INTRODUCTION
• Preterm delivery is one of the most serious problems in obstetrics. Prematurity is the leading cause of neonatal morbidity and mortality in the United States (1). Despite advances in research and medical care, the incidence of prematurity in the United States remains among the highest compared to other industrialized nations.
• The incidence of preterm birth peaked in 2006 and has slightly declined over the last 7 years.
• Spontaneous preterm birth is a multidimensional problem that includes preterm labor, preterm premature rupture of membranes, cervical insufficiency, and short cervix.
PRETERM LABOR
Key Points
• The complex mechanisms leading to preterm labor limit the effectiveness of any single treatment intervention.
• Preterm labor is diagnosed clinically by evidence of regular uterine contractions associated with cervical change.
• Tocolytic medications may prolong pregnancy for a short period of time (48 to 72 hours).
• Antenatal corticosteroids should be administered to women at risk of preterm delivery.
• Progesterone supplementation may reduce the rate of recurrent spontaneous preterm delivery in women with a prior spontaneous preterm birth. It may also reduce preterm birth risk in asymptomatic singleton pregnancies with midtrimester cervical shortening.
Background
Although the causes of preterm labor are not well understood, its clinical impact is clear. Infant prematurity is the leading cause of newborn morbidity, mortality, and health expenditure in the United States. The incidence of serious complications of prematurity increases dramatically as the gestational age at delivery decreases. Neonatal mortality also increases with declining gestational age at delivery (2). The serious complications of prematurity include, but are not limited to, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and patent ductus arteriosus. The costs related to these complications increase exponentially with the degree of prematurity. The economic burden attributed to preterm birth is estimated to be at least 26 billion dollars annually in the United States, with most of that cost incurred in the care of infant survivors of prematurity (3).
Definition
• Preterm labor is defined as regular uterine contractions associated with cervical change occurring from 20 to 36 6/7 weeks of gestational age.
Pathophysiology
• The pathophysiologic mechanisms that lead to the onset of preterm labor are complex and multifactorial. Because of this complexity, the identification of an effective intervention for preterm labor has been elusive.
• In addition to mechanisms as yet unknown, preterm labor likely occurs as a result of the concomitant activation or a cascade of the following events (4,5):
• Functional progesterone withdrawal
• Increase in corticotrophin-releasing hormone
• Premature decidual activation
• Increased prostaglandin production
• Oxytocin initiation
• Increased cytokine production
Etiology
Numerous factors contribute to the high incidence of preterm delivery, including the increase in pregnancies in women over 35 years of age and the increase in the incidence of multiple gestations due to more frequent use of artificial reproductive technologies (6).
There are a multitude of causes of preterm delivery. In general, preterm deliveries can be classified as (a) iatrogenic or indicated due to a significant maternal or fetal complication of pregnancy, (b) spontaneous due to preterm labor, or (c) a result of preterm, premature rupture of membranes (PROM). Spontaneous preterm labor accounts for approximately 50% of preterm deliveries. Iatrogenic prematurity and PROM constitute the remaining 50%, contributing approximately 25% each (7).
This chapter focuses on spontaneous preterm birth, which is divided primarily into two categories: preterm labor with intact membranes and PROM. In addition, we review cervical disorders that predispose a pregnant woman to spontaneous preterm birth: cervical insufficiency and asymptomatic short cervix.
Epidemiology
• The incidence of preterm delivery remains high, with the most recent estimate being 11.5% (8). Preterm delivery occurs more frequently in black women than in white women, especially at the very early gestational ages of less than 28 weeks (9). Of all etiologies of preterm birth, preterm labor is the major contributor.
• Risk factors for preterm labor include (10,11)
• Prior preterm delivery
• African American race
• Low socioeconomic status
• Lack of prenatal care
• Intense physical exertion or stress
• Low body mass index
• Extremes of maternal age (younger than 18 or older than 40)
• Tobacco use
• Substance abuse
• Prior induced abortion
• Prior cervical surgery
• Periodontal disease
• Uterine overdistension (i.e., multiple gestation or polyhydramnios)
• Vaginal bleeding during pregnancy
• Uterine anomaly
• Anemia
• Reproductive tract infections
• Short cervix in the midtrimester of pregnancy
• Numerous risk factor scoring systems have been proposed for the prediction of preterm labor. Unfortunately, these scoring systems have not been proven to reliably predict spontaneous preterm birth, and most lack clinically important reference standards (12).
Evaluation
History and Physical
• Symptoms may or may not be present in women presenting with preterm labor. When present, these symptoms may vary greatly. Some of the most common presenting symptoms of preterm labor are
• Rhythmic contractions (some women describe this as a feeling of “balling up”)
• Lower abdominal cramping
• Low back pain
• Pelvic pressure
• Increase in vaginal discharge
• Bloody vaginal discharge (bloody show)
• Cervical examination can be performed by any one or a combination of the following tools:
• Digital cervical exam:
A change in dilation and/or effacement of the cervix in the presence of regular uterine contractions is sufficient for the diagnosis of preterm labor.
