypertension. The ductal constriction occurs because formation of prostacyclin and prostaglandin E2, which maintain ductal vasodilation, is inhibited by indomethacin. Moise and colleagues reported Doppler evidence of ductal constriction in 7 of 14 fetuses exposed to indomethacin between 27 and 31 weeks gestation. Tricuspid regurgitation occurred in three fetuses. All ductal abnormalities resolved within 24 hours of discontinuation of indomethacin, and none of the neonates had pulmonary hypertension. The Moise group later reported on the effect of advancing gestational age on ductal constriction in association with indomethacin and stated that “a dramatic increase in constriction was noted at 32 weeks gestation when the rate of compromise approached 50%.” However, ductal constriction was noted as early as 24 weeks and occurred in 11 of the 23 fetuses prior to 30 weeks. This was a retrospective analysis of echocardiograms performed on 44 patients with premature labor or hydramnios treated with indomethacin. Although never clearly stated, these patients appeared to be on courses of therapy for greater than 48 hours. Indomethacin was the “third-line agent” in premature labor unresponsive to terbutaline or magnesium sulfate.
Oligohydramnios associated with indomethacin tocolysis is common, dose-related, and reversible. The oligohydramnios is a consequence of reduced fetal urine production due in turn to reduction by indomethacin of the normal prostaglandin inhibition of antidiuretic hormone and by direct effects on the renal blood flow. Indomethacin can be an effective therapy for hydramnios, especially when complicated by preterm labor.
Primary pulmonary hypertension in the neonate is a serious condition that also has been reported with prolonged (more than 48 hours) indomethacin therapy. This complication has not been reported when therapy was restricted to 24 to 48 hours; however, the incidence may be as high as 5% to 10% with long-term therapy.
Necrotizing enterocolitis and intraventricular hemorrhage have been observed in the LBW neonate exposed to indomethacin in utero when it was used outside of standardized protocols that did not limit the duration of treatment or was the second or third agent added to recalcitrant preterm labor. Since such patients have an increased risk of subclinical intra-amniotic infection, and since intra-amniotic infection is associated with a greater risk of such complications, it is not clear that indomethacin incurs independent risk for these morbidities. Subsequently, two larger studies have not confirmed this finding or demonstrated any association between indomethacin exposure and any adverse neonatal outcome. Follow-up studies of children treated in utero with indomethacin have not found significant long-term effects, although they did not specifically target the LBW neonate.
Indomethacin has been reported to be effective in two small randomized, placebo-controlled trials. The first found that indomethacin was superior to placebo in delaying delivery for 48 hours (80% vs. 33%). The second demonstrated a sustained delay in delivery for patients treated with indomethacin (95% at 48 hours and 83% at 7 days) compared with placebo (23% at 48 hours and 16% at 7 days). Additional prospective, randomized trials have found indomethacin to be comparable to ritodrine and magnesium sulfate and superior to nylidrin for tocolysis. There are additional reports that describe indomethacin tocolysis favorably, but many used other tocolytic agents simultaneously or sequentially.
Indomethacin appears to be an effective tocolytic agent that is well tolerated by the mother and appears to be tolerated by the fetus when used appropriately. Exposure should be limited to 48 consecutive hours to allow for administration of antenatal corticosteroids and should be restricted to gestational ages less than 32 weeks.
Other Tocolytic Agents
Several other tocolytic agents have been proposed for use. These include the oxytocin analogs, nitroglycerin, cyclooxygenase 2 (COX-2) inhibitors, ketorolac, progestins, and nitric-oxide inhibitors. The oxytocin analogs have been the most widely tested. Atosiban is an oxytocin receptor antagonist that has been shown to be more effective than placebo in quieting uterine contractions and comparable to β-mimetics in prolonging gestation with fewer maternal side effects. A Cochrane review “failed to demonstrate the superiority of atosiban over beta-mimetics or placebo in terms of tocolytic efficacy or infant outcomes” and concluded that “compared with placebo, atosiban did not reduce incidence of preterm birth or improve neonatal outcome.” Atosiban was not approved as a tocolytic by the FDA.
Maintenance Tocolysis Following Arrest of Preterm Labor
If preterm labor is arrested, the patient remains at high risk for a recurrent episode of preterm labor and preterm birth. Maintenance tocolytic therapy may decrease chances for delivery in some cases. Several agents including β-mimetics (ritodrine and terbutaline), magnesium sulfate, prostaglandin synthetase inhibitors, and the calcium channel blockers have been tested in randomized trials.
