Preterm Labor ManagementWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC). Preterm labor is the leading cause of neonatal mortality in the United States and accounts for about 11.5% of all live births. It is responsible for three quarters of neonatal mortality and one half of long-term neurologic impairments in children. Despite the numerous management methods proposed, the incidence of preterm birth has changed little over the past 40 years. Uncertainty persists about the best strategies for managing preterm labor (1). The purpose of this document is to discuss the various methods proposed to manage preterm labor and the evidence for their roles in clinical practice. The information is designed to aid practitioners in making decisions about appropriate obstetrical care. Variations in practice may be warranted based on the needs of the individual patient, resources, and limitations unique to the institution or type of practice. Definition: Preterm labor generally can be defined as regular contractions that occur before 37 weeks of gestation and are associated with changes in cervix. The causes of preterm labor are not well understood, the burden of preterm births are clearer. It is important to recognize that preterm labor is not the only mechanism leading to preterm birth; numerous preterm births are preceded by either rupture of membranes or other medical problems. Predictive Markers: Spontaneous preterm labor does not have an identifiable etiology, but most likely results from the interaction of multiple factors and independent pathways. Various factors found to be predictive of increased likelihood of preterm labor can be used to classify women as high or low risk. The most important predictors are previous preterm delivery, bacterial vaginosis, and a cervix <2.5 cm in length. Other risk factors are: <18 or >40 years of age; substance abuse history; anemia; African-American ethnicity; low socioeconomic status; low weight gain during pregnancy; oligohydramnios or polyhydramnios; multiple gestation; bleeding in 1st and 2nd trimester; chronic maternal illness (e.g. diabetes, hypertension); fetal congenital anomalies; cervical insufficiency; inadequate prenatal care; uterine anomalies; short inter-conception period (<1 year); uterine contractions; and emotional stressors (e.g. domestic violence, job loss, family illness). Women who have a prior preterm labor or 2 or more preterm risk factors are considered to be high-risk (6). For these individuals, determining the absence or presence of fetal fibronectin in cervical vaginal secretions between 22 and 34 weeks of gestation is an additional tool for preterm risk assessment. Clinical use of the Fetal Fibronectin Test - Fibronectins are large extracellular matrix proteins. A heavily glycosylated form, termed fetal fibronectin, is present in the amniotic fluid and placental and fetal membranes. Assays for fetal fibronectin have two clinical applications. The first is to predict the risk of preterm labor in symptomatic patients, since identifying women with preterm contractions who will go on to deliver prematurely is an imprecise process. The second use is to identify asymptomatic women, particularly those who are high-risk (e.g. previous preterm delivery, current multiple gestation), who are most likely to deliver preterm. A positive test (>50 ng/ml) suggests about a 20-40% risk of delivery within 14 days for high-risk patient. For those with a negative fetal fibronectin, >99% remain pregnant 2 weeks later (7). Recommendations in case of a positive fetal fibronectin test are: advise patient to stop work and decrease activity; treat positive urine culture or genital infection; monitor contractions; treat >4 contractions per hour with nifedipine if an outpatient; and give course of antenatal steroids if >24 weeks of gestation. Fetal fibronectin is also a useful predictor of preterm birth in asymptomatic patients who are at high risk of preterm labor, including in the following situations: for women who have had a prior preterm, a positive fetal fibronectin result is associated with about a 10% risk of delivery in asymptomatic patients with other risk factors for preterm birth. However, in cases of a negative fetal fibronectin result, >99% of patients remain pregnant at the end of a 14-day period. Fetal fibronectin results are best predictive for the subsequent 2-3 week period, and should be repeated if longer intervals are involved. In twin gestation, a positive fetal fibronectin result, not cervical length has been shown to be the only predictor of preterm birth at >28 weeks. In fact, investigators have shown that fetal fibronectin testing performed even better in twin pregnancies compared to singletons. More than 50% of women with a twin gestation who had a positive fetal fibronectin test delivered prematurely (8). Sonographic measurement of the cervical length: Several groups have evaluated cervical length at 16-24 weeks in women with prior preterm births and found that a cervical shortening to less than the 10th percentile (less than 25 mm at 20-24 weeks, less than 30 mm at 16-20 