Obstentrics_Williams

Obstentrics_Williams. One potential mechanism for stress-induced preterm birth is premature activation of the placental-adrenal endocrine axis. One trigger may be elevations in cortisol from maternal psychological stress (Lockwood, 1999; Petraglia, 2010; Wadhwa, 2001). Activation of this axis yields rising maternal serum levels of placentalderived corticotropin-releasing hormone (CRH). This raises adult and fetal adrenal steroid hormone production and promotes early loss of uterine quiescence (Fig. 21-10, p. 410). If preterm delivery is associated with early activation of the fetal adrenal-placental endocrine axis, maternal estrogen levels would likely be prematurely elevated. Indeed, an early rise in serum estriol concentrations is noted in women with subsequent preterm labor (Heine, 2000; McGregor, 1995). Physiologically, this premature rise in estrogen levels may alter myometrial quiescence and accelerate cervical ripening.


Obstentrics_Williams

Obstentrics_Williams. Another mechanism by which stress may translate to preterm birth is premature cellular senescence. As part of normal physiology, aging of fetal and decidual cells precipitates the release of uterotonic signals for uterine activation at term (Menon, 20 14a). Animal studies supported by correlative studies in women demonstrate that accelerated senescence of the decidua results in preterm birth (Cha, 2013; Hirota, 2010). In addition, premature cellular senescence may contribute to PPROM (Menon, 2016).


Obstentrics_Williams

Obstentrics_Williams. In most cases, premature cervical remodeling precedes premature labor onset. In some instances, cervical dysfunction of either the epithelia or stromal extracellular matrix is the underlying cause. For example, an intact cervical epithelial barrier is critical to prevent ascending infection. Disruption of this barrier, such as that in mice lacking the glycosaminoglycan hyaluronan, predisposes mice to ascending infection and preterm birth (Akgul, 2014). Interestingly, the enhanced risk of preterm birth from group B streptococcal colonization may be in part due to the bacteria's ability to secrete hyaluronidase. his enzyme degrades hyaluronic acid in the cervicovaginal epithelia to aid bacterial ascension (V ornhagen, 2017).


Obstentrics_Williams

Obstentrics_Williams. Second, the mechanical competence of the cervix can be reduced. For example, genetic mutations in components of collagen and elastic fibers or proteins required for their assembly are risk factors for cervical insuiciency, PPROM, and preterm birth (Anum, 2009; Nallasamy, 2017; Pyeritz, 2000).


Obstentrics_Williams

Obstentrics_Williams. A patent female reproductive tract, although essential for conception and delivery, is theoretically problematic during phase 1 of parturition. Bacteria can gain access to intrauterine tissues through: (1) transplacental transfer of maternal systemic infection, (2) retrograde flow of infection into the peritoneal cavity via the fallopian tubes, or (3) ascending infection with bacteria from the vagina and cervix. Because the lower pole of the fetal membrane-decidual junction is contiguous with the cervical canal oriice, this anatomical arrangement provides a passageway for microorganisms. Ascending infection is considered to be the most common entry route. Ascending microorganisms colonize the cervix, decidua, and possibly the membranes, where they then may enter the amnionic sac.


Obstentrics_Williams

Obstentrics_Williams. Intraamnionic infection as a primary cause of preterm labor in pregnancies with intact membranes accounts for 25 to 40 percent of preterm births (Goncalves, 2002; lams, 1987). In some instances, histological evidence of inflammation is found in the fetal membranes, decidua, or umbilical cord. Other cases are deemed "subclinical." Current data suggest that microbial invasion of the reproductive tract is suicient to induce infection-mediated preterm birth. ffected women are more likely to develop clinical chorioamnionitis and PPROM compared with women with sterile cultures. Moreover, their neonates are also more likely to have perinatal complications that include RDS, intraventricular hemorrhage, and necrotizing enterocolitis (Hitti, 2001). Although the clinical course is more severe when intraamnionic infection is obvious, inlammation in the absence of detectable intraamnionic microorganismstermed sterile intraamnionic inlammation-is also a risk factor for an inlammatory response,


Obstentrics_Williams

Obstentrics_Williams. intraamnionic infection is obvious, inlammation in the absence of detectable intraamnionic microorganismstermed sterile intraamnionic inlammation-is also a risk factor for an inlammatory response, described in the next section (Lee, 2007, 2008; Romero, 2014). In sum, the earlier the onset of preterm labor, the greater the likelihood of underlying infection (Goldenberg, 2000; Goncalves, 2002; Watts, 1992).


Obstentrics_Williams

Obstentrics_Williams. he incidence of culture-positive amnionic luid collected by amniocentesis during spontaneous term labor is similar to that with preterm labor (Gomez, 1994; Romero, 1993). It has been suggested that at term, amnionic luid is iniltrated by bacteria as a consequence oflabor, whereas in preterm pregnancies, bacteria represent an inciting cause of labor. hus, fetal infection, as deined by bacteria detected within the amnionic luid, has both difering etiologies and consequences.


Obstentrics_Williams

Obstentrics_Williams. Despite these observations, considerable data associate chorioamnionitis with preterm labor (Goldenberg, 2002; Ustiin, 2001). With chorioamnionitis, microbes may invade maternal tissue only and not amnionic fluid. Despite this, endotoxins can stimulate amnionic cells to secrete cytokines that enter amnionic luid. his scenario may serve to explain the apparently contradictory observations concerning an association between amnionic luid cytokines and preterm labor in cases in which microbes are not detected in the amnionic luid.