Efficacy of Oral Tocolysis with β-Mimetics
The authors have been able to identify eight randomized placebo-controlled trials of oral β-mimetic maintenance therapy to prevent recurrent preterm labor and preterm delivery. A total of 915 patients were randomized in these eight trials. In six of the eight trials, there was no decrease in the preterm delivery rate or a prolongation of pregnancy with maintenance tocolytic therapy when compared with controls receiving no treatment. Seven of the eight trials
reported on the number of women treated for recurrent preterm labor. Overall, for women receiving a β-mimetic, the rate of recurrent preterm labor was 32.5% (range, 2% to 59%) and for patients receiving placebo or no therapy 28.3% (range, 12.9% to 63%). Despite obvious differences in the trials, Sanchez-Ramos and colleagues combined these data by using meta-analysis (Table 11.10). When they restricted the analysis to trials comparing β-mimetics to placebo or no therapy, there was no benefit of treatment for prevention of preterm birth (OR 1.08; 95% CI 0.82 to 1.43) or risk of recurrent preterm labor (OR 0.90; 95% CI 0.63 to 1.28). One could argue that it is not appropriate to combine trials when there is no consistency between the trials in inclusion criteria and definitions of preterm labor and recurrent preterm labor. Regardless, whether the trials are evaluated individually, cumulatively as a review, or by using meta-analysis, there does not appear to be any benefit of oral β-mimetic tocolysis.
| TABLE 11.10 Impact of Maintenance Tocolysis on Preterm Delivery | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Several potential explanations can be offered as to why oral β-mimetic therapy appears to be ineffective. Oral administration of terbutaline results in inconstant drug levels, characterized by peaks and troughs. The need to take the drug every 2 to 4 hours throughout the day, including awakening at regular intervals throughout the night, may decrease compliance. Finally, long-term exposure to β-mimetic agents results in desensitization of the β-adrenergic receptors in the myometrium. Development of tolerance is related to both the duration of therapy and the total dose of β-mimetics. As a result, the drugs may lose effectiveness over time.
Efficacy of Continuous Subcutaneous Administration of Terbutaline
Terbutaline may be administered by a continuous portable subcutaneous pump for maintenance therapy. Its theoretical advantages over oral maintenance therapy are continuous low-maintenance drug levels and the ability to bolus the drug if uterine contractions develop, thus preventing or decreasing the development of tolerance of the β-receptors to the β-agonist terbutaline.
A number of descriptive studies of terbutaline pump therapy for prevention of preterm birth have been published in peer-review journals. It was not until 1997 that the first randomized, placebo-controlled trial of the terbutaline pump was published. In this study, women with preterm labor were assigned to receive terbutaline pump therapy (n = 15), placebo pump therapy (n = 12), or oral terbutaline (n = 15). If women developed recurrent preterm labor, the blind was broken and women receiving placebo were crossed over to terbutaline. Although conclusions were limited by the small number of patients in each group and the crossover design, there were no differences in the mean delay to delivery or in neonatal morbidity.
Despite very limited information regarding terbutaline pump therapy, its use has been widely promoted by several home health care corporations that target the majority of their services to the obstetric patient. Terbutaline pump therapy, whether used alone or in conjunction with HUAM programs, is extremely expensive, averaging over $200 per day, when compared to oral therapy or no therapy. As its use has increased, so have reports of complications related to therapy. As a result, the FDA issued an alert regarding the potential dangers associated with terbutaline pump therapy and the lack of data supporting the efficacy of this treatment.
Risks Associated with Oral or Subcutaneous β-Mimetic Therapy
Frequent unwanted effects of β-mimetic therapy include palpitations, tremor, nausea, vomiting, headache, thirst, nervousness, and restlessness. Complications of oral β-mimetics and the subcutaneous administration of terbutaline include sudden death, pulmonary edema, cardiac arrhythmias, hepatitis, glucose intolerance, and gestational diabetes. There has also been one case of neonatal myocardial necrosis in a woman receiving high doses of subcutaneous terbutaline.
Summary of β-Mimetics for Maintenance Therapy
There is no compelling evidence from the randomized controlled trials to support the use of β-mimetics for maintenance therapy. Given the potential risks associated with β-mimetics, there is no justification for its continued use as a chronically administered therapy.
Other Maintenance Tocolytic Agents
Compared with β-mimetics, there have been relatively few trials exploring options for maintenance therapy. Magnesium sulfate has been administered on a chronic basis intravenously and orally. Long-term magnesium exposure can result in significant osteopenia, especially when used in conjunction with multiple doses of corticosteroids and bed rest. There have been reports of both mothers and neonates developing significant osteopenia following prolonged magnesium exposure. In the randomized trials that compare oral magnesium with placebo, no apparent benefits were noted in time to delivery or neonatal outcomes.