weeks) results in a significant increase in risk of preterm births before 35 weeks. Women with recurrent preterm births have shorter, more dilated, softer cervixes, with higher Bishop scores on physical examination, when evaluated remote from delivery. The studies suggest that, for women with prior spontaneous preterm births, evaluation of the cervical length serially (every 2 weeks) between 16 and 24 weeks of gestation may aid in the identification of those at increased risk for recurrent preterm birth (9). Those women with cervical length less than the 10th percentile (less than 25 mm at 16-24 weeks) are at increased risk. Possible benefit of cerclage in such women with prior preterm births and cervical lengths less than 25 mm between 16 and 24 weeks needs to be confirmed by a large multicenter trial, which is underway. Combination of clinical and biological markers: It allows for more accurate prediction of recurrent preterm births. The more markers are present higher the risk (10). Corticotropin-releasing hormone (CRH) is shown to rise in maternal plasma during pregnancy and in low-risk women has been found in the second trimester to be elevated in women destined to deliver preterm. In women with prior preterm births and cervical lengths less than 25 mm at 22-24 weeks, 35% delivered before 37 weeks. In women with prior preterm births with a positive fetal fibronectin, 48% delivered before 37 weeks. Among women with both cervical lengths less than 25 mm and positive fetal fibronectin, 60% delivered before 37 weeks and 50% delivered before 32 weeks. Although there has been some movement toward development of a multiple-marker screening test for prediction of preterm birth that would include clinical characteristics as well as serum, ultrasonography, and/or fetal fibronectin testing, further work is needed. Management: Non-pharmacologic Treatment: The effectiveness of these interventions is uncertain. It includes bed rest, abstention from intercourse and orgasm, and hydration either orally or parenterally. It is also used in conjunction with pharmacological treatment. Tocolytic Drugs for Treatment of Preterm Labor: Tocolytic drugs inhibit myometrial contractions. It can be administered either parenterally or orally. Many agents have been used, including ethanol, magnesium sulfate, calcium channel blockers, oxytocin antagonists, nonsteroidal antiinflammatory drugs (NSAIDs), and betamimetic agonists. Tocolytic drugs may prolong gestation for 2-7 days if needed, which can provide time for administration of steroids and maternal transport to a facility with a neonatal intensive care unit. There is no clear first-line tocolytic drug. The choice of drug should be individualized and based on maternal condition, potential drug side effects, and gestational age. Combining tocolytic drugs potentially increases maternal morbidity and should be used with caution. Contraindications for tocolysis include severe preeclampsia, placental abruption, intrauterine infection, lethal congenital or chromosomal abnormalities, advanced cervical dilatation, and evidence of fetal compromise or placental insufficiency. The commonly used drugs and their side effects are (2): Tocolytic Agents Dosage and Administration Contraindications Maternal Side Effects Fetal and Neonatal Side Effects Beta-mimetic Terbutaline, 0.25 mg subcutaneously every 20 min. to 3 h. (hold for pulse >120 beats/min) Ritodrine initial dose of 50-100 micro-gm, increase 50 micro-gm/min every 10 min until contractions cease or side effects develop. Max. dose = 350 micro-gm/min Cardiac Arrhythmias Poorly controlled Thyroid Disease; Poorly controlled Diabetes Cardiac or cardiopulmonary arrhythmias, pulmonary edema, myocardial ischemia, hypotension, tachycardia Metabolic hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, physiological tremor, palpitations, nervousness, nausea or vomiting, fever, hallucinations. Fetal tachycardia, hyperinsulinemia, hyperglycemia, myocardial and septal hypertrophy, myocardial ischemia. Neonatal tachycardia, hypoglycemia, hypocalcemia, Hyperbilirubinemia, hypotension, intravascular hemorrhage. Magnesium sulfate 4-6 g bolus for 20 min, then 2-3 g/h. Myasthenia gravis Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest Lethargy, hypotonia, respiratory depression, demineralization with prolonged use Calcium channel blockers 30 mg loading dose, then 10-20 mg every 4-6 h. Cardiac disease, use caution with renal disease, neonatal hypotension, avoid concomitant use with Magnesium sulfate Flushing, headache, dizziness, nausea, transient hypotension None noted as yet Prostaglandin synthetase inhibitors Indomethacin loading dose of 50 mg rectally or 50-100 mg orally, then 25-50 mg orally every 6 h. x 48 h. Ketorolac loading dose of 60 mg IM, then 30 IM every 6 h. x 48 h. Sulindac, 200 mg orally every 12 h. x 48 h. Significant renal or hepatic impairment Active peptic ulcer disease Coagulation disorders or thrombocytopenia, NSAID-sensitive asthma, other sensitivity to NSAIDs Nausea, heartburn Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, intraventricular