Obstentrics_Williams

Obstentrics_Williams. Inflammatory Responses. Inlammatory responses drive the pathogenesis of infection-induced preterm labor. lipopolysaccharide (LPS) or other toxins elaborated by bacteria are recognized by pattern-recognition receptors such as toll-like receptors (Janssens, 2003). hese receptors are present on mononuclear phagocytes, decidual cells, cervical epithelia, and trophoblasts (Chuang, 2000; Gonzalez, 2007; Holmlund, 2002). Loss of specific toll-like receptors results in delayed parturition in mouse models (Montalbano, 2013). Instead, activation of tolllike receptors induces a signaling cascade that activates production of chemokines such as interleukin 8 (IL-8) and cytokines such as IL-13. Activation also recruits immune cells into the reproductive tract. Cytokines are produced by immune cells and by cells within the cervix, decidua, membranes, or fetus itsel.


Obstentrics_Williams

Obstentrics_Williams. LPS-induced production ofIL-13 in turn promotes a series of responses that include: (1) increased synthesis of others, that is, IL-6, IL-8, and tumor-necrosis factor alpha (TNF-.); (2) proliferation, activation, and migration of leukocytes; (3) modiications in extracellular matrix proteins; and (4) mitogenic and cytotoxic efects such as fever and acute-phase response (EI-Bastawissi, 2000). Also, in many tissues, including myometrium, decidua, and amnion, IL-1 3 promotes prostaglandin formation that induces cervical ripening and loss of myometrial quiescence (Casey, 1990; Challis, 2002; Keelan, 2003). he importance of prostaglandins to infection-mediated pre term birth is supported by the observation that prostaglandin inhibi tors can reduce the rate of LPS-induced preterm birth in both the mouse and nonhuman primate (Gravett, 2007; Timmons, 2014). Inhibition of cyclooxygenase-2 prevents inlammation mediated preterm labor in the mouse. And, immunomodula intraamnionic infection in a


Obstentrics_Williams

Obstentrics_Williams. the mouse and nonhuman primate (Gravett, 2007; Timmons, 2014). Inhibition of cyclooxygenase-2 prevents inlammation mediated preterm labor in the mouse. And, immunomodula intraamnionic infection in a nonhuman primate model.


Obstentrics_Williams

Obstentrics_Williams. Proteases such as matrix metalloproteinases (MMPs) are also induced by IL-1 3 and function to break down extracel lular matrix components such as collagen or elastic ibers. This disrupts the structural integrity of fetal membranes and the cer vix. Current evidence from animal and human studies suggests that many aspects of infection-mediated preterm birth difer from pathways that regulate term parturition (Hamilton, 2012; Holt, 2011; Shynlova, 2013a,b; Timmons, 2014). Origin of Cytokines. Uterine cytokines are likely important for preterm labor. For example, it appears that cytokines produced side, whereas cytokines produced in the membranes or in cells within the amnionic fluid will not be transferred to maternal tissues. he transfer of cytokines such as IL-1 3 from decidua across the membranes into amnionic luid, however, appears to be severely limited. Additionally, the human myometrium expresses chemokine receptors that decline during labor (Hua, 2013).


Obstentrics_Williams

Obstentrics_Williams. he requirement of leukocytes for initiation of term labor in women remains inconclusive. In general, resident and invading leukocytes produce the bulk of cytokines in cases of inlammation resulting from infection. Indeed, with infection, leukocytesmainly neutrophils, macrophages, and T lymphocytes-iniltrate the cervix, lower uterine segment, fundus, and membranes at the time of labor. Invading leukocytes and certain parenchymal cells produce cytokines and appear to be the primary source of myometrial cytokines (Young, 2002). By contrast, in the decidua, both stromal cells and leukocytes likely contribute. In the cervix, glandular and surface epithelial cells appear to produce cytokines.


Obstentrics_Williams

Obstentrics_Williams. he presence of cytokines in amnionic fluid and their association with preterm labor is well documented. But, their exact cellular origin-with or without recoverable microorganismsis not well deined. Amnionic fluid cytokines are most likely secreted by mononuclear phagocytes or neutrophils activated and recruited into the amnionic luid. Thus, the amount of amnionic luid IL-1 3 would be determined by the number of leukocytes recruited, their activational status, or the efect of amnionic fluid constituents on their IL-1 3 secretion rate.


Obstentrics_Williams

Obstentrics_Williams. Vaginal Microbiota. Factors that predispose to ascending infection and then preterm birth are a key focus of ongoing basic research. \1ucosal immunity and barrier function of the cervicovaginal epithelia, the microbiota composition in the vaginal tract, and their interplay are a major topic (Smith, 2017). From animal studies, mucosal immunity of the lower reproductive tract can be disrupted by viral infection with a subsequent enhanced susceptibility to ascending bacterial infection (Racicot, 2013, 2017). Along with the ability of the cervico vaginal epithelia to respond to environmental insults, the com position of the microbe ecosystem in the vaginal tract may also determine susceptibility to ascending infection. that the nonpregnant vaginal tract hosts a complex microbial community (Gajer, 2012; White, 201l). Also described in


Obstentrics_Williams

Obstentrics_Williams. that the nonpregnant vaginal tract hosts a complex microbial community (Gajer, 2012; White, 201l). Also described in Chapter 65 (p. 1245), these community state types can difer widely among women who are all healthy. And, the vaginal microbiome changes during normal pregnancy (Aagaard, 2012; Stout, 2017). Namely, the diversity and richness of microbe populations are reduced during pregnancy and become more stable. Compared with nonpregnant controls, Lactobacillus species show an enhanced dominance. Some but not all stud ies report an increased population of certain microbes-for example, Gardnerella vaginalis and Ureaplasma ureayticumqi in women with preterm birth (Donders, 2009; Nelson, 2014). However, diferences in populations of pregnant women stud ied, in deinitions of preterm birth, and in data analysis may complicate interpretation of these data.