Alternatively, regular uterine contractions and a cervix greater than 2 cm dilated or ≥80% effaced upon a single examination are sufficient for the diagnosis.
• Visual estimation of cervical dilation and effacement by speculum examination
• Ultrasonography of the cervix to measure cervical length (CL)
• In some cases where the diagnosis of preterm labor is uncertain, that is, frequent preterm contractions without cervical change or cervical dilation less than 2 cm, a combined approach of cervical length measurement and fFN testing may assist in the diagnosis. This approach has been shown to be reliable for diagnosis of PTL or exclusion of PTL compared to the standard approach of digital cervical exam (13,14).
Laboratory Tests
• Rectovaginal culture for group B streptococcus (GBS) (Streptococcus agalactiae) should be obtained.
• Wet mount (swab of vaginal secretions mixed with saline placed on a microscope slide). The presence of “clue cells” indicates bacterial vaginosis. The presence of flagellated microorganisms indicates Trichomonas vaginalis infection.
• Urinalysis and culture to evaluate for evidence of urinary tract infection or asymptomatic bacteriuria.
• Fetal fibronectin test from a swab of cervicovaginal secretions. This test
• Can be especially useful if the diagnosis of preterm labor is in question.
• Has a high negative predictive value. If negative, the risk of delivering in the upcoming 2 weeks is less than 1% (15).
• Has a relatively low positive predictive value if used alone. If positive, the risk of delivering in 1 week is 18% (16).
• Has a relatively high positive predictive value for preterm birth within a short period of time if used in combination with cervical length in symptomatic patients (13).
• Microscope slide of dried vaginal sidewall secretions (do not use a cover slip) to evaluate for evidence of “ferning,” which is suggestive of the diagnosis of PROM.
• This is only necessary if PROM is suspected based on patient’s history or exam.
• Avoid contaminating the slide with saline, which may result in the false appearance of ferning.
• Cervical mucus may also fern, so close attention should be paid to the collection of the specimen.
• A new test, AmniSure, may also be used for diagnosis of PROM. It has high screen accuracy for diagnosis of PROM.
• Cervical cultures for Chlamydia trachomatis and Neisseria gonorrhoeae may be collected as clinically indicated.
• Drug abuse screen, either serum or urine, as clinically indicated.
Ultrasound
• A thorough obstetrical ultrasound is helpful in evaluating the etiology of preterm labor in order to
• Identify obvious fetal malformations. Some major congenital malformations may be a contraindication to tocolysis, and some may warrant aggressive tocolysis.
• Identify abnormalities in fetal growth.
• Identify abnormalities in amniotic fluid volume (oligohydramnios or polyhydramnios).
• Confirm fetal presentation to aid in planning mode of delivery.
• Evaluate placenta, identifying its location and noting any abnormalities.
• Ultrasound evaluation of the cervix may help to further refine the risk of preterm delivery (15). Short cervical lengths are associated with an increased risk of preterm delivery.
• Cervical length of 30 mm or greater is useful to exclude the diagnosis of preterm labor.
• Short cervical lengths (less than 25 mm or less than 20 mm, depending on gestational age) may assist in confirming the diagnosis of preterm labor, especially when used in combination with positive fFN result (13).
Diagnosis
• Preterm labor is a clinical diagnosis. It should be suspected in any gravida with regular preterm uterine contractions and is confirmed with documented cervical change. The previously mentioned objective criteria may also be useful in establishing the diagnosis (fetal fibronectin and ultrasound measurement of cervical length).
Treatment
Bed Rest and Hydration
• There is no scientific evidence to prove that bed rest, although commonly prescribed, is useful in preventing or treating preterm labor. The American College of Obstetricians and Gynecologists (ACOG) states that “although bed rest and hydration have been recommended to women with symptoms of preterm labor to prevent preterm delivery, these measures have not been shown to be effective for the prevention of preterm birth and should not be routinely recommended. Furthermore, the potential harm, including venous thromboembolism, bone demineralization, and deconditioning, and the negative effects, such as loss of employment, should not be underestimated” (17).
• Hydration, both orally and intravenously, is commonly used in the treatment of preterm labor. Several studies that have evaluated the effect of hydration on preterm labor have demonstrated no benefit (18,19).
Tocolytic Medications
• Women who meet criteria for the diagnosis of preterm labor are candidates for tocolytic therapy. There is no clear “first-line” tocolytic medication (17). Little evidence exists that any tocolytic medication can effectively prolong gestation longer than 2 to 7 days (20). However, this short prolongation is usually sufficient to administer corticosteroids for fetal benefit and to transfer the patient to a tertiary care facility before delivery. These interventions have been shown to improve perinatal outcome.
