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SECTION III
DIAGNOSIS AND TREATMENT OF PRETERM LABOR



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Preterm Birth: Causes, Consequences, and Prevention SECTION III DIAGNOSIS AND TREATMENT OF PRETERM LABOR

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Preterm Birth: Causes, Consequences, and Prevention 9 Diagnosis and Treatment of Conditions Leading to Spontaneous Preterm Birth ABSTRACT The diagnosis and treatment of preterm labor is currently based on an inadequate literature. Not only is there a paucity of welldesigned and adequately powered clinical trials, but there is incomplete understanding of the sequence and timing of events that precede clinical evidence of preterm labor. To date, there is no single test or sequence of assessment measures to accurately predict preterm birth. Prevention of preterm birth has primarily focused on the treatment of the woman with symptomatic preterm labor. Treatment has been directed toward the inhibition of contractions. This approach has not decreased the incidence of preterm birth but can delay delivery long enough to allow administration of antenatal steroids and to transfer the mother and the fetus to an appropriate hospital, two interventions that have consistently been shown to reduce the rates of perinatal mortality and morbidity. Preterm birth has historically not been emphasized in prenatal care, in the belief that the majority of preterm births are due to social rather than medical or obstetric causes or are the appropriate result of pathological processes that would benefit the mother or the infant, or both. Because preterm labor or premature rupture of membranes may occur in response to conditions that threaten fetal or maternal well-being, whether preterm birth is appropriately preventable is a topic that regularly influences clinical decision making. The ultimate goal of treatment for preterm labor is to eliminate or reduce

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Preterm Birth: Causes, Consequences, and Prevention perinatal morbidity and mortality. Thus, despite several interventions designed to inhibit preterm labor and prolong pregnancy, the frequency of preterm birth continues to pose a major barrier to the health of newborns worldwide. Although current obstetric and neonatal strategies have resulted in improved rates of neonatal survival and an earlier threshold for viability, effective strategies for the prevention of preterm birth are urgently needed. As basic and translational research continues to reveal more of the complex endocrinological and immunological aspects of parturition, investigators must continue to search for biologically plausible new therapies to prevent preterm birth and develop markers or multiple markers to diagnose the disease accurately in its early stages. Nearly 75 percent of the cases of perinatal mortality and approximately half of the cases of long-term neurologic morbidity occur in infants born preterm. Preterm births have been organized into two broad categories, spontaneous and indicated, based on the presence or absence of factors that place the mother or the fetus at risk (Meis et al., 1987, 1995, 1998). Spontaneous preterm births occur as a result of preterm labor or preterm premature rupture of fetal membranes before 37 weeks of gestation and account for the majority of preterm births in developed countries. Preterm births that are the result of conditions that directly threaten the health of the mother or fetus, such as preeclampsia, placenta previa, and fetal growth restriction, are categorized as indicated preterm births and account for the remaining 25 to 30 percent of preterm deliveries (Meis et al., 1987, 1995, 1998). Although categorization of preterm births as indicated versus spontaneous allows analysis of preterm births according to those that might be prevented versus those that might be beneficial, there is increasing recognition that this distinction may understate the contribution of factors such as vascular compromise or fetal stress to the pathogenesis of preterm labor. This is suggested by reports that infants born after spontaneous preterm labor in the absence of apparent maternal disease have a higher than expected rate of poor intrauterine growth (Bukowski et al., 2001b; Gardosi, 2005). Figure 9-1 shows the negative skew in birth weights for fetuses destined for preterm birth versus the range of fetal weights of fetuses ultimately born at term. Efforts to prevent preterm birth must therefore be applied and evaluated primarily for their effects on perinatal mortality and morbidity. The care of infants born preterm and their mothers may be described as primary (prevention and reduction of risk in the population), secondary (identification of and treatment for individuals with an increased risk), and tertiary (treatment aimed at reducing morbidity and mortality after the