Obstentrics_Williams

Obstentrics_Williams. Some speciic microorganisms are detected more frequently than others in amnionic fluid of women with preterm labor (Gerber, 2003; Hillier, 1988; Yoon, 1998). hese include G vaginalis, Fusobacterium species, Mycoplasma hominis, and U ureayticum. Their identification was interpreted by some as presumptive evidence that speciic microorganisms are more commonly involved as pathogens in the induction of preterm labor. Another interpretation, however, is that given direct access to the membranes after cervical dilation, selected micro organisms, such as fusobacteria, are more capable of burrowing through these exposed tissues and will do so. Fusobacteria are found in the vaginal luid of only 9 percent of women but in 28 percent of positive amnionic luid cultures from pregnancies with preterm labor and intact membranes (Chaim, 1992).


Obstentrics_Williams

Obstentrics_Williams. • Preterm Premature Rupture of Membranes his term deines spontaneous rupture of the fetal membranes before 37 completed weeks and before labor onset (American College of Obstetricians and Gynecologists, 20 16d). Such rupture likely has various causes, but intrauterine infection, oxidative stress-induced DNA damage, and premature cellular senescence are major predisposing events (Dutta, 2016; Gomez, 1997; Mercer, 2003). Associated risk factors include lower socioeconomic status, body mass index < 19.8, nutritional deiciencies, and cigarette smoking. Women with PPROM carry an enhanced risk for recurrence during a subsequent pregnancy (Bloom, 2001). Despite these known risk factors, none is identified in most cases of pre term rupture.


Obstentrics_Williams

Obstentrics_Williams. Increased apoptosis or necroptosis of membrane cellular components and greater levels of specific proteases in membranes and amnionic luid are related to PPROM. Most tensile strength of the membranes is provided by the amnionic extracellular matrix and interstitial amnionic collagens that are produced in mesenchymal cells (Casey, 1996). Thus, collagen degradation has been a focus of research. he MMP family is involved with normal tissue remodeling and particularly with collagen degradation. Some members are found in higher concentrations in amnionic luid from pregnancies with PPROM (Maymon, 2000; Park, 2003; Romero, 2002). MMP activity is in part regulated by tissue inhibitors of matrix metalloproteinases-TI\1Ps. Several of these inhibitors are found in lower concentrations in amnionic fluid from women with ruptured membranes. Elevated MMP levels found at a time when protease inhibitor expression declines urther supports that their expression alters amnionic tensile strength.


Obstentrics_Williams

Obstentrics_Williams. Studies of amniochorion explants show greater MMP expression following treatment with certain cytokines (Fortunato, 1999a,b, 2002). With membrane rupture, thrombin activity rises, which activates MMPs and prostaglandin synthesis. Studies by Mogami (2013) provide a mechanism b) which bacterial endotoxin or TNF-. elicits release of fetal fibronectin (FN) by amnion epithelial cells. The FN then binds toll-like receptor 4 in the amnion mesenchymal cells to activate signaling cascades. hese result in augmented prostaglandin E (PGEJ synthesis and elevated activity of MJlIPs. Higher prostaglandin levels promote cervical ripening and uterine contractions. Greater MMP concentrations allow collagen breakdown in the fetal membranes resulting in premature rupture.


Obstentrics_Williams

Obstentrics_Williams. In pregnancies with PPROM, the amnion exhibits a higher degree of cell death and more apoptosis markers than that in term amnion (Arechavaleta-Velasco, 2002; Fortunato, 2003). In vitro studies indicate that apoptosis is likely regulated by bacterial endotoxin, IL-13, and TNF-.. In addition, oxidative stress initiated by events other than infection can induce DNA damage, premature senescence, and subsequent inflammation and proteolysis that leads to PPROM (Menon, 2014a,b). Last, there are proteins involved in the synthesis of mature crosslinked collagen or matrix proteins that bind collagen and thereby promote tensile strength. These proteins are altered in membranes with premature rupture (Wang, 2006).


Obstentrics_Williams

Obstentrics_Williams. Several studies have investigated the incidence of infectioninduced PPROM. Bacterial cultures of amnionic luid support a role for infection in a significant proportion. One review of 18 studies and almost 1500 women with PPROM found that bacteria were isolated from amnionic fluid in a third of cases (Goncalves, 2002). Accordingly, some have given antimicrobial treatment to women in spontaneous preterm labor with intact membranes, however, results have been disappointing as discussed later on page 825 (Kenyon, 2008b). The inflammatory response that leads to membrane weakening and mediators of this process are currently areas of research. One goal is to identiy early risk markers for PPROM.


Obstentrics_Williams

Obstentrics_Williams. The inflammatory response that leads to membrane weakening and mediators of this process are currently areas of research. One goal is to identiy early risk markers for PPROM. Twins and higher-order multifetal births account for approximately 3 percent of neonates born in the United States (Martin, 2017). Preterm delivery continues to be the major cause of the excessive perinatal morbidity and mortality with multifetal pregnancies. The efects of uterine stretch discussed on page 809 are obvious. Many of these interrelationships are discussed in Chapter 45 (p. 885).


Obstentrics_Williams

Obstentrics_Williams. Several genetic and environmental factors afect the frequency of preterm labor. Of these, threatened abortion in early pregnancy is associated with higher rates of later adverse outcomes. Weiss (2004) reported outcomes with vaginal bleeding at 6 to 13 weeks' gestation in nearly 14,000 women. Both light and heavy bleeding were associated with subsequent preterm labor, placental abruption, and pregnancy loss before 24 weeks. Birth defects in the fetus may also predispose to preterm birth. In a secondary analysis of data from the First-and Second-Trimester Evaluation of Risk (FASTER) Trial, birth defects were associated with preterm birth and low birthweight neonates (Dolan, 2007).