Long-term tocolysis with the prostaglandin synthetase inhibitors is contraindicated. The fetal risk is far in excess of any potential benefits. It is possible that more selective COX-2 inhibitors will be useful for maintenance therapy. Calcium channel blockers appear to be gaining popularity to reduce recurrent preterm labor. Two trials have compared nifedipine with β-sympathomimetic agents. These investigations were equivalent or superior to β-mimetics for prolonging pregnancy, with lessened maternal side effects. Carr and colleagues published the only randomized trial of nifedipine compared with no therapy. They randomized 74 women to receive oral nifedipine (20 mg every 4 to 6 hours) or no treatment. The groups were well balanced at randomization for potential confounders. There were no differences in the time gained from initiation of therapy until delivery in the two groups (37 days nifedipine and 32 days no therapy) or gestational age at delivery (35.4 weeks nifedipine and 35.3 weeks no therapy). Oral nifedipine following successful tocolysis with magnesium sulfate did not improve pregnancy outcome. While this study did not report any significant complications of therapy, there has been a report of a myocardial infarction following treatment with nifedipine for maintenance tocolysis.
Conclusions Regarding Maintenance Tocolysis
At this time, there is no evidence that any of the available maintenance tocolytic agents are effective in prolonging gestation, reducing preterm births, or improving neonatal outcome. Each of the therapies has been associated with significant complications. Therefore, the authors cannot recommend that any of these agents be used outside of properly designed randomized trials.
Ancillary Therapy for Women in Preterm Labor
Several investigators have studied the impact of adjunctive antibiotic therapy in women with preterm labor and intact membranes. These studies have included women across the spectrum of gestational ages and cervical dilations and have used a variety of antibiotic regimens. This subject was reviewed by King and Flenady in the Cochrane Database. Beneficial effects of antibiotics included a significant prolongation of pregnancy (5.4 days), reduction in maternal infectious morbidity, and a trend toward reduction in neonatal sepsis. However, this was coupled with an increase in perinatal mortality (OR 3.36; 95% CI 1.21 to 9.32). The largest study published to date was ORACLE II. This study included women in preterm labor between 20 and 37 weeks gestation. In this trial, 6,295 women were enrolled, and data from 6,241 women was available for analysis. Overall, use of antibiotics was not associated with a reduction in neonatal morbidity or mortality or prolongation of pregnancy. The only exception was decreased use of postpartum antibiotic prescription in women who had received antibiotics. Based on the results of this trial and the Cochrane Database review, at this time, adjunctive antibiotic therapy for women in preterm labor (with intact membranes) is not indicated. GBS prophylaxis should be administered following the 2002 Centers for Disease Control and Prevention (CDC)/ACOG guidelines.
Hydration therapy, either oral or intravenously, is widely used as adjunctive therapy for women with preterm contractions and preterm labor. This practice was popularized during the 1980s when β-mimetics were being widely prescribed. Prior to administration of β-mimetics, women were hydrated to prevent hypotension. In many cases, as women were receiving their hydration therapy, their contractions reduced in frequency, thus obviating the need for parenteral tocolysis. Guinn and associates published a randomized trial comparing two commonly used therapies for preterm contractions to observation only. Women were included who had cervical dilation less than 2 cm, effacement less than 80%, gestational age 24 to 33 completed weeks gestation, and regular uterine contractions. Women were randomly assigned to receive intravenous hydration, one dose of subcutaneous terbutaline (0.25 mg), or observation only. There were no differences between the groups with time gained in utero, the proportion of women who delivered preterm, or the proportion of women who developed cervical change and received parenteral treatment with tocolytic agents. Intravenous hydration was associated with the highest hospital costs and charges and has the highest potential for adverse effects. Intravenous hydration should be reserved only for women who are obviously dehydrated.
Bed rest also has been widely prescribed for women in preterm labor. There is little if any data that suggests that bed rest is efficacious in women with threatened preterm labor or arrested preterm labor. There are significant costs associated with bed rest, including hospital days, lost wages, and lost domestic productivity. It should not be routinely prescribed to women at risk for preterm labor or delivery.