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Preterm Birth: Causes, Consequences, and Prevention FIGURE 9-1 Ultrasound versus birth weight standard at 32 weeks of gestation. SOURCE: Gardosi et al. (2005). Reprinted with permission from Early Human Development, Vol. 81, Pg. 45, © 2004 by Elsevier. preterm parturitional process has begun). In the past 30 years, important strides in obstetric and neonatal tertiary care have been made to reduce the rates of infant morbidity and mortality related to preterm birth. However, the primary and secondary interventions used to date have not reduced the rate of spontaneous preterm birth. This chapter describes and assesses the success of secondary- and tertiary-care practices. As will become evident as these are recounted, there are major impediments to the appropriate application of reasonable interventions for the risk factors for preterm birth. Many risk factors have been identified and removed without affecting the rate or morbidity of preterm birth. Cofactors, both exogenous and innate, that might contribute to or impede the success of an intervention are not well understood. Because clinically overt evidence of preterm labor is often preceded by weeks or months of activation of the parturitional process, the optimal timing for effective interventions is not always clear. Figure 9-2 presents these interactions. Remarkably, current prenatal care is focused on risks other than preterm birth. Birth defects, adequate fetal growth, preeclampsia, gestational diabetes, selected infections (urinary tract, group B streptococcus, and rubella virus infections), and complications of postdate pregnancy are emphasized in the prenatal record (see Attachment 9-1). Preterm birth has historically not been emphasized in prenatal care in the belief that the majority of preterm births are due to social rather than medical or obstetrical causes (Main et al., 1985; Taylor, 1985) or are the appropriate result of pathological processes that would benefit the mother or the infant, or both. More recently, the failure of repeated efforts to prevent preterm birth (see

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Preterm Birth: Causes, Consequences, and Prevention FIGURE 9-2 Interventions for preterm birth. below) has lent support to the historical view. Because preterm labor or preterm premature rupture of membranes may occur in response to conditions that threaten fetal or maternal well-being, whether preterm birth is appropriately preventable is a topic that regularly influences clinical decision making. Thus, efforts to prevent preterm birth have increasingly focused on early pregnancy and preconceptional care. Some risks are amenable to intervention, whereas others serve primarily to inform theories of causation or to identify at-risk groups for further study. Finding 9-1: Prenatal care was designed to address one complication of pregnancy; namely, preeclampsia. The proper timing of visits and the appropriate content of prenatal care for the detection or management of preterm delivery are not known. PREDICTION AND ASSESSMENT OF RISK OF PRETERM BIRTH The rationale for prediction of spontaneous preterm birth is threefold. First, by delineating factors predictive of preterm birth, the mechanisms and biological pathways that lead to spontaneous preterm parturition may be better understood. Second, the use of predictors of spontaneous preterm

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Preterm Birth: Causes, Consequences, and Prevention birth permits identification of a group of women at the highest risk for whom an intervention may be tested and for whom intervention is most needed. The third motivation for prediction of spontaneous preterm birth is a corollary of the second: by identifying women at low risk for preterm birth, unnecessary, costly, and sometime hazardous interventions might be avoided. To date, no single test or sequence of tests has an optimal sensitivity or predictive value. This section reviews clinical, biophysical, and biochemical tests that can be used as predictors for preterm birth. CLINICAL PREDICTORS Clinical risk factors alone or in combination most frequently report a sensitivity of about 25 percent for prediction of preterm birth (Goldenberg et al., 1998; Mercer et al., 1996). Low prepregnancy weight (body mass index less than 19.8), genitourinary bacterial colonization or infection, and African American ethnicity have relative risks (RRs) of about twofold but contribute significant attributable risk because of their prevalence in the population. African American women deliver before 37 weeks of gestation twice as often as women of other races and ethnicities and deliver before 32 weeks of gestation three times as often as white women. The strongest risk factors in all racial-ethnic groups are multiple gestation (RR = five- to six-fold), a history of preterm birth (RR = three- to fourfold), and vaginal bleeding (RR = threefold). The risk of preterm and low-birth-weight delivery rises in direct proportion to the number of fetuses, as can be seen Table 9-1. Vaginal bleeding in pregnancy is a risk factor for preterm birth because of placenta previa, because of placental abruption, and when the origin is unclear (Ekwo et al., 1992; Meis et al., 1995; Yang et al., 2004b). Unexplained vaginal bleeding is particularly associated with preterm birth if it is persistent and if it occurs in white women (Yang et al., 2004b). The risk of recurrent preterm birth rises with the number of prior preterm births, with maternal African American ethnicity, and as the gestational age of the prior preterm birth decreases (Adams et al., 2000; Mercer et al., 1999). The effect of a woman’s prior obstetrical history on the risk of preterm birth is shown in Table 9-2. The data in Table 9-2 describe a homogeneous population from Norway. Data from the United States show the same phenomenon, with markedly increased rates of preterm birth for African Americans, reaching 50 percent or more for an African American woman with two or more prior preterm deliveries (Adams et al., 2000; Mercer et al., 1996). Other reported risk factors include the use of assisted reproductive technology, poor nutrition, periodontal disease, absent or inadequate prenatal care, age less than 18 years or over 35 years, strenuous work, high levels of personal stress,