Obstentrics_Williams

Obstentrics_Williams. Cigarette smoking, inadequate maternal weight gain, and illicit drug use afect the incidence and outcome of low-birthweight neonates (Chap. 44, p. 849). Extremes of maternal weight-both underweight and obese mothers-have an enhanced risk of preterm birth (Cnattingius, 2013; Girsen, 2016). Other maternal factors implicated include young or advanced maternal age, poverty, short stature, and vitamin C deficiency (Casanueva, 2005; Gielchinsy, 2002; Kramer, 1995; Leveno, 2009; Meis, 1995). As discussed on page 809, psychological factors such as depression, anxiety, and chronic stress are associated with preterm birth (Hofman, 2016; Venkatesh, 2016). In one review of more than 50 studies, Donovan and coworkers (2016) found a signiicant link between low birthweight and preterm birth in women injured by physical abuse (Chap. 47, p. 925).


Obstentrics_Williams

Obstentrics_Williams. Studies of work and physical activity related to preterm birth have yielded conlicting results (Goldenberg, 2008). Some evidence suggests that working long hours and hard physical labor are probably linked to a higher risk of preterm birth (Luke, 1995). However, aerobic exercise in normal-weight women with uncomplicated singleton pregnancies appears to be safe and not associated with preterm birth (American College of Obstetricians and Gynecologists, 2017d; Di Mascio, 2016). One metaanalysis of physical activity found that leisure-time physical activity was associated with a reduced risk of preterm birth (Aune, 2017).


Obstentrics_Williams

Obstentrics_Williams. he recurrent, familial, and racial nature of preterm birth suggests that genetics may playra causal role. Accumulating literature on genetic variants buttresses this concept (Gibson, 2007; Hampton, 2006; Macones, 2004; Velez, 2009). Several such studies have also implicated immunoregulatory genes in potentiating chorioamnionitis in cases of preterm delivery due to infection (Varner, 2005). Gum inflammation is a chronic anaerobic inflammation that afects as many as 50 percent of pregnant women in the United


Obstentrics_Williams

Obstentrics_Williams. Gum inflammation is a chronic anaerobic inflammation that afects as many as 50 percent of pregnant women in the United States (Goepfert, 2004). Vergnes and Sixou (2007) performed a metaanalysis of 17 studies and concluded that periodontal disease was signiicantly associated with preterm birth. To better study this relationship, Michalowicz (2006) randomly assigned 813 pregnant women between 13 and 17 weeks' gestation who had periodontal disease to treatment during pregnancy or postpartum. Treatment during pregnancy improved periodontal disease and was safe. However, treatment failed to significantly alter preterm birth rates. his position was reafirmed by a joint workshop of the European Federation of Periodontology and the American Academy of Periodontology (Sanz, 2013).


Obstentrics_Williams

Obstentrics_Williams. he intervals between pregnancies are linked with adverse perinatal outcomes. In a metaanalysis, intervals < 18 months and > 59 months were associated with greater risks for both preterm birth and small-for-gestational age newborns (Conde-Agudelo, 2006). he causal efect of short interpregnancy intervals, however, has been questioned (Ball, 2014).


Obstentrics_Williams

Obstentrics_Williams. he most important risk factor for preterm labor is a prior preterm delivery. Data from nearly 16,000 women delivered at Parkland Hospital are instructive. Namely, the recurrent preterm delivery risk for women with a preterm first delivery was threefold greater than that of women whose first neonate was born at term. More than a third of women whose irst two newborns were preterm subsequently delivered a third preterm newborn. Most-70 percent-of the recurrent births in this study occurred within 2 weeks of the gestational age of the prior preterm delivery. he causes of prior preterm delivery also recurred. Although women with prior preterm births are clearly at risk for recurrence, they represented only 10 percent of the total preterm births in this study. Expressed another way, 90 percent of the preterm births at Parkland Hospital could not be predicted based on a history of preterm birth. Laughon and associates (2014) confirmed the importance of prior spontaneous preterm birth.


Obstentrics_Williams

Obstentrics_Williams. of the preterm births at Parkland Hospital could not be predicted based on a history of preterm birth. Laughon and associates (2014) confirmed the importance of prior spontaneous preterm birth. Notably, these investigators also found that prior indicated preterm birth was strongly associated with subsequent spontaneous preterm birth. Variations in the deinition of spontaneous and indicated used may explain this association.


Obstentrics_Williams

Obstentrics_Williams. Ultimately, risk of recurrent preterm birth is influenced by three factors: the frequency of prior preterm deliveries, severity as measured by gestational age, and the order in which the prior preterm delivery occurred (McManemy, 2007). That is, an individual woman's risk for recurrent preterm birth is inluenced by her past number and sequence of preterm and term births. For example, a risk of recurrent preterm birth for a gravida 3 para 2 woman with a prior preterm birth followed by a term birth difers from a woman with a prior term birth followed by preterm birth. Thus, the inluence of reproductive history has a profound prognostic significance for risk of recurrence. Moreover, this may also inluence the supposed benefit attributed to various interventions described later.


Obstentrics_Williams

Obstentrics_Williams. As discussed on page 810, a link between some cases of preterm birth and infection seems irrefutable (Goldenberg, 2008). In several studies, antimicrobial treatment has been given to prevent preterm labor thought to be due to microbial invasion. These strategies especially targeted Mycoplasma species. Morency and colleagues (2007) performed a metaanalysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth. Andrews and associates (2006) reported results of a randomized trial in which they gave a course of azithromycin plus metronidazole 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. Using a subgroup analysis of these same


Obstentrics_Williams

Obstentrics_Williams. study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth. Using a subgroup analysis of these same women, Tita and coworkers (2007) concluded that such use of antimicrobials may be harmful. In another randomized study, 2661 women received placebo or metronidazole plus erythromycin between 20 and 24 weeks' gestation followed by ampicillin plus metronidazole during labor (Goldenberg, 2006). his antimicrobial regimen did not reduce the rate of preterm birth or that of histological chorioamnionitis. At this time, antibiotic prophylaxis to prevent preterm birth is not recommended in women with preterm labor and intact membranes (Flenady,r2013).