• Tocolytic medications are, most often, given to women with preterm labor at less than 34 weeks of gestational age. After 34 weeks of gestation, the risk of complications of tocolytic therapy may outweigh the benefits of prolonging the pregnancy for a short period of time. After a determined period of time (48 hours), tocolytic therapy is usually discontinued because prolonged use of tocolysis may increase the maternal–fetal risk without offering a clear benefit (3). Eighty percent of women with presumed preterm labor subsequently deliver at term (15). Therefore, careful consideration should be given before initiating tocolytic therapy.
• There are a number of contraindications to tocolysis including, but not limited to, placental abruption, lethal fetal congenital anomaly, intrauterine infection (chorioamnionitis), severe preeclampsia, and evidence of fetal compromise (3).
• Calcium channel blockers (5,21):
• The most common calcium channel blocker used for tocolysis is nifedipine.
• Mechanism of action: decreases the influx of intracellular calcium ions into myometrial cells, promoting relaxation (22).
• Dosage: 20- to 30-mg loading dose, followed by 10 to 20 mg every 4 to 8 hours orally.
• Precautions: use with caution in patients with cardiac disease or renal disease and avoid concomitant use with magnesium sulfate.
• Side effects: flushing, headache, dizziness, hypotension, and peripheral edema.
• Complications: some side effects can be severe, resulting in the discontinuation of therapy in 2% to 5% of patients. Severe hypotension can occur if used with magnesium sulfate. There are no known adverse fetal effects.
• Magnesium sulfate:
• Tocolytic agent of choice of many obstetricians and perinatologists in the United States (23).
• Mechanism of action: inhibits smooth muscle contractions by inhibiting calcium uptake.
• Dosage: 4 to 6 g as intravenous (IV) bolus over 15 to 30 minutes, followed by 2 to 6 g/h (24). A common clinical approach is to start with a 6-g IV bolus followed by 3 g/h. The hourly rate is titrated until uterine contractions abate or until a serum level of 5 to 8 ng/dL is reached (25). Magnesium sulfate may be discontinued simply by ceasing IV infusion at any time. Weaning the drug is not necessary (26). Serum magnesium levels will slowly decrease as magnesium is cleared by the kidneys.
• Precautions: magnesium sulfate should be avoided in women with myasthenia gravis, cardiac impairment, renal impairment, or with concomitant use of a calcium channel blocker due to the potential of causing profound hypotension (24,27).
• Side effects: flushing, nausea, headache, drowsiness, and blurred vision. These are common side effects with therapeutic doses of magnesium and not necessarily evidence of magnesium toxicity.
• Complications:
Monitoring for evidence of magnesium toxicity should be performed at frequent intervals in all patients receiving magnesium tocolysis.
– Diminished or loss of deep tendon reflexes with serum magnesium levels of greater than 10 ng/dL.
– Respiratory depression (greater than 15 ng/dL).
– Cardiac arrest (greater than 18 ng/dL).
– Magnesium toxicity can be rapidly reversed with 1 g of IV calcium gluconate.
Pulmonary edema may occur, especially in women with multiple gestation, multiagent tocolytic therapy, or fluid overload (5).
• Ritodrine is the only medication approved by the Food and Drug Administration (FDA) for tocolysis in the United States. Ritodrine is associated with significant side effects and patient intolerance. Because of these side effects, ritodrine has not been marketed in the United States since 1998.
• Terbutaline is currently the most commonly used β-sympathomimetic and is β2 selective. Most studies have shown that it is effective in temporarily arresting preterm labor, but it does not reduce the rate of preterm delivery.
• Mechanism of action: stimulation of β receptors (some β2 selective), resulting in uterine smooth muscle relaxation.
• Dosage:
Subcutaneous: 0.25 mg every 20 minutes for 4 to 6 doses. Hold for pulse greater than 120 beats/min.
Subcutaneous pump: Although available, this method is not recommended due to increased risk of maternal cardiac toxicity and death. The FDA recommends against its use for more than 48 hours.
• Precautions: avoid or use with caution in patients with cardiac arrhythmias, diabetes, hyperthyroidism, or hypertension.
• Side effects: tachycardia, tremor, decreased appetite, and hypotension.
• Complications: pulmonary edema (especially with multiagent tocolysis), cardiac arrhythmias, hyperglycemia, hypokalemia, neonatal cardiac arrhythmias, and hypoglycemia.
• Prostaglandin synthase inhibitors (5,29):
• Agents available: aspirin, ibuprofen, indomethacin, sulindac, ketorolac. Indomethacin is the most commonly used agent.
• Mechanism of action: inhibition of prostaglandin synthetase or cyclooxygenase, blocking prostaglandin production.
