Threshold of Viability
It appears generally accepted that births before 26 weeks, especially those weighing less than 750 g, are at the current threshold of viability and that these preterm infants pose a variety of complex medical, social, and ethical considerations (American College of Obstetricians and Gynecologists, 2002, 2008c). For example, Sidney Miller is a child who was born at 23 weeks, weighed 615 g, and survived but developed severe physical and mental impairment (Annas, 2004). At age 7 years, she was described as a child who "could not walk, talk, feed herself, or sit up on her own . . . was legally blind, suffered from severe mental retardation, cerebral palsy, seizures and spastic quadriparesis in her limbs." An important issue for her family was the need for a lifetime of medical care estimated to cost tens of millions of dollars
According to current guidelines developed by the American Academy of Pediatrics (Braner and co-workers, 2000), it is considered appropriate not to initiate resuscitation for infants younger than 23 weeks or those whose birthweight is less than 400 g. The involvement of the family is considered critical to the decision-making process with regard to resuscitation. Thus, infants now considered to be at the threshold of viability are those born at 22, 23, 24, or 25 weeks. These infants have been described as fragile and vulnerable because of their immature organ systems (Vohr and Allen, 2005). Moreover, they are at high risk for brain injury from hypoxic-ischemia injury and sepsis (Stoll and associates, 2004). In this setting, hypoxia and sepsis start a cascade of events that lead to brain hemorrhage, white-matter injury that causes.periventricular leukomalacia, and poor subsequent brain growth eventuating in neurodevelopmental impairment (see Chap. 29, Periventricular Leukomalacia). It is thought that because active brain development normally occurs throughout the second and third trimesters, those infants born at 22 to 25 weeks are especially vulnerable to brain injury because of their extreme immaturity.
Considerable outcome data for preterm live births between 22 and 25 weeks have become available since the last edition of this textbook. Shown in Table 36-3 are rates of overall survival as well as survival with selected complications in 250-g birthweight increments for very-low-birthweight infants. Of those with birthweights 500 to 750 g, only 55 percent survived, and most had severe complications. Survival, even with no complications apparent at initial hospital discharge, does not preclude serious developmental impairment at age 8 to 9 years (Fig. 36-3). Importantly, survival of very low-birthweight infants with and without complications of prematurity was not substantially improved when two epochs—1997 to 2002 and 1995 to 1996 are compared (Eichenwald and Stark, 2008). Saigal and Doyle (2008) collated 16 reports based on geographically defined cohorts from Australia and several European countries. Survival increased progressively from 1.7 percent at 22 weeks to 54 percent at 25 weeks. Overall, 25 percent of infants born at 22 to 25 weeks had severe neurological disabilities, and 72 percent of those with birthweights < 750 g experienced difficulty in school. Marlow and colleagues (2005) identified all infants born between 22 and 25 weeks in the United Kingdom and Ireland between March and December 1995 and examined the children at age 6 years. As shown in Table 36-4, survival was rare at 22 weeks—only 2 of 138 infants lived. This rate increased to 10 percent, 26 percent, and 43 percent, at 23, 24 and 25 weeks, respectively. Moderate to severe disability at age 6 years was identified in more than 90 percent of infants surviving following birth at 22 to 24 weeks. As shown in Figure 36-4, cognitive scores were much lower for infants born at 22 to 25 weeks compared with those of normal term births.
Importantly, female gender, singleton pregnancy, corticosteroids given for lung maturation, and higher gestational age improved the prognosis for these infants born at the threshold of viability.
Cesarean delivery at the threshold of viability is controversial. For example, if the fetus-infant is perceived to be too immature for aggressive support, then cesarean delivery for common indications such as breech presentation or nonreassuring fetal heart rate patterns might be preempted. This aside, national data clearly show a high frequency of cesarean delivery for the smallest infants (Fig. 36-5). Moreover, neonatal mortality rates in the very smallest infants—500 to 700 g—are approximately half if cesarean delivery is used compared with vaginal birth
Parkland guidelines: From an obstetrical standpoint, all fetal indications for cesarean delivery in more advanced pregnancies are practiced in women at 25 weeks. Cesarean delivery is not offered for fetal indications at 23 weeks. At 24 weeks, cesarean delivery is not offered unless fetal weight is estimated at 750 g or greater. Aggressive obstetrical management is practiced in cases of growth restriction.