Obstentrics_Williams

Obstentrics_Williams. In this condition, normal, hydrogen peroxide-producing, lactobacillus-predominant vaginal flora is replaced with anaerobes (Hillier, 1995; Nugent, 1991). Its diagnosis and management are discussed in Chapter 65 (p. 1245). Using Gram staining, relative concentrations of the bacterial morphotypes characteristic of bacterial vaginosis are determined and graded by the Nugent score or assessed clinically with Amsel criteria.


Obstentrics_Williams

Obstentrics_Williams. Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, PPROM, chorioamnionitis, and amnionic fluid infection (Hillier, 1995; Kurki, 1992; Leitich, 2003a,b). Environmental factors appear to be important in bacterial vaginosis development. Exposure to chronic stress, ethnic diferences, and frequent or recent douching are associated with higher rates of the condition (Culhane, 2002; Ness, 2002). A gene-environment interaction has also been described (Macones, 2004). Women with bacterial vaginosis and a susceptible TNF-a genotype had a ninefold increased incidence of preterm birth.


Obstentrics_Williams

Obstentrics_Williams. From all of these studies, adverse vaginal flora seems associated with spontaneous preterm birth. Unfortunately, to date, screening and treatment have not prevented preterm birth. These are discussed further in Chapter 65 (p. 1246). Indeed, microbial resistance or antimicrobial-induced change in the vaginal flora results from regimens intended to eliminate bacterial vaginosis (Beigi, 2004; Carey, 2005).


Obstentrics_Williams

Obstentrics_Williams. Early diferentiation between true and false labor is diicultespecially before demonstrable cervical efacement and dilation. Uterine activity alone can be misleading because of Braxton Hicks contractions. These irregular, nonrhythmical contractions can cause considerable confusion in the diagnosis of true labor. Not infrequently, women who deliver before term have uterine activity that is attributed to Braxton Hicks contractions that prompt an incorrect diagnosis of false labor. Accordingly, the American College of Obstetricians and Gynecologists (2016b) defines preterm labor to be regular contractions before 37 weeks that are associated with cervical change. In addition to contractions, pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain have been empirically associated with impending preterm birth. Such complaints are thought by some to be common in normal pregnancy and are therefore often minimized by patients and obstetrical care providers.


Obstentrics_Williams

Obstentrics_Williams. he importance of these symptoms as a harbinger of labor has been emphasized by some but not all investigators (lams, 1990; Kragt, 1990). lams and coworkers (1994) found that the signs and symptoms signaling preterm labor, including uterine contractions, appeared only within 24 hours of preterm labor.


Obstentrics_Williams

Obstentrics_Williams. Chao (2011) prospectively studied 843 women with a singleton fetus who presented to Parkland Hospital with preterm labor symptoms between 24°/7 and 336/7 weeks, intact membranes, and cervical dilation <2 em. hose whose cervix remained <2 em were sent home with a diagnosis of false preterm labor. When analyzed against the general obstetrical population, women sent home had a similar rate of birth before 34 weeks-2 versus 1 percent. However, these women did have significantly higher rates of birth between 34 and 36 weeks-5 percent compared with 2 percent. Women with cervical dilation of 1 em at discharge were signiicantly more likely to deliver before 34 weeks compared with women without cervical dilation-5 percent versus 1 percent. Importantly, almost 90 percent of the I-em group delivered within 21 days of the initial presentation.


Obstentrics_Williams

Obstentrics_Williams. Researchers have evaluated asymptomatic cervical changes that may predict preterm labor. Asymptomatic cervical dilation after midpregnancy is suspected to be a risk factor for preterm delivery, although some clinicians consider it to be a normal anatomical variant. Moreover, study results have suggested that parity alone is not suicient to explain cervical dilation discovered early in the third trimester.


Obstentrics_Williams

Obstentrics_Williams. Cook (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks in nulliparas and multiparas who all subsequently gave birth at term. Cervical length and diameter were identical in both groups throughout these critical weeks. In a study from Parkland Hospital, routine digital cervical examinations were performed between 26 and 30 weeks in 185 asymptomatic women. Approximately 25 percent of women whose cervix was dilated 2 or 3 em delivered before 34 weeks (Leveno, 1986a). Other investigators have verified cervical dilation as a predictor of increased preterm delivery risk (Copper, 1995) .


Obstentrics_Williams

Obstentrics_Williams. Although women with dilation and efacement in the third trimester are at greater risk for preterm birth, detection does not necessarily improve pregnancy outcome. Buekens and associates (1994) randomly assigned 2719 women to undergo routine cervical examinations at each prenatal visit and compared them with 2721 women in whom serial examinations were not performed. Knowledge of antenatal cervical dilation did not afect any pregnancy outcome related to preterm birth or the frequency of interventions for preterm labor. The investigators also reported that cervical examinations were not related to PPROM. hus, it seems that prenatal cervical examinations in asymptomatic women are neither beneficial nor harmful.


Obstentrics_Williams

Obstentrics_Williams. An external tocodynamometer belted around the abdomen and connected to an electronic waist recorder allows a woman to ambulate while uterine activity is recorded. Results are transmitted via telephone daily. Women are educated concerning signs and symptoms of preterm labor, and clinicians are kept apprised of their progress. The 1985 approval of this monitor by the Food and Drug Administration (FDA) prompted its widespread clinical use. Subsequently, it was proven that the use of this expensive and time-consuming system does not reduce preterm birth rates (Collaborative Home Uterine Monitoring Study Group, 1995; lams, 2002; Urquhart, 2017). Despite improvements in technology with the internet and cellular telephones, use of such monitoring is discouraged (merican College of Obstetricians and Gynecologists, 20 16c).