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Preterm Birth: Causes, Consequences, and Prevention TABLE 9-1 Risks of Preterm and Low Birth Weight Births by Number of Fetuses Births Twin Triplet Quadruplet Quintuplet <32 wk 12 percent 36 percent 60 percent 78 percent <37 wk 58 percent 92 percent 97 percent 91 percent Mean GA 35 wk 32 wk 30 wk 28 wk <1.5 kg 10 percent 34 percent 61 percent 84 percent <2.5 kg 55 percent 94 percent 99 percent 94 percent   Risk of Preterm Birth or Low Birth Weight (%) No. of Births <32 wk of Gestation <37 wk of Gestation Birth Weight <1.5 kg Birth Weight <2.5 kg Twin 12 58 10 (35 wk)a 55 (35 wk) Triplet 36 92 34 (32 wk) 94 (32 wk) Quadruplet 60 97 61 (30 wk) 99 (30 wk) Quintuplet 78 91 84 (28 wk) 94 (28 wk) aTimes in parentheses are mean gestational age. SOURCE: CDC (2002c). TABLE 9-2 Risk of Preterm Delivery by Obstetrical History Outcome of First Birth Outcome of Second Birth Number of Women Likelihood of Peterm Birth in Next Pregnancy       Percent RR Term   25,817 4.4 1.0 Preterm   1,860 17.2 3.9 Term Term 24,689 2.6 .6 Preterm Term 1,540 5.7 1.3 Term Preterm 1,128 11.1 2.5 Preterm Preterm 320 28.4 6.5 SOURCE: Bakketeig and Hoffman (1981). anemia, cigarette smoking, cervical injury or abnormality, and uterine anomaly (Meis et al., 1995; Mercer et al., 1996). As discussed in Chapter 5, the increased number of pregnancies conceived after the use of assisted reproductive technologies is associated with a rise in preterm birth not only because of multiple gestations but also because the singleton gestations that

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Preterm Birth: Causes, Consequences, and Prevention occur after the use of assisted reproductive technologies have a twofold increased risk of preterm birth (Jackson et al., 2004; Schieve et al., 2004; Van Voorhis, 2006). Biophysical Predictors Uterine Contractions The detection of uterine contractions through maternal self-perception (Mercer et al., 1996) and electronic monitoring (Iams et al., 2002; Main et al., 1993; Nageotte et al., 1988) has been studied to predict preterm delivery. The threshold number of contractions most often studied is four per hour. An increased frequency of self-reported contractions is associated with preterm delivery before 35 weeks of gestation in both nulliparous women (RR 2.41; 95% interval [CI] 1.47–3.94; p < 0.001) and parous women (RR 1.62; 95% CI 1.20–2.18; p = 0.002) women (Mercer et al., 1996). In a study of 306 women in whom uterine contraction frequency was electronically recorded for 2 or more hours a day at least twice weekly between 22 and 37 weeks of gestation, contraction frequency was significantly greater in women who delivered before 35 weeks of gestation than in women who delivered after 35 weeks of gestation (Table 9-3) (Iams et al., 2002). Con- TABLE 9-3 Prediction of Spontaneous Preterm Birth before 35 Weeks of Gestation (22 to 24 and 27 to 28 Weeks of Gestation) in 306 Women at Risk of Preterm Birth Gestational Length and Test Sensitivity (%) Specificity (%) Predictive Value (%) Positive Negative 22 to 24 wk UC ≥4/h 6.7 92.3 25.0 84.7 Bishop score ≥4 32.0 91.4 42.1 87.4 CL ≤25 mm 40.8 89.5 42.6 88.8 Fibronectin level ≥50 ng/ml 18.0 95.3 42.9 85.6 27 to 28 wk UC ≥4/h 28.1 88.7 23.1 91.1 Bishop score ≥4 46.4 77.9 18.8 92.9 CL ≤25 mm 53.6 82.2 25.0 94.1 Fibronectin level ≥50 ng/ml 21.4 94.5 30.0 91.6 NOTE: UC = uterine contractions; CL = cervical length. SOURCE: Iams et al. (2002).