Late Preterm Birth
Infants between 34 and 36 weeks account for approximately 75 percent of all preterm births, as shown in Figure 36-7, and are the fastest increasing and largest proportion of singleton preterm births in the United States
Thus, late preterm births accounted for three fourths of all preterm births. Approximately 80 percent of late preterm births were due to idiopathic spontaneous preterm labor or prematurely ruptured membranes (Fig. 36-8). Complications such as hypertension or placental accidents were implicated in approximately 20 percent of cases. Neonatal mortality rates were significantly increased in each late preterm week compared with those at 39 weeks as the referent and as shown in Figure 36-9.
Reasons for Preterm Delivery
There are four main direct reasons for preterm births in the United States:
1. Delivery for maternal or fetal indications in which labor is induced or the infant is delivered by prelabor cesarean delivery
2. Spontaneous unexplained preterm labor with intact membranes
3. Idiopathic preterm premature rupture of membranes (PPROM)
4. Twins and higher-order multifetal births.
Of preterm births, 30 to 35 percent are indicated, 40 to 45 percent are due to spontaneous preterm labor, and 30 to 35 percent follow preterm rupture of membranes. Reasons for preterm birth have multiple, often interacting, antecedents and contributing factors. This complexity has greatly confounded efforts to prevent and manage this complication. This is particularly true for preterm ruptured membranes and spontaneous preterm labor, which together lead to 70 to 80 percent of preterm births.
Medical and Obstetrical Indications
Ananth and Vintzileos (2006) used Missouri birth data from 1989 to 1997 to analyze factors leading to indicated birth before 35 weeks. Preeclampsia, fetal distress, small for gestational age, and placental abruption were the most common indications for medical intervention resulting in preterm birth. Other less common causes were chronic hypertension, placenta previa, unexplained bleeding, diabetes, renal disease, Rh isoimmunization, and congenital malformations.
Preterm Prematurely Ruptured Membranes
Defined as rupture of the membranes before labor and prior to 37 weeks, preterm premature rupture of membranes can result from a wide array of pathological mechanisms, including intra-amnionic infection. Other factors implicated include low socioeconomic status, low body mass index—less than 19.8, nutritional deficiencies, and cigarette smoking. Women with prior preterm ruptured membranes are at increased risk for recurrence during a subsequent pregnancy (Bloom and associates, 2001). Most cases of preterm rupture, however, occur without risk factors
Spontaneous Preterm Labor
Most commonly, preterm birth—up to 45 percent of cases—follows spontaneous labor. Goldenberg and colleagues (2008b) reviewed the pathogenesis of preterm labor and implicated: (1) progesterone withdrawal, (2) oxytocin initiation, and (3) decidual activation. Deviations from normal fetal growth have also been noted in spontaneous preterm labor and suggest a fetal role (Morken and co-workers, 2006).
The progesterone withdrawal theory stems from studies in sheep. As parturition nears, the fetal-adrenal axis becomes more sensitive to adrenocorticotropic hormone, increasing the secretion of cortisol (see Chap. 6, Actions of Corticotropin-Releasing Hormone on the Fetal Adrenal Gland). Fetal cortisol stimulates placental 17--hydroxylase activity, which decreases progesterone secretion and increases estrogen production. The reversal in the estrogen/progesterone ratio results in increased prostaglandin formation, which initiates a cascade that culminates in labor. In human beings, serum progesterone concentrations do not fall as labor approaches. Even so, because progesterone antagonists such as RU486 initiate preterm labor and progestational agents prevent preterm labor, decreased local progesterone concentrations may play a role.
Because intravenous oxytocin increases the frequency and intensity of uterine contractions, oxytocin is assumed to play a part in labor initiation. But serum concentrations of oxytocin do not rise before labor, and the clearance of oxytocin remains constant. Accordingly, oxytocin is an unlikely initiator.
An important pathway leading to labor initiation implicates inflammatory decidual activation. At term, such activation seems to be mediated at least in part by the fetal-decidual paracrine system and perhaps through localized decreases in progesterone concentration. In many cases of early preterm labor, however, decidual activation seems to arise in the context of intrauterine bleeding or occult intrauterine infection.