Obstentrics_Williams

Obstentrics_Williams. his glycoprotein is produced in 20 diferent molecular forms by various cell types, including hepatocytes, fibroblasts, endothelial cells, and fetal amnion cells. Present in high concentrations in maternal blood and amnionic luid, fFN is thought to function in intercellular adhesion during implantation and in maintenance of placental adherence to uterine decidua (Leeson, 1996). Detected in cervicovaginal secretions in women who have normal pregnancies with intact membranes at term, fFN appears to reflect stromal remodeling of the cervix before labor.


Obstentrics_Williams

Obstentrics_Williams. Lockwood (1991) reported that FN detection in cervicovaginal secretions before membrane rupture was a possible marker for impending preterm labor. Qualitative and quantitative FN levels are measured using enzyme-linked immunosorbent assays, and values exceeding 50 ng/mL are considered positive. Sample contamination by amnionic luid and maternal blood should be avoided. Interventional studies based on the use of FN screening in asymptomatic women have not demonstrated improved perinatal outcomes (Andrews, 2003; Esplin, 2017; Grobman, 2004). The American College of Obstetricians and Gynecologists (2016c) does not recommend screening with FN tests. Its use in conjunction with cervical length measurement is discussed next.


Obstentrics_Williams

Obstentrics_Williams. are associated with increased rates of preterm birth (lams, 1996). he technique to measure cervical length with sonog raphy is described in Chapter 10 (p. 189). When performed by trained operators, cervical length analysis using transvagi nal sonography is safe, highly reproducible, and more sensitive lege of Obstetricians and Gynecologists, 20 16c). The Society for the performance of proper cervical length measurement. obtain speciic training in the acquisition and interpretation of cervical length imaging through accreditation programs. Transvaginal cervical sonography is not afected by maternal obesity, cervix position, or shadowing from the fetal presenting part. Because of the inability to easily distinguish the lower uterine segment from the cervix in early gestation, transvaginal cervical length assessment is typically performed ater 16 weeks' gestation.


Obstentrics_Williams

Obstentrics_Williams. Such interrogation is currently limited to singleton gestations and not recommended for multifetal gestations outside of research tri als (American College of Obstetricians and Gynecologists, 2016c). Indications for cervical length measurement are somewhat controversial. For those women with a history of prior spontaneous preterm birth, the Society for Maternal-Fetal Medicine (20 16b) recommends transvaginal cervical length screening. But, the American College of Obstetricians and Gynecologists (2016c) only recommends consideration of screening for this indication. In women with singleton pregnancies but without a history of prior preterm birth, the Society for Maternal-Fetal Medicine (20 16b) views cervical length screening as reasonable yet acknowledges that this remains an area of debate.


Obstentrics_Williams

Obstentrics_Williams. A irst concern with screening surrounds the eicacy of interventions to improve perinatal outcomes once cervical length screening has isolated at-risk gravidas. Of interventions, cervical cerclage and administration of vaginal progesterone have both been evaluated. Vaginal progesterone for this indication is discussed on page 817. For prophylactic cerclage in women with prior preterm births and shortened cervices, many studies have failed to show superior primary outcomes. But, piecemeal subgroup analyses from the trials have been subsequently used as the basis for recommendations in current practice guidelines regarding cervical length assessment and consideration for cerclage placement. A second concern is the accuracy and utility of the screening test, especially in low-risk women, who represent most of the population with preterm birth (p. 813).


Obstentrics_Williams

Obstentrics_Williams. To address this issue in low-risk women, Esplin and colleagues (2017) prospectively studied 9410 nulliparas with singleton pregnancies. Universal screening of sonographically measured cervical length and quantitative measurement of vaginal fFN levels were evaluated as predictors of women who would spontaneously deliver before 37 weeks. hese measures had poor predictive performance as a screening test. In fact, all screening modalities had relative low sensitivity and low positive-predictive values. Based on these indings, routine use of these screening tests in this low-risk population is not recommended. Bloom and Leveno (2017) subsequently critiqued the use of transvaginal cervicalrlength screening in low-risk women and the promulgation of consensus guidelines. As described in Chapter 1 (p. 7), they highlighted the staggering costs encumbering the health-care system in the United States as a result of such strategies.


Obstentrics_Williams

Obstentrics_Williams. Prevention of preterm birth remains an elusive goal. Still, may be achievable. Of options, cerclage placement may be used to prevent pre term birth in at least three circumstances. First, the procedure may beneit women who have a history of recurrent midtrimester losses and who are diagnosed with cervical insuiciency. A second instance is the woman identiied during sonographic examination to have a short cervix. The third indication is a "rescue" cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor.


Obstentrics_Williams

Obstentrics_Williams. As is the case for virtually all obstetrical conditions, an accurate history is critical for management decisions. For recurrent abortion from cervical incompetence, historical clues are outlined in Chapter 18 (p. 354). For women with a short cervix incidentally detected by sonography, the beneit of cerclage placement appears directly related to whether the woman has a history of prior preterm birth. In those without a prior preterm birth, cerclage for a sonographically detected short cervix alone ofers no advantage. To and associates (2004) screened 47,123 women and randomly assigned the 253 women with cervices < 15 mm, with or without a history of preterm birth, to cerclage or no cerclage. he frequency of preterm delivery before 33 weeks did not difer signiicantly. In contrast, women with a sonographically diagnosed short cervix and a history of preterm birth may beneit. Owen and colleagues (2009) randomly assigned 302 women with prior preterm birth and with a short cervix-deined as


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Obstentrics_Williams. a sonographically diagnosed short cervix and a history of preterm birth may beneit. Owen and colleagues (2009) randomly assigned 302 women with prior preterm birth and with a short cervix-deined as length <25 mm-to cerclage or no procedure. The primary study outcome was not supported by the intervention. However, women with a cervical length < 15 mm delivered before 35 weeks signiicantly less oten following cerclage compared with women with no cerclage-30 versus 65 percent. his study suggested that recurrent preterm birth could be prevented in a subset of women with asymptomatic singleton gestations with both previous pre term birth and short cervical length.