• Dosage: indomethacin can be administered orally, rectally, or vaginally. Common regimens include a 50- to 100-mg loading dose, followed by 25 mg every 6 to 8 hours. Many obstetricians limit the use to 48 to 72 hours to avoid complications (30).
• Precautions: contraindicated in patients with active peptic ulcer disease, sensitivity to nonsteroidal anti-inflammatory drugs, significant renal or hepatic impairment, or hematologic abnormalities (especially thrombocytopenia).
• Side effects: nausea and gastrointestinal upset.
• Complications: indomethacin use has been associated with several fetal and neonatal complications, including premature closure of the fetal ductus arteriosis (especially at gestational ages greater than 32 weeks) (31), pulmonary hypertension, oligohydramnios, intraventricular hemorrhage, and necrotizing enterocolitis. Most of these reported complications occurred in pregnancies with prolonged administration, and these results should be viewed with caution due to multiple potential confounders (32).
• Multiple-agent tocolysis:
• No clear evidence exists that combining tocolytic drugs improves efficacy. Combining tocolytic agents potentially increases the risk of maternal and neonatal complications (17). Using multiple tocolytic agents simultaneously should be approached with caution.
• Maintenance tocolysis:
• No clear evidence exists that maintenance tocolysis increases gestational age at birth, increases birth weight, or effectively prolongs pregnancy (33).
Corticosteroids
• Antepartum corticosteroids effectively reduce the incidence of neonatal respiratory distress, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death in preterm infants. A single course of corticosteroids should be administered to all pregnant women between 24 and 34 weeks of gestation who are at risk of preterm delivery within 7 days (34).
• Either betamethasone or dexamethasone may be used. Neither the National Institutes of Health (NIH) nor the American College of Obstetricians and Gynecologists (ACOG) recommend the use of one over the other (35).
• Betamethasone, 12 mg intramuscularly (IM) every 24 hours for two doses
• Dexamethasone, 6 mg IM every 12 hours for four doses
• A single additional dose may be considered if the initial dose was given more than 2 weeks prior and there is additional risk for preterm delivery, as recommended by ACOG. Multiple repeat doses of steroids have not been shown to provide added benefit and may be harmful (35).
Magnesium Sulfate for Neuroprotection
• Several studies have been published to evaluate the use of magnesium prior to delivery of a preterm infant to assess the reduction in risk of neonatal complications (36–40).
• Meta-analyses of these studies have shown that there is a reduction of the incidence of cerebral palsy in these preterm infants when exposed to magnesium sulfate prior to delivery (41,42).
• ACOG Committee on Obstetric Practice has recognized this reduction in the risk of cerebral palsy and has recommended that institutions choosing to use magnesium sulfate for neuroprotection should “develop specific guidelines regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials” (43).
Antibiotics
• There is no evidence that treating women with preterm labor with antibiotics is effective in prolonging pregnancy, and this practice is not recommended (35).
• Antibiotic prophylaxis to prevent GBS sepsis in the newborn is recommended in women with preterm labor (44). The Centers for Disease Control and Prevention recommends GBS culture of all women in preterm labor. If the culture is negative within 4 weeks of delivery, prophylaxis is not recommended.
Prevention
• Progesterone
• Studies have demonstrated that progesterone given to women with a history of spontaneous preterm birth can effectively decrease the incidence of recurrent preterm birth in a subsequent pregnancy (45). The optimal formulation for this indication has not been identified, but the most commonly used agent, based on data from the largest clinical trial, is
17-Hydroxyprogesterone caproate.
Dose: 250 mg IM weekly initiated at 16 to 20 weeks of gestational age and continued until 37.
Other studies have demonstrated that women with a singleton pregnancy and asymptomatic cervical shortening in the midtrimester of pregnancy (less than 20 mm) benefit from vaginal progesterone therapy (45).
Micronized progesterone 200 mg capsule, one per vagina once daily.
Progesterone 8% vaginal gel, one applicator daily.
Complications of Preterm Labor
• There are a number of complications that may be either the cause or the result of preterm labor:
• Placental abruption
• Intra-amniotic infection (chorioamnionitis)
• PROM
Patient Education
• Incidence of preterm delivery in patients with preterm labor:
• Eighty percent of women with presumptive preterm labor go on to deliver at term (15).
• Recurrence of preterm labor in future pregnancies:
• The incidence of recurrent, spontaneous preterm birth varies greatly in numerous series (from 15% to greater than 50%).
• The risk increases with multiple factors, including a history of a very early preterm delivery (i.e., less than 28 weeks of gestational age) (46).
PRETERM, PREMATURE RUPTURE OF THE MEMBRANES
Key Points
• PPROM accounts for 25% to 30% of all preterm deliveries.
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