Two therapies are extremely beneficial to women with preterm labor. The first is antenatal corticosteroids. There have been 15 randomized, placebo-controlled trials that tested the efficacy of antenatal corticosteroids in women at risk for preterm birth. Exposure to a complete course of antenatal corticosteroids (betamethasone 12 mg i.m. q24h — 2 doses or dexamethasone 6 mg i.m. q12h — 4 doses) significantly improves neonatal outcomes, including a reduction in respiratory distress syndrome, intraventricular hemorrhage, and death. The data are so compelling that the ACOG and the NIH recommend that all women at risk for preterm birth prior to 34 weeks gestation receive antenatal corticosteroids. Repeat courses of antenatal corticosteroids are not recommended, as they may reduce respiratory morbidity while increasing the potential for intraventricular hemorrhage and chorioamnionitis. Long-term follow-up studies are under way that will help to define the long-term risks and benefits of repeat courses of antenatal corticosteroids.
The other therapy that appears to be highly efficacious in improving neonatal outcomes is the administration of GBS prophylaxis to women at risk for preterm birth. The attack rates for preterm neonates colonized with GBS are significantly higher than in term infants. As a result, prophylaxis has been demonstrated to be highly beneficial in preventing invasive GBS and its sequelae in preterm neonates.
Conclusions
Prevention of preterm birth remains an elusive goal. However, recent data support the use of progestational agents to prevent recurrent preterm birth. Despite widespread recognition and interest in the problem, the rate of preterm delivery is increasing in the
Prolonged Pregnancy
A prolonged pregnancy, also commonly called post-term pregnancy, is one that has lasted longer than 42 weeks, or 294 days beyond the first day of the last menstrual period. Postdatism implies pregnancy lasting beyond the estimated due date at 40 weeks. The term postmature is reserved for the pathologic syndrome in which the fetus experiences placental insufficiency and resultant intrauterine growth restriction.
Postdatism occurs in 3% to 12% of all pregnancies. The definition of prolonged pregnancy is, however, somewhat arbitrary and was formulated before ultrasound dating of gestation became routine. Browne described perinatal mortality after 41 weeks as 10.5 per 1,000 pregnancies, doubling that at 43 weeks, and tripling that amount at 44 weeks.
Prolonged pregnancies are at risk for macrosomia resulting in shoulder dystocia and fetal injury, oligohydramnios, meconium aspiration, intrapartum fetal distress, and stillbirth. Maternal risks include trauma, hemorrhage, and labor abnormalities (Table 11.11). Interventions for preventing or improving outcomes in low-risk, prolonged pregnancies have proven to be of minimal benefit.
Etiology
The most common cause of an apparently prolonged pregnancy is inaccurate dating. Early ultrasound dating of pregnancies has been shown to reduce the number of women who are induced for apparently prolonged pregnancies. One condition associated with prolonged pregnancy is placental sulfatase deficiency, an X-linked disorder that affects male fetuses. The sulfatase-deficient placenta is unable to use DHEA-S and other fetal adrenal precursors to synthesize estrogens. These pregnancies are associated with poor response to cervical ripening and induction as well as postdatism. Other postulated maternal risk factors for prolonged pregnancy include primiparity, previous prolonged pregnancy, and young maternal age.
| TABLE 11.11 Complications of Prolonged Pregnancy | ||||||||||||||
|
Amniotic Fluid
Reduced amniotic fluid (i.e., oligohydramnios) is a frequent finding in prolonged pregnancies. It presents a problem because it can be a marker for fetal compromise and because it puts the fetus at risk for cord accidents. Commonly used ultrasound techniques to estimate the amount of amniotic fluid include the four-quadrant amniotic fluid index (AFI) and the largest vertical pocket.
Antenatal Testing
Any pregnancy at risk for uteroplacental insufficiency is a candidate for antenatal fetal monitoring. It is most likely that the morbidity and mortality associated with prolonged gestation is due to placental insufficiency. The goal of antenatal testing is to identify those fetuses that should be delivered. It is useful to remember that no form of antenatal testing will predict random unfortunate events such as sudden significant umbilical cord compression.
If a pregnancy is managed expectantly beyond 41 weeks, some form of antenatal testing should be initiated in otherwise healthy pregnancies. The frequency and type of antenatal testing is based mostly on physician preference and experience.
The contraction stress test (CST) was the first test used for antepartum fetal monitoring, whereas the nonstress test (NST) is the first-line screening test at many medical centers. It is quickly and easily performed in an outpatient setting. The NST is based on the knowledge that fetal hypoxia interrupts the pathway between the fetal heart and an intact central nervous system (CNS). The fetus with an intact CNS will have heart rate accelerations with movement or stimulation. The CST has a high false-positive rate, and the NST has a false-negative rate of 2.7 per 1,000 in a high-risk population. The biphasic profile (BPP) score predicts the presence or absence of asphyxia. The loss of the components of the BPP reflects sequential adaptive deletions to reduce fetal oxygen requirements. A normal BPP has a false-negative rate of 0.7 to 0.8 per 1,000.