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Obstentrics_Williams. These findings prompted a reassessment by Berghella and coworkers (201r1), who performed a metaanalysis using individual patient data (Fig. 42-7). he primary outcomes from the included trials did not support cerclage placement. However, these investigators concluded that cerclage signiicantly prevented preterm birth and improved composite perinatal mortality and morbidity in women with prior spontaneous preterm birth, singleton gestation, and cervical length <25 mm. One caveat in the interpretation of this cerclage data is the inluence of obstetrical history. For example, all of the trials comprising the metaanalysis included preterm birth as early as 16 to 17 weeks' gestation. Deining these early second trimester losses as preterm births, rather than cervical incompetence, is problematic. Thus, it is diicult to distinguish whether these women were treated in the context of cervical incompetence or of preterm labor at 16 weeks. Nonetheless, based on these


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Obstentrics_Williams. Risk Ratio StudyorSubgroup M-H, Fixed, 95% CI 0.01 0.1 10 100 FIGURE 42-7 Cerclage versus no cerclage for prevention of recur rent preterm birth in women with a cervical length <25 mm. Forest plot analysis of composite perinatal mortality and morbidity. CI = confidence index. (Adapted with permission from Berghella V, Rafael TJ, Szychowski JM, et al: Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis, Obstet Gynecol 117(3):663,2011.) indings, the American College of Obstetricians and Gynecologists (2016c) concluded that in women with a singleton pregnancy, prior spontaneous preterm birth before 34 weeks, cervical length <25 mm, and gestational age <24 weeks, cerclage placement may be considered. • Prophylaxis with Progestogen Compounds


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Obstentrics_Williams. • Prophylaxis with Progestogen Compounds In most mammals, progesterone withdrawal is considered to be a parturition-triggering event. During human parturition, however, maternal, fetal, and amnionic fluid progesterone levels remain elevated. It has been proposed that human parturition involves functional progesterone withdrawal mediated by decreased activity of progesterone receptors (Chap. 21, p. 401). It follows conceptually that the administration of progesterone may block preterm labor. This hypothesis has stimulated several studies of both 17 -alpha hydroxyprogesterone caproate (17OHP-C) and vaginally administered progesterone in women with varying risks for preterm birth.


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Obstentrics_Williams. At present, the reported benefits of either of these progestogen therapies are limited to women with singleton pregnancies. Progesterone prophylaxis speciically in multifetal gestations has not lowered preterm birth rates (Caritis, 2009; Rouse, 2007). Accordingly, both the American College of Obstetricians and Gynecologists (2016c) and the Society for Maternal-Fetal Medicine (2017 a) approve the use of progestogen therapy for prevention of preterm birth in select women with singleton pregnancies. Criteria are a history of prior preterm birth or no prior preterm birth but a sonographically identified short cervix.


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Obstentrics_Williams. 17 -OHP-C is a synthetic progestogen, and the first and only drug approved by the FDA for prevention of recurrent preterm birth. The approval in 2011 was supported by a study by the Maternal-Fetal Medicine Units (MFNIU) Network (Meis, 2003). In this trial, 463 women with a prior preterm birth were randomly assigned to receive weekly intramuscular injections of inert oil or 17-0HP-C from 16 through 36 weeks' gestation. They reported a significantly reduced recurrence of preterm birth in 36 percent of women receiving 17-0HP-C compared with 55 percent of those given placebo.


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Obstentrics_Williams. This MFMU study has been challenged because of the unexpectedly high preterm delivery rate in the placebo arm (Romero, 2013). One explanation for this high rate in the placebo group was asymmetry in the risks of recurrence. Indeed, 41 percent of the control group had ::2 prior preterm births compared with only 28 percent in the 17-0HP-C group. Another concern was that the injection dosage of 17-0HP-C, which was 250 mg weekly, was empirically chosen (Caritis, 2014). Only later reports described the pharmacokinetics of 17-0HP-C (Caritis, 2012). Nonetheless, the Society for Maternal-Fetal Medicine (2017a) recently reairmed the use of 17-0HP-C, rather than vaginal progesterone, for prevention of recurrent preterm birth.


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Obstentrics_Williams. Sharma and associates (2008) reported that the metabolism of 17-0HP-C was predominantly mediated by the CYP3A enzymatic system. Thus, other agents that induce or inhibit this enzymatic system as well as hepatic impairment may alter drug levels. They also showed that 17-0 HP -C is not converted after administration to the primary progesterone metabolite, 17a-hydroxyprogesterone. The relative binding ainity of 17-0 HP -C to progesterone receptors approximates only 30 percent of that by progesterone (Attardi, 2007). Because synthetic 17-0HP-C is not converted to a naturally occurring progestogen and is not superior to progesterone in eliciting a hormonal response via the classic steroid-receptor mediated pathway, alternative pathways are now being considered to explain its eicacy (Manuck, 2011).


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Obstentrics_Williams. Caritis and colleagues (2012) examined 61 women receiving 17-0HP-C therapy and found that the hlf-life was relatively long (median 16.2 days). Pharmacokinetic parameters were ffected by maternal body habitus and varied widely between subjects. In addition, 17 -OHP-C crossed the placental barrier and was detectible in cord plasma 44 days ater the last maternal injection (Caritis, 2012). Despite this, evidence to date suggests that 17-0HP-C is safe for the fetus. No abnormalities, including abnormal genitlia, were found in a 48-month follow-up study of infants exposed in the 2003 MFMU Network trial (Northen, 2007).