Threatened Abortion
Vaginal bleeding in early pregnancy is associated with increased adverse outcomes later
Cigarette smoking, inadequate maternal weight gain, and illicit drug use have important roles in both the incidence and outcome of low-birthweight neonates (see Chap. 14, Tobacco). In addition, Ehrenberg and colleagues (2009) found that overweight women at risk for preterm birth had lower rates of preterm delivery before 35 weeks than at-risk women with normal weight. Some of these effects are undoubtedly due to restricted fetal growth, but Hickey and colleagues (1995) linked prenatal weight gain specifically with preterm birth. Other maternal factors implicated include young or advanced maternal age, poverty, short stature, vitamin C deficiency, and occupational factors such as prolonged walking or standing, strenuous working conditions, and long weekly work hours
In the United States and in the United Kingdom, women classified as black, African-American, and Afro-Caribbean are consistently reported to be at higher risk of preterm birth.
Studies of work and physical activity related to preterm birth have produced conflicting results (Goldenberg and colleagues, 2008b). There is some evidence, however, that working long hours and hard physical labor are probably associated with increased risk of preterm birth.
Vergnes and Sixou (2007) performed a meta-analysis of 17 studies and concluded that periodontal disease was significantly associated with preterm birth—odds ratio 2.83 (CI 1.95–4.10). In an accompanying editorial, Stamilio and colleagues (2007) concluded that the data used were not robust enough to recommend screening and treatment of pregnant women.
Birth Defects
Short intervals between pregnancies have been known for some time to be associated with adverse perinatal outcomes. In a recent meta-analysis, Conde-Agudelo and co-workers (2006) reported that intervals shorter than 18 months and longer than 59 months were associated with increased risks for both preterm birth and small-for-gestational age infants. Prior Preterm Birth
A major risk factor for preterm labor is prior preterm delivery (Spong, 2007). Shown in Table 36-6 is the incidence of recurrent preterm birth in nearly 16,000 women delivered at Parkland Hospital (Bloom and associates, 2001). The risk of recurrent preterm delivery for women whose first delivery was preterm was increased threefold compared with that of women whose first neonate was born at term Self-reported coitus during early pregnancy was not associated with an increased risk of recurrent preterm birth (Yost and co-workers, 2006).
Infection: It is hypothesized that intrauterine infections trigger preterm labor by activation of the innate immune system. In this hypothesis, microorganisms elicit release of inflammatory cytokines such as interleukins and tumor necrosis factor (TNF), which in turn stimulate the production of prostaglandin and/or matrix-degrading enzymes. Prostaglandins stimulate uterine contractions, whereas degradation of extracellular matrix in the fetal membranes leads to preterm rupture of membranes. It is estimated that 25 to 40 percent of preterm births result from intrauterine infection. Potential routes of intrauterine infection are shown in Figure 36-10.
Two microorganisms, Ureaplasma urealyticum and Mycoplasma hominis, have emerged as important perinatal pathogens. Goldenberg and colleagues (2008a) reported that 23 percent of neonates born between 23 and 32 weeks have positive umbilical blood cultures for these genital mycoplasmas.
Morency and Bujold (2007) performed a meta-analysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth. Andrews and colleagues (2006) reported results of a double-blind interconceptional trial from the University of Alabama in Birmingham. A course of azithromycin plus metronidazole was given every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery before 34 weeks. Approximately 80 percent of the women with subsequent pregnancies had received study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth. Tita and co-workers (2007) performed a subgroup analysis of these same data and concluded that such use of antimicrobials may be harmful. In another study, Goldenberg and colleagues (2006) randomized 2661 women at four African sites to placebo or metronidazole plus erythromycin between 20 and 24 weeks followed by ampicillin plus metronidazole during labor. This antimicrobial regimen did not reduce the rate of preterm birth nor that of histological chorioamnionitis.
Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, preterm rupture of membranes, chorioamnionitis, and amnionic fluid infection
Diagnosis
Early differentiation between true and false labor is difficult before there is demonstrable cervical effacement and dilatation. Uterine activity alone can be misleading because of Braxton Hicks contractions, which are discussed in detail in Chapter 18, Patterns of Uterine Activity. These contractions, described as irregular, nonrhythmical, and either painful or painless, can cause considerable confusion in the diagnosis of true preterm labor. Not infrequently, women who deliver before term have uterine activity that is attributed to Braxton Hicks contractions, prompting an incorrect diagnosis of false labor. Because uterine contractions alone may be misleading, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (1997) had earlier proposed the following criteria to document preterm labor:
1. Contractions of four in 20 minutes or eight in 60 minutes plus progressive change in the cervix
2. Cervical dilatation greater than 1 cm
3. Cervical effacement of 80 percent or greater
In addition to painful or painless uterine contractions, symptoms such as pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain have been empirically associated with impending preterm birth
Cervical Dilatation
Asymptomatic cervical dilatation after midpregnancy is suspected as a risk factor for preterm delivery, although some clinicians consider it to be a normal anatomical variant, particularly in parous women. Studies, however, have suggested that parity alone is not sufficient to explain cervical dilatation discovered early in the third trimester. Cook and Ellwood (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks in both nulliparous and parous women who all subsequently gave birth at term. Cervical length and diameter were identical in both groups throughout these critical weeks.
Iams and co-workers (1996) measured cervical length at approximately 24 weeks and again at 28 weeks in 2915 women not at risk for preterm birth. The mean cervical length at 24 weeks was approximately 35 mm, and those women with progressively shorter cervices experienced increased rates of preterm birth.
These investigators correlated sonographic cervical length, funneling, and prior history of preterm birth with delivery before 35 weeks. Funneling was defined as bulging of the membranes into the endocervical canal and protruding at least 25 percent of the entire cervical length (Fig. 36-11). As shown in Figure 36-12, a short cervix by itself was the poorest predictor of preterm birth, whereas funneling plus a history of prior preterm birth was highly predictive.
Incompetent Cervix
Cervical incompetence is a clinical diagnosis characterized by recurrent, painless cervical dilatation and spontaneous midtrimester birth in the absence of spontaneous membrane rupture, bleeding, or infection
Fibronectin: Lockwood and co-workers (1991) reported that fibronectin detection in
Prevention of Preterm Birth
Weekly intramuscular injections of either inert oil or 17-hydroxyprogesterone caproate were given from 16 through 36 weeks. Rates of delivery before 37, 35, and 32 weeks were all significantly reduced by progestin therapy. But similar studies of 17-hydroxyprogesterone caproate in both twins and triplets done by the Network showed no improvement in preterm birth rates. In the first study, 142 women with a prior preterm birth, prophylactic cervical cerclage, or uterine malformation were randomly assigned to daily 100-mg progesterone or placebo suppositories. Progesterone suppositories were associated with a significant reduction in births before 34 weeks.
At this time, the American College of Obstetricians and Gynecologists (2008c) has concluded that progesterone therapy should be limited to women with a documented history of a previous spontaneous birth at less than 37 weeks. Further studies are needed as to optimal preparation, dosage, and route of administration.
Cervical Cerclage
There are at least three circumstances when cerclage placement may be used to prevent preterm birth. First, cerclage may be used in women who have a history of recurrent midtrimester losses and who are diagnosed with an incompetent cervix (see Chap. 9, Incompetent Cervix). A second circumstance is in women identified during sonographic examination to have a short cervix. The third indication is "rescue" cerclage, done emergently when cervical incompetence is recognized in the women with threatened preterm labor
Management of Preterm Rupture of Membranes and Preterm Labor
Diagnosis of Preterm Prematurely Ruptured Membranes – check
Although this complication was identified in only 1.7 percent of pregnancies, it contributed to 20 percent of all perinatal deaths. By the time they presented, 75 percent of the women were already in labor, 5 percent were delivered for other complications, and another 10 percent were delivered within 48 hours. The time from preterm ruptured membranes to delivery is inversely proportional to the gestational age when rupture occurs (Carroll and associates, 1995). As shown in Figure 36-15, very few days were gained when membranes ruptured during the third trimester compared with midpregnancy
Most clinicians hospitalize women with preterm ruptured membranes. Concerns about the costs of lengthy hospitalizations are usually moot, because most women enter labor within a week or less after membrane rupture. Carlan and co-workers (1993) randomly assigned 67 women with ruptured membranes to home or hospital management. No benefits were found for hospitalization, and maternal hospital stays were reduced by 50 percent in those sent home.