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Preterm Birth: Causes, Consequences, and Prevention tractions increased significantly as gestational age advanced and were more frequent between 4 p.m. and 4 a.m. Although the difference in contraction frequency was statistically significant, contraction frequency was not a clinically efficient predictor of preterm birth at 24 or 28 weeks of gestation. The threshold of four or more contractions per hour at 24 and 28 weeks of gestation for prediction of the risk of preterm birth had sensitivities of 8.6 and 28 percent, respectively, and positive predictive values of 25 and 23 percent, respectively (Iams et al., 2002). Clinical studies of the symptoms of preterm birth (Hueston, 1998; Macones et al., 1999b) confirm the poor performance of contraction frequency as a test for acute preterm labor as well. Cervical Examination Manual examination Cervical dilatation, effacement, consistency, position, and station of the presenting part as determined by manual examination have been related to an increased risk of preterm birth (Copper et al., 1990; Iams et al., 1996; Mercer et al., 1996; Newman et al., 1997). However, even when these features are combined in composite scores (e.g., Bishop scores [Bishop, 1964] or cervical scores [Newman, 1997]) of cervical readiness for labor, the sensitivity is low. The RRs for birth before 35 weeks of gestation were increased at 24 weeks of gestation: 5.3 (95% CI 3.4–8.5) for the cervical score (defined as cervical length in centimeters minus the cervical dilatation in centimeters) and 3.5 (95% CI 2.4–5.0) for the Bishop score. The sensitivities of both scores for prediction of the risk of preterm birth in a general obstetrical population were low, however: 13.4 and 27.6 percent, respectively (Iams et al., 1996; Newman et al., 1997). Sonographic evaluation A decreased cervical length as measured by endovaginal ultrasound examination has also been related to an increased risk of preterm birth. The RR of preterm birth before 35 weeks of gestation was about sixfold higher (95% CI 3.84–9.97) among women whose cervical length was less than the 10th percentile (25 millimeters [mm]) than that among women with a cervical length above the 75th percentile (40 mm), but the absolute risk of birth before 35 weeks of gestation and the sensitivity were both only 40 percent in two studies performed in the United States (Iams et al., 1996, 2002). A study of cervical length in low-risk women found an eightfold increased risk of preterm birth when the cervix was less than 29 mm at 18 to 22 weeks of gestation, but the sensitivity and positive predictive value were low: 19 and 6 percent, respectively (Taipale and Hiilesmaa, 1998). Finally, the likelihood ratio for prediction of birth before 34 weeks of gestation for a cervical length of 25 mm or less when the length was measured before 20 weeks of gestation was estimated to be +6.3 (95%