The CST, NST, and BPP were compared in 583 women who had completed 42 weeks gestation. There were three protocols:
- Weekly NST with CST for nonreactive NST.
- Twice weekly NST with BPP for nonreactive NST with induction for a 4/10 BPP.
- Twice weekly NST with BPP for nonreactive NST and a weekly determination of the amniotic fluid volume.
Patients were induced for low fluid or decelerations on the NST. In protocol 1, patients were reevaluated in 24 hours for a suspicious CST and induced for a positive CST. Protocol 3 had the highest intervention rate and the least perinatal morbidity. Protocol 1 had no interventions and the highest perinatal morbidity rate. Cesarean delivery was more common in protocols 2 and 3. Of note, the best outcomes were achieved with a low threshold for intervention.
The Fetus
In 1954, Clifford described the fetal postmaturity syndrome, in which the postmature infant was characterized by peeling, parchmentlike skin; wasted appearance; and meconium staining of skin, membranes, and the cord. The syndrome progressed in three stages from placental insufficiency with minimal associated morbidity and mortality to chronic insufficiency with an associated anoxic event.
The postmaturity syndrome described by Clifford is seen in only a small percentage of prolonged pregnancies. By far, the most common complication is macrosomia, resulting in dystocia with associated brachial plexus injuries and fractures.
Seven thousand infants were studied to determine the rate of growth after 39 weeks. Mean birth weight increased from 39 to 42 completed weeks. A similar increase was seen in head circumference and crown-to-heel length. In a study of 519 pregnancies beyond 41 weeks, 23% weighed more than 4,000 g and 4% were larger than 4,500 g.
To assess the risk to the fetus in a prolonged uncomplicated gestation, 1,408 infants delivered at 41 weeks and 340 delivered at 42 weeks were compared with 5,915 delivered at 39 or 40 weeks. Fetal distress and meconium release were twice as common at or after 42 weeks than at term. There was an eightfold increase in meconium aspiration, which occurred 1 per 455 at term, 1 per 175 at 41 weeks, and 1 per 57 at 42 weeks. There was no increase in the incidence of birth asphyxia measured by the need for mechanical ventilation at birth.
Management
An adverse event in a pregnancy that has carried beyond 40 weeks seems especially difficult because it might have been avoided by simply delivering the patient. Although rare, the risk of stillbirth increases as gestational age increases. Nonetheless, available data indicate that induction and expectant management have similar outcomes, and either is suitable for managing the uncomplicated prolonged gestation.
The NIH sponsored a clinical trial to compare induction at 41 weeks (n = 265) with expectant management (n = 175) consisting of twice weekly NST and AFI. There were no differences in outcome between the two groups. The trial concluded that either approach was acceptable.
The Parkland Group studied 56,317 pregnancies at 40, 41, and 42 weeks. Labor was induced at 42 weeks. Neonatal outcomes were similar in all groups. Sepsis and neonatal intensive care unit admission were more common in the 42-week group. Labor complications increased between 40 and 42 weeks, including length of labor and operative delivery. Their data suggest that routine induction at 41 weeks would increase labor complications with little or no neonatal benefit.
In the Canadian Multicenter Post-term Pregnancy Trial, singleton pregnancies at 41 weeks or more were assigned to induction or monitoring. In the monitored group, women were asked to perform kick counts each day. In addition, the fetuses received NSTs three times a week and AFI determinations two or three times weekly. Patients in the monitored group were delivered either at 44 weeks or for maternal-fetal indication(s). Perinatal morbidity and mortality were the same for both groups.
Prevention
Separation of the membranes from the lower uterine segment (membrane sweeping) is a safe and inexpensive method of inducing labor. In one study, the treatment group had a significant reduction in prolonged gestation-3.3% compared with 15.6% in the control group. In summary, membrane sweeping prior to 40 weeks appears to be an effective method for reducing postdate inductions, but its safety in women who are positive for GBS has not been established.
Induction of Labor
In the presence of a favorable cervix, induction after 41 weeks is the most favored course. Even though induction with an unfavorable cervix may be unsuccessful and lead to cesarean delivery, most practitioners now recommend cervical ripening and induction at 41 weeks with an unfavorable cervix. A recent Cochrane Review noted the following clinical implications: (a) induction of labor at 41 or 42 weeks does not increase the risk of cesarean delivery; (b) induction of labor port term reduces the risk of perinatal death, but the absolute risk is very low; and (c) fetal monitoring should be part of expectant management.