hemorrhage, Hyperbilirubinemia, necrotizing entrocolitis. Source: Hearne AE, Nagey DA. Therapeutic agents in preterm labor: Clin Obstet Gynecol 2000;43:787-801. Antenatal Corticosteroid Use: The most beneficial intervention for patients in true preterm labor is the administration of corticosteroids. The incidence and severity of neonatal respiratory distress syndrome, intraventricular hemorrhage and necrotizing entrocolitis are reduced by the use of antenatal corticosteroids. The administration of betamethasone has been shown to decrease neonatal mortality (3). All women who are at risk for preterm delivery between 24 weeks and 34 weeks of gestation are potential candidates for corticosteroid therapy. Treatment should consist of either two doses of betamethasone or four doses of dexamethasone, both administered intramuscularly. Progesterone and the prevention of preterm labor: Based on the accumulating data on prevention of preterm labor with progesterone, the American College of Obstetricians and Gynecologists reported in 2003 that progesterone supplementation appears to provide an effective means to reduce the preterm birth rate in a selected group of very-high-risk women and supported its use in this important population (11). Progestational agents are available in oral, transvaginal (gel and suppositories), and injectable formulations. The efficacy of the oral route appears to be limited by first-pass metabolism in the liver, where some drug is targeted for excretion and some is converted to ineffective metabolites, the remaining portion being largely ineffective. Transvaginal formulations, which are absorbed into the bloodstream and distributed directly to target tissues, also more readily achieve biologic plasma levels. To address the long-term effects of progesterone, the NICHD's MFMU Network followed up on the children from the progesterone trial to determine whether there was a difference in achievement of developmental milestones and physical health between children exposed to progesterone and those exposed to placebo by using the Ages and Stages Questionnaire score and differences in developmental milestones. Over 80% of the children from the original trial were evaluated, and no differences in achievement of developmental milestones or physical health were identified between the two groups. Because the progesterone for this indication would not be started until 16 weeks, it is unlikely to have effects on congenital malformations (12). Antibiotics for Treatment of Preterm Labor: It has been theorized that infections or inflammation are associated with contractions, and this theory provided the rationale for studies using antibiotics to decrease the risk of preterm birth. Studies have shown mixed results, but most of the evidence has failed to show a benefit from treatment with antibiotics (4). Treating women in preterm labor with antibiotics for the sole purpose of preventing preterm delivery is not recommended. Tests that can help identify patients at risk for progressing to preterm labor: Many tests to identify women at risk of preterm birth have been proposed and evaluated; however, only ultrasonography and fetal fibronectin testing have been shown to have benefit. Ultrasonography to determine cervical length, fetal fibronectin testing or combination of both may be useful in determining which women are at high risk for preterm delivery. 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 (5). Women with multiple gestations who have preterm contractions but no cervical change do not require tocolytic therapy. The women with multiple gestations, who are experiencing preterm labor, may benefit from short-term tocolysis to allow for steroid administration. They have a greater risk of pulmonary edema when exposed to beta-mimetics or magnesium sulfate. The role of repeated acute tocolytic therapy in women with recurring symptoms of preterm labor is unknown. Given the limited benefits of an initial course of treatment with a tocolytic drug and current recommendations that corticosteroids be administered only as a single course, the effectiveness of subsequent acute tocolysis is uncertain. Maternal transport is a potential rationale for a subsequent treatment course. Summary: There are no clear "first-line" tocolytic drugs to mange preterm labor. Clinical circumstances and physician preferences should dictate treatment. Antibiotics do not appear to prolong gestation and should be reserved for group B streptococcal prophylaxis in patients whom delivery is imminent. Neither maintenance treatment with tocolytic improve perinatal outcome; nor should be undertaken as a general practice. Cervical ultrasound examination and fetal fibronectin testing have good negative predictive value; thus either approach or both combined may be helpful in determining which patients do not need tocolysis. Amniocentesis may be used in women in preterm labor to assess fetal lung maturity and intraamniotic infection. Bed rest, hydration, and pelvic rest do not appear to improve the rate of preterm birth and should not be routinely recommended. References: |