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Preterm Birth: Causes, Consequences, and Prevention CI 3.3–12.0), indicating that the risk of preterm birth is 6.3 times greater for women whose cervical length is < 25 mm than for those whose cervical length is >25 mm (Honest et al., 2003). Biological Predictors Biological markers may be collected from maternal blood or urine, cervicovaginal fluid secretions, or amniotic fluid. Maternal blood and vaginal fluids have been the most studied. Table 9-4 summarizes the myriad efforts used to identify the risk of preterm birth based on biomarkers from asymptomatic women (Vogel et al., 2005). Serum Biomarkers Maternal serum is routinely drawn several times during prenatal care. Screening of serum biomarkers for various conditions, such as open neural tube defects and aneuploidy, is already part of routine prenatal care (Canick et al., 2003; Cheschier, 2003). The use of serum biomarkers of spontaneous preterm birth to identify several pathways to preterm birth have been investigated, as described by Romero and colleagues (1994) and Lockwood and Kuczynski (2001) and described in Chapter 6, including (1) activation of maternal or fetal hypothalamic-pituitary-adrenal axis (e.g., corticotropinreleasing hormone) and (2) inflammation due to upper genital tract infection (e.g., defensins and tumor necrosis factor alpha) or decidual hemorrhage or ischemia (e.g., thrombin-antithrombin III complex). No serum biomarkers of pathologic uterine overdistension have been described. Lower Genital Tract Markers Bacterial vaginosis (BV) is an alteration of the maternal vaginal flora in which normally predominant lactobacilli are largely replaced by gram-negative anaerobic bacteria, such as Gardnerella vaginalis and Bacteroides, Prevotella, Mobiluncus, and Mycoplasma species. BV in pregnancy is consistently associated with a twofold increased risk of spontaneous preterm birth (Hillier et al., 1995; Meis et al., 1995). The association of BV with preterm birth has been reported to be stronger when the condition is present in the first half of pregnancy (Hay et al., 1994), but a recent analysis of the relationship between gestational age at the time of detection of BV and pregnancy outcome in 12,937 women found “the odds ratio of preterm birth among BV-positive versus -negative women raged from 1.1 to 1.6 and did not vary significantly according to the gestational age at which BV was screened” (Klebanoff et al., 2005, p 470). Despite the consistency of the reports relating BV to preterm birth, the clinical utility of tests for BV to

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Preterm Birth: Causes, Consequences, and Prevention administration of glucocorticoids to women at risk of preterm birth. A 1994 National Institutes of Health Consensus Conference recommended the administration of corticosteroids to women with preterm labor before 34 weeks of gestation and women with PPROM before 32 weeks of gestation by the use of a single course of either betamethasone (two doses of 12 mg intramuscularly administered 24 hours apart) or dexamethasone (four doses of 6 mg intramuscularly administered 12 hours apart). Studies have shown conclusively that the antepartum administration of the glucocorticoids betamethasone or dexamethasone to the mother reduces the risk of death, respiratory distress syndrome, intraventricular hemorrhage, necrotizing entercolitis, and patent ductus arteriosus in the preterm neonate (Crowley, 1999). Other morbidities of preterm birth reduced by antenatal glucocorticoid administration include necrotizing enterocolitis, patent ductus arteriosus, and bronchopulomary dysplasia. Betamethasone and dexamethasone are apparently equally effective in reducing perinatal morbidity, but there may be some advantage to the use of betamethasone. In a study of infants born between 24 and 31 weeks of gestation, the rate of periventricular leukomalacia was 4.4 percent among 361 infants who were treated antenatally with betamethasone, 11.0 percent among 165 infants who received dexamethasone, and 8.4 percent among 357 infants who were not treated with antenatal corticosteroids (Baud et al., 1999). Other fetal effects of glucocorticoids have been reported. Transient reductions in fetal breathing and body movements sufficient to affect the interpretation of the biophysical profile have been described after the administration of both drugs but are more common after administration of betamethasone and typically last for 48 to 72 hours after administration of the second dose (Mulder et al., 1997; Rotmensch et al., 1999; Senat et al., 1998). Transient suppression of neonatal cortisol levels has been reported, but the neonatal response to adrenocorticotropin stimulation was unimpaired (Teramo et al., 1980; Terrone et al., 1997, 1999). Neonatal leukocyte counts are not affected by antenatal steroid administration (Zachman et al., 1988). Although maternal adrenal suppression has been described with repeated courses of antenatal steroids, the adrenal suppression had no clinical consequences (Wapner et al., 2005). Concern about whether corticosteroids given to women with ruptured membranes might increase the risk of neonatal infection has been addressed by reports that found no such association (Harding et al., 2001; Lewis et al., 1996). Harding and colleagues (2001) found no evidence of increased maternal infections (RR 0.86; 95% CI 0.61–1.2) or neonatal infections (RR 1.05; 95% CI 0.66–1.68) in a meta-analysis of steroid treatment of women with PPROM. The duration of the beneficial effects on the fetus after the administra-