Fetal lung maturity, as evidenced by mature surfactant profiles, was present in all cases. Intentional delivery reduced the length of maternal hospitalization and also reduced infection rates in both mothers and neonates. Cox and Leveno (1995) similarly apportioned 129 women between 30 and 34 weeks. Fetal lung maturity was not assessed. One fetal death resulted from sepsis in the pregnancies managed expectantly. Among those intentionally delivered, there were three neonatal deaths—two from sepsis and one from pulmonary hypoplasia. Thus, neither management approach proved to be superior.
Despite extensive literature concerning expectant management of preterm ruptured membranes, tocolysis has been used in few studies. In randomized studies, women were assigned to receive either tocolysis or expectant management. The investigators concluded that active interventions did not improve perinatal outcomes.
McElrath and associates (2002) studied 114 women with cerclage in place who later had ruptured membranes prior to 34 weeks. They were compared with 288 controls who had not received a cerclage. Pregnancy outcomes were equivalent in both groups.
Risks of Expectant Management
Maternal and fetal risks vary with the gestational age at membrane rupture. Morales and Talley (1993b) expectantly managed 94 singleton pregnancies with ruptured membranes prior to 25 weeks. The average time gained was 11 days. Although 41 percent of infants survived to age 1 year, only 27 percent were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their associates. Lieman and colleagues (2005) found no improved neonatal outcomes with expectant management beyond 33 weeks. In contrast, McElrath and co-workers (2003) found that prolonged latency after membrane rupture was not associated with an increased incidence of fetal neurological damage
Virtually all women with oligohydramnios delivered before 25 weeks, whereas 85 percent with adequate amnionic fluid volume were delivered in the third trimester. Carroll and colleagues (1995) observed no cases of pulmonary hypoplasia in fetuses born after membrane rupture at 24 weeks or beyond. This suggests that 23 weeks or less is the threshold for development of lung hipoplasia.
Corioamnionitis: Clinical Chorioamnionitis
Most authors report that prolonged membrane rupture is associated with increased fetal and maternal sepsis (Ho and colleagues, 2003). If chorioamnionitis is diagnosed, prompt efforts to effect delivery, preferably vaginally, are initiated. Fever is the only reliable indicator for this diagnosis, and temperature of 38°C (100.4°F) or higher accompanying ruptured membranes implies infection. Maternal leukocytosis alone has not been found to be reliable. During expectant management, monitoring for sustained maternal or fetal tachycardia, for uterine tenderness, and for a malodorous vaginal discharge is warranted
Accelerated Pulmonary Maturation
A variety of clinical events—some well defined—were once proposed to accelerate fetal surfactant production (Gluck, 1979). These included chronic renal or cardiovascular disease, hypertensive disorders, heroin addiction, fetal-growth restriction, placental infarction, chorioamnionitis, and preterm ruptured membranes. Although this view was widely held for many years, subsequent observations do not support this association
Antimicrobial therapy: To further address this issue, the Maternal-Fetal Medicine Units Network designed a trial to study expectant management combined with a 7-day treatment of ampicillin, amoxicillin plus erythromycin, or placebo. The women had membrane rupture between 24 and 32 weeks. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had significantly fewer newborns with respiratory distress syndrome, necrotizing enterocolitis, and composite adverse outcomes (Mercer and colleagues, 1997). The latency period was significantly longer. Specifically, 50 percent of women given an antimicrobial regimen remained undelivered after 7 days of treatment compared with only 25 percent of those given placebo. There was also significant prolongation of pregnancy at 14 and 21 days. Cervicovaginal group B streptococcal colonization did not alter these results
Corticosteroids: Since then, a number of meta-analyses have addressed this issue, and according to the American College of Obstetricians and Gynecologists (2007), single-dose therapy is recommended from 24 to 32 weeks. There is no consensus regarding treatment between 32 and 34 weeks. They are not recommended prior to 24 weeks.