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Preterm Birth: Causes, Consequences, and Prevention tion of a single course of glucocorticoids is not clear. The issue is difficult to study because the interval between treatment and delivery in clinical trials varies and because some effects may be transient, whereas others are permanent. The benefit to the neonate has been most easily observed when the interval between the first dose and delivery exceeds 48 hours, but some benefit is evident after an incomplete course. One large multicenter trial (Gamsu et al., 1989) found evidence of a benefit for as long as 18 days after the initial course of treatment. The increasing use of repeated courses of antenatal steroid treatment prompted animal and human studies that have raised concerns about the effects of prolonged exposure to steroids on fetal growth and neurological function. The animal studies showed reduced fetal growth and adverse brain and neurological development and a pattern of decreased fetal growth in several species (Aghajafari et al., 2002; Cotterrell et al., 1972; Huang et al., 1999; Jobe et al., 1998; Quinlivan et al., 2000; Stewart et al., 1997). Human studies also found reduced growth in fetuses exposed to multiple courses of antenatal steroids. An Australian study found a twofold increase in the numbers of infants with birth weights below the 10th percentile and a significantly reduced head circumference in infants exposed to more than three antenatal courses of steroids (French et al., 1999). A reduced head circumference was also reported in other studies (Abbasi et al., 2000). These reports led NICHD to reconvene the Consensus Conference Panel in August 2000 to review the available information about repeated courses of steroids. That panel reemphasized the benefit and safety of a single course of antenatal corticosteroids (given either as two intramuscular doses of 12 mg 24 hours apart or four doses of dexamethasone every 12 hours) for women between 24 and 34 weeks of gestation who are deemed to be at risk of preterm delivery within 7 days. The panel noted data suggesting a benefit for repeat courses of steroids, but in the absence of appropriate clinical studies, the panel recommended that “repeat courses of corticosteroids … should not be used routinely … [but] should be reserved for patients enrolled in randomized controlled trials” (NIH, 2001, p. 146). Five prospective, randomized, clinical trials of repeat antenatal corticosteroids in humans have been performed. Three (Guinn et al., 2001; Mercer et al., 2001a,b; Wapner, 2003) have been reported in articles or abstracts, and two (Australian and Canadian trials) are ongoing or have not yet been described. Guinn and colleagues (2001) enrolled 502 women who had received one course of steroids to receive betamethasone once weekly or no further treatment. There was no difference in the composite rates of morbidity (defined as severe respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, sepsis, necrotizing enterocolitis, or death) in the two groups (22.5 and 28.0 percent, respectively; p = 0.16). There was a reduction in the

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Preterm Birth: Causes, Consequences, and Prevention rate of severe respiratory distress syndrome (15.3 and 24.1 percent, respectively; p = 0.01) and composite morbidity (96.4 and 77.4 percent, respectively; p = 0.03) in infants treated repeatedly if they were delivered at between 24 and 27 weeks of gestation. Another trial (Mercer et al., 2001a,b) compared weekly betamethasone to rescue treatment from enrollment through 34 weeks of gestation. Notably, only 37 percent of women assigned to receive rescue steroids were so treated, indicating the difficulty in predicting imminent preterm delivery. More than 75 percent of the women in the weekly treatment group received corticosteroids within a week of preterm birth (p = 0.001) (Mercer et al., 2001a). The NICHD MFMU Network Study (Wapner, 2003) randomized 495 women, of whom 492 (591 infants) were available for analysis and 252 received repetitive steroids. The trial was stopped by the independent data and safety monitoring board before the planned sample size was reached because of slow enrollment. The investigators found no difference in the primary (composite) outcome for infants who were exposed to multiple courses compared with that for infants who received placebo (7.7 and 9.2 percent, respectively; p = 0.67). Trends toward improvement were seen in the group receiving multiple courses of steroids for each component of the primary outcome and for secondary outcomes related to lung function: use of surfactant (12.5 and 18.4 percent, respectively; p = 0.02), mechanical ventilation (15.5 and 23.5 percent, respectively; p = 0.005), and treatment for hypotension (5.7 and 11.2 percent, respectively; p = 0.02). Among infants delivered before 32 weeks of gestation, the composite morbidities1 included in the primary outcome were less common in the group receiving multiple courses of steroids (21.3 and 38.5 percent, respectively; p = 0.083). Multiple courses of steroid treatment were associated with insignificant trends toward reduced infant weight (2,194 and 2,289 grams for the treatment and placebo groups, respectively; p = 0.09) and length (44.2 and 44.7 cm for the treatment and placebo groups, respectively; p = .09). Infants exposed to four or more courses of steroids had a significant decrease in birth weight (2,396 and 2,561 grams for the treatment and placebo groups, respectively; p = 0.01) (Wapner, 2003). Other Antenatal Treatments to Reduce Fetal Morbidity Respiratory distress Several alternative approaches to reducing the rate of occurrence of neonatal respiratory distress syndrome that are used before 1 Defined as stillbirth, neonatal death, severe respiratory distress syndrome, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, or chronic lung disease (Wapner, 2003).

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Preterm Birth: Causes, Consequences, and Prevention and after birth have been studied. Neonatal treatment with surfactant is an effective adjunctive therapy that adds independently and synergistically to the benefit offered by corticosteroids in reducing respiratory distress syndrome-related morbidity (St. John and Carlo, 2003). The use of antenatal thyrotropin-releasing hormone (TRH) to reduce neonatal lung disease has been studied in trials that enrolled more than 4,600 women. TRH did not improve any neonatal outcome when TRH treatment was compared with corticosteroid treatment alone and actually increased the risk of poor outcomes for the infants in some trials (Crowther et al., 2004). Neurological morbidity Antenatal maternal treatment with phenobarbital, vitamin K, and magnesium sulfate has been studied as a means of reducing or preventing neonatal neurological morbidity. Phenobarbital did not decrease intraventricular hemorrhage when it was given alone (Shankaran et al., 1997) or in combination with vitamin K (Thorp et al., 1995). Antenatal maternal treatment with magnesium has also been studied after observational reports found reduced rates of intraventricular hemorrhage, cerebral palsy, and perinatal mortality in premature infants exposed to antenatal magnesium (Grether et al., 1998, 2000; Mittendorf et al., 1997; Nelson and Grether, 1995; Paneth et al., 1997; Schendel et al., 1996). A randomized placebo-controlled trial of antenatal magnesium conducted with 1,062 women who delivered before 30 weeks of gestation found that magnesiumtreated infants had significantly improved gross motor dysfunction and a trend suggesting a lower rate of cerebral palsy at 2 years of age (Crowther et al., 2003). No significant adverse effects were noted in infants exposed to antenatal magnesium sulfate in this study. The NICHD- and National Institute of Neurological Disorders and Stroke-Sponsored MFMU Network’s BEAM Trial (Randomized Clinical Trial of the Beneficial Effects of Antenatal Magnesium Sulfate) has concluded enrollment and will report on the outcomes for the infants in 2007, when the infants will be 2 years old. Maternal Transfer Many states have adopted systems of regionalized perinatal care, in recognition of the advantages of concentrating care for preterm infants, especially those born before 32 weeks of gestation. Hospitals and birth centers caring for healthy mothers and infants are typically designated Level I. Larger hospitals that care for the majority of maternal and infant complications are designated Level II centers; these hospitals have neonatal intensive care units staffed and equipped to care for most infants with birth weights between 1,250 and 1,500 grams. Level III centers typically provide care for the sickest and the smallest infants and for maternal complications requiring intensive care. The use of this approach has been associated with

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Preterm Birth: Causes, Consequences, and Prevention improved outcomes for preterm infants (Towers et al., 2000; Yeast et al., 1998) (see Chapters 10 and 14 for further discussion). FUTURE DIRECTIONS Despite several interventions designed to inhibit preterm labor and prolong pregnancy, the frequency of preterm birth continues to pose a major barrier to the health of newborns worldwide. Although current obstetric and neonatal strategies have resulted in improved rates of neonatal survival and an earlier threshold for viability, effective strategies for prevention of preterm birth are urgently needed. As basic and translational research continues to reveal more of the complex endocrinological and immunological aspects of parturition, investigators must continue to search for biologically plausible new therapies to prevent preterm birth and develop markers or multiple markers to diagnose the syndrome accurately in its early stages.

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Preterm Birth: Causes, Consequences, and Prevention ATTACHMENT 9-1 (SAMPLE)

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Preterm Birth: Causes, Consequences, and Prevention