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Preterm Labor with Intact Membranes
Women with signs and symptoms of preterm labor with intact membranes are managed much the same as described above for those with preterm ruptured membranes. The cornerstone of treatment is to avoid delivery prior to 34 weeks, if possible. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed
The American College of Obstetricians and Gynecologists (2003) has concluded that there is no evidence to support routine amniocentesis to identify infection.
The issue of the fetal and infant safety with single versus repeat courses of corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneficial in reducing neonatal respiratory morbidity rates, the long-term consequences were much different. Specifically, Crowther and colleagues (2007) studied outcomes in 982 women from the Australian Collaborative Study. These women were given a single weekly dose of 11.4 mg of betamethasone. These investigators found no adverse effects in the infants followed to age 2 years. Wapner and colleagues (2007) studied infants born to 495 women in a Network study who were randomized to receive two weekly 12-mg betamethasone doses given 24 hours apart. They were concerned by their finding of a nonsignificant increase in cerebral palsy rates in infants exposed to repeated courses. The twice-as-large betamethasone dose in the Network study was worrisome because there is some experimental evidence to support the view that adverse corticosteroid effects are dose dependent. Bruschettini and colleagues (2006) studied the equivalent of 12-mg versus 6-mg betamethasone given to pregnant cats. They reported that the lower dose had less severe effects on somatic growth without affecting cell proliferation in the fetal brain.
"Rescue" Therapy
This refers to administration of a repeated corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. The 2000 Consensus Development Conference recommended that rescue therapy should not be routinely used and that it should be reserved for clinical trials. The first randomized trial reported by Peltoniemi and colleagues (2007) allocated 326 women to placebo or 12-mg betamethasone single-dose rescue regimens. Paradoxically, they found that the rescue dose of betamethasone increased the risk of respiratory distress syndrome! Subsequently, the American College of Obstetricians and Gynecologists (2008a) also recommended such therapy for trials
Elimian and co-workers (2007) randomized 299 women between 24 and 33 weeks in a double-blinded trial of betamethasone versus dexamethasone. These two drugs were comparable in reducing the rates of major neonatal morbidities in preterm infants.
Antimicrobials: As with preterm ruptured membranes, antimicrobials have been given to arrest preterm labor. Here too, results have been disappointing. A Cochrane meta-analysis by King and Flenady (2000) of 10 randomized trials found no difference in the rates of newborn respiratory distress syndrome or of sepsis between placebo- and antimicrobial-treated groups.
Emergency or Rescue Cerclage There is support for the concept that cervical incompetence and preterm labor are part of a spectrum leading to preterm delivery. Consequently, investigators have evaluated the role of cerclage done after preterm labor begins to manifest clinically. Harger (1983) concluded that if cervical incompetence is recognized with threatened preterm labor, emergency cerclage can be attempted, albeit with an appreciable risk of infection and pregnancy loss. Althuisius and associates (2003) randomly assigned 23 women with cervical incompetence prior to 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with that of bed rest alone—54 versus 24 days.
Inhibition of Preterm Labor
Although a number of drugs and other interventions have been used to prevent or inhibit preterm labor, none has been shown to be completely effective. The American College of Obstetricians and Gynecologists (2007) has concluded that tocolytic agents do not markedly prolong gestation, but may delay delivery in some women for at least 48 hours. This may facilitate transport to a regional obstetrical center and allow time for administration of corticosteroid therapy. It is estimated that 72,733 women giving birth in the United States in 2006 received tocolytic drugs (Martin and colleagues, 2009). The rate of tocolysis use was 1.7 percent in 2006, a rate that has fluctuated only slightly since 1996. Norwitz and co-workers (2004) performed an interactive survey of tocolytic treatment at the 2004 Annual Meeting of the Society of Maternal-Fetal Medicine. As shown in Figure 36-16, intravenous magnesium sulfate was the most commonly used tocolytic—about 70 percent of respondents. Approximately the same proportion of respondents would not prescribe maintenance therapy
Bed Rest
Hydration and Sedation
Helfgott and associates (1994) compared hydration and sedation with bed rest in a randomized trial of 119 women with threatened preterm labor. Women who were randomly selected to receive 500 mL of crystalloid over 30 minutes and 8 to 12 mg of intramuscular morphine sulfate had outcomes similar to those prescribed bed rest. Although women with preterm contractions treated with 0.25-mg subcutaneous terbutaline may have contractions that cease more quickly and may be discharged significantly earlier compared with women not treated, pregnancy outcomes are similar
-Adrenergic Receptor Agonists: A number of compounds react with -adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (see Chap. 6, Regulation of Myometrial Contraction and Relaxation). In the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine had been approved for preterm labor by the Food and Drug Administration.
Ritodrine: In a multicenter trial, neonates whose mothers were treated with ritodrine for threatened preterm labor had lower rates of death and respiratory distress. They also achieved a gestational age of 36 weeks or a birthweight of 2500 g more often than did those of untreated mothers (
The infusion of -agonists has resulted in frequent and at times, serious and fatal side effects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 42. Tocolysis was the third most common cause of acute respiratory distress and death in pregnant women during a 14-year period in Mississippi (Perry and associates, 1996). The cause of pulmonary edema is multifactorial, and risk factors include tocolytic therapy with -agonists, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and large intravenous crystalloid volume infusion. Because -agonists cause retention of sodium and water, with time—usually 24 to 48 hours, these can cause volume overload (Hankins and colleagues, 1988). The drugs have been implicated as a cause of increased capillary permeability, disturbance of cardiac rhythm, and myocardial ischemia. Finally, maternal sepsis—a relatively common occurrence with preterm labor—appreciably increases this risk
Terbutaline: Elliott and co-workers (2004) have used continuous terbutaline subcutaneous infusion in 9359 patients and reported that only 12 women experienced severe adverse events—primarily pulmonary edema. Two randomized trials found no benefit for terbutaline pump therapy. Oral terbutaline therapy to prevent preterm delivery has also not been effective.
Magnesium Sulfate
Ionic magnesium in a sufficiently high concentration can alter myometrial contractility. Its role is presumably that of a calcium antagonist. Clinically, magnesium in pharmacological doses may inhibit labor. Steer and Petrie (1977) concluded that intravenously administered magnesium sulfate—a 4-g loading dose followed by a continuous infusion of 2 g/hr—usually arrests labor. Women given magnesium sulfate must be monitored closely for evidence of hypermagnesemia. PE in 8.5%. These women were at appreciable risk, and few reached 33 weeks. Magnesium-treated women and their fetuses had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital.
In intriguing reports, very-low-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether and associates, 2000; Nelson and Grether, 1995). This was logical, as magnesium has been shown in adults to stabilize intracranial tone, minimize fluctuations in cerebral blood flow, reduce reperfusion injury, and block calcium-mediated intracellular damage (Aslanyan and colleagues, 2007; Marret and associates, 1995). Magnesium reduces synthesis of cytokines and bacterial endotoxins and thus, also may minimize the inflammatory effects of infection (Nelson and Grether, 1997.
This trial was interpreted differently depending upon statistical philosophy. Those who disdain subgroup analysis opted to interpret these findings to mean that magnesium sulfate infusion prevents cerebral palsy regardless of the gestational age at which the therapy is given. Those with a differing view concluded that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks. What is certain, however, is that maternally administered magnesium sulfate infusions cannot be implicated in increased perinatal deaths as reported by Mittendorf and colleagues (1997.
Because of these findings, at Parkland Hospital, our policy is to give magnesium sulfate for threatened preterm delivery from 24 to 28 completed weeks. At the University of Alabama at Birmingham Hospital, we administer neuroprotection magnesium from 23 to 32 completed weeks. In both, a 6-g loading dose is followed by an infusion of 2 g per hour for at least 12 hours.
Morales and co-workers (1989, 1993a), however, compared indomethacin with either ritodrine or magnesium sulfate and found no difference in their efficacy to forestall preterm delivery. Berghella and colleagues (2006) reviewed four trials of indomethacin given to women with sonographically short cervices and found such therapy to be ineffective.
Indomethacin is administered orally or rectally. A dose of 50 to 100 mg is followed at 8-hour intervals not to exceed a total 24-hour dose of 200 mg. Serum concentrations usually peak 1 to 2 hours after oral administration, whereas levels after rectal administration peak slightly sooner. Most studies have limited indomethacin use to 24 to 48 hours because of concerns of oligohydramnios, which can develop with these doses. If amnionic fluid is monitored, oligohydramnios can be detected early, and it is reversible with discontinuation of indomethacin
Case-control studies have been performed to assess neonatal effects of indomethacin exposure given for preterm labor. In a study of neonates born before 30 weeks, Norton and associates (1993) identified necrotizing enterocolitis in 30 percent of 37 indomethacin-exposed newborns compared with 8 percent of 37 control newborns. Higher incidences of intraventricular hemorrhage and patent ductus arteriosus were also documented in the indomethacin group. The impact of treatment duration and its timing in relation to delivery were not reported. In contrast, several investigators have challenged the association between indomethacin exposure and necrotizing enterocolitis (Muench and co-workers, 2001; Parilla and colleagues, 2000.
Using the Cochrane Database, Keirse (1995a) compared nifedipine and -agonists and concluded that although nifedipine treatment reduced births of neonates weighing less than 2500 g, significantly more of these were admitted for intensive care. Other investigators have also concluded that calcium-channel blockers, especially nifedipine, are safer and more effective tocolytic agents than are -agonists (King and colleagues, 2003; Papatsonis and co-workers, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks to either magnesium sulfate or nifedipine and found no substantial differences in efficacy or adverse effects. Finally, oral nifedipine does not significantly prolong pregnancy in women initially treated with intravenous magnesium sulfate for preterm labor (Carr and colleagues, 1999).
The combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami and co-workers (1994) and Kurtzman and associates (1993) reported that nifedipine enhances neuromuscular blocking effects of magnesium that can interfere with pulmonary and cardiac function
In randomized clinical trials, however, atosiban failed to improve relevant neonatal outcomes and was linked with significant neonatal morbidity.
In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. In a meta-analysis of tocolytic therapy, Gyetvai and colleagues (1999) concluded that although delivery may be delayed long enough for administration of corticosteroids, treatment does not result in improved perinatal outcome. Berkman and associates (2003) reviewed 60 reports and concluded that tocolytic therapy can prolong gestation, but that 
-agonists are not better than other drugs and pose potential maternal danger. They also concluded that there are no benefits of maintenance tocolytic therapy.
As a general rule, if tocolytics are given, they should be given concomitantly with corticosteroids. The gestational age range for their use is debatable, but because corticosteroids are not generally used after 33 weeks and because the perinatal outcomes in preterm neonates are generally good after this time, most practitioners do not recommend use of tocolytics at or after 33 weeks (
Recommended Management of Preterm Labor
The following considerations should be given to women in preterm labor:
1. Confirmation of preterm labor as detailed in Diagnosis
2. For pregnancies less than 34 weeks in women with no maternal or fetal indications for delivery, close observation with monitoring of uterine contractions and fetal heart rate is appropriate. Serial examinations are done to assess cervical changes
3. For pregnancies less than 34 weeks, corticosteroids are given for enhancement of fetal lung maturation
4. Consideration is given for maternal magnesium sulfate infusion for 12 to 24 hours to afford fetal neuroprotection
5. For pregnancies less than 34 weeks in women who are not in advanced labor, some practitioners believe it is reasonable to attempt inhibition of contractions to delay delivery while the women are given corticosteroid therapy and group B streptococcal prophylaxis. Although tocolytic drugs are not used at Parkland Hospital, they are given at University of Alabama at Birmingham Hospital
6. For pregnancies at 34 weeks or beyond, women with preterm labor are monitored for labor progression and fetal well-being
7. For active labor, an antimicrobial is given for prevention of neonatal group B streptococcal infection
Group B streptococcal infections are common and dangerous in the preterm neonate. Tachycardia in preterm fetus-->> sepsis.
Malloy and colleagues (1991) analyzed 1765 newborns with birthweights less than 1500 g and found that cesarean delivery did not lower the risk of mortality or intracranial hemorrhage. Anderson and co-workers (1988), however, made an interesting observation regarding the role of cesarean delivery in the prevention of neonatal intracranial hemorrhages. These hemorrhages related to whether or not the fetus had been subjected to the active phase of labor. They emphasized that avoidance of active-phase labor is impossible in most preterm births because the route of delivery cannot be decided until the active phase of labor is firmly established
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