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Obstentrics_Williams. here are special concerns involving 17-0HP-C and subsequent price-gouging claims (Cohen, 2011; Romero, 2013). In 2011, the FDA gave temporary approval to V Pharmaceutical to market 17 -OHP-C under the brand name Makena. Because regulations prohibited compounding, there was no competitor for this relatively inexpensive drug, and Makena was priced at $1500 per injection. This caused widespread concern because the cumulative cost of Makena would be more than $30,000 per pregnancy. Use of 17-0HP-C at Parkland Hospital A program for implementation of 17-0HP-C was incorporated at Parkland Hospital in 2012. Given the concerns above, Preterm Birth 81.7 TABLE 42-6. Prior Obstetrical History of 430 Women with Births ;35 weeks and Recurrence Rates After 17-0HP-C at Parkland Hospital Prior Birth <35 Weeks Recurrence Ratea No. No. Rate p valueb Overall 16.8% 430 106 25% 1.0 Para 1 18% 141 44 31 % 1.0 Para 2: Only 2nd birth :;35 weeks 17% 48 20 42% 0.49 11 21 % 0.84


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Obstentrics_Williams. Prior Birth <35 Weeks Recurrence Ratea No. No. Rate p valueb Overall 16.8% 430 106 25% 1.0 Para 1 18% 141 44 31 % 1.0 Para 2: Only 2nd birth :;35 weeks 17% 48 20 42% 0.49 11 21 % 0.84 Only 1 st birth :;35 weeks Para 3+: 11 % 5% 0.18 All :;35 weeks 45% 12 44% 0.56 Other sequences of :;35 weeks 12% 123 17 14% 0.78 aRecurrence rate is derived from the Parkland obstetrical population for 1988-201n1 prior to introduction of 17-0HP-C. bp values are one-sided. Reproduced with permission from Nelson, 2017.


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Obstentrics_Williams. a local compounding pharmacy provided 250-mg, single-dose From the foregoing studies, evidence to support the use of vials of 17-0HP-C in sesame oil at a cost of $25 per dose. 17-0HP-C to prevent recurrent preterm birth is problematic Nelson and colleagues (2017) recently reported their indings (Young, 2017). he mechanism of action remains unknown, from this program in a prospective study of 430 women given and the pharmacological properties have yet to be established. compounded 17-0HP-C. Use of 17-0HP-C was inefective Evidence of clinical efectiveness has yet to be replicated. A confor prevention of recurrent preterm birth at 35 weeks or less dition of the FDA approval for 17-0HP-C was that a conircompared with a historical cohort from Parkland. As shown matory multicenter, double-blind randomized controlled trial in Table 42-6, 17-0HP-C did not signiicantly reduce the be conducted with a preferred primary end point of delivery rates of recurrent preterm birth regardless of prior


Obstentrics_Williams

Obstentrics_Williams. randomized controlled trial in Table 42-6, 17-0HP-C did not signiicantly reduce the be conducted with a preferred primary end point of delivery rates of recurrent preterm birth regardless of prior preterm <35 weeks. This international trial-PRO LONG-is currently birth number or sequence. Moreover, plasma concentrations of underway with scheduled completion in 2018 and with an esti17-0HP-C were not diferent at 24 weeks or 32 weeks between mated enrollment of 1707 participants (PROLONG, 2014). women delivered :;35 weeks and those delivered later. Interestingly, levels were consistent with those previously reported using castor oil as a vehicle (Caritis, 2014). Last, the gestational age interval at which preterm birth recurred did not difer after use of 17-0HP-C. A side efect of 17-0HP-C was a signifiThree randomized trials are at the center of whether progestocant increase in the rate of gestational diabetes. Taken together, gen therapy should be used in women without prior preterm 17


Obstentrics_Williams

Obstentrics_Williams. a signifiThree randomized trials are at the center of whether progestocant increase in the rate of gestational diabetes. Taken together, gen therapy should be used in women without prior preterm 17 -0 HP -C use was inefective to prevent recurrent preterm births. hese trials, shown in Table 42-7, hinge on sonographbirth and was associated with a significant side efect. ically determined cervical length. In the irst trial, Fonseca and


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Obstentrics_Williams. TABLE 42-7. Randomized Trials of Progestogen Compounds Given Prophylactically to Prevent Preterm Labor Fonseca (2007) n = 250; 5% nulliparous, 10% <15 mm Progesterone, 200-mg Delivery <34 weeks: twins, 15% prior PTB; 8 hospitals: vaginal capsules daily 19% vs 34%, P = .02 UK, Greece, Brazil, Chile Hassan (201l) n = 465; singletons only; 55% 10-20 mm Progesterone, 90-mg Delivery <33 weeks: 9% nulliparous; 13% prior PTB; vaginal gel daily vs 16%, p = .02 Grobman (2012) n = 657; singletons only; nulliparous <30nmm 17-0HP-C, 250 mg 1M Delivery <37 weeks: only; 14 centers across US weekly 25% vs 24%, p = NS Determined sonographically. 17-0HP-C = 17-hydroxyprogesterone caproate; 1M = intramuscularly; NS = nonsignificant; PTB = preterm birth; UK = United Kingdom; US = United States.


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Obstentrics_Williams. Determined sonographically. 17-0HP-C = 17-hydroxyprogesterone caproate; 1M = intramuscularly; NS = nonsignificant; PTB = preterm birth; UK = United Kingdom; US = United States. colleagues (2007) randomly assigned 250 women with short cervices measuringr:;15 mm identified during routine prenatal care. Women were given nightly 200-mg micronized progesterone vaginal capsules or placebo from 24 to 34 weeks' gestation. Spontaneous delivery <34 weeks was significantly reduced by progesterone therapy. Importantly, this trial included not only nulliparas but also those with twins or prior pre term birth. In the second trial, Hassan and coworkers (2011) randomly assigned 465 women with a short cervix-IO to 20 mm-to vaginal progesterone gel, 90 mg daily, or placebo. his trial also included nulliparas and women with prior preterm births.


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Obstentrics_Williams. From these studies, the FDA rejected progesterone gel for use because the results did not meet the level of statistical significance required to show eicacy in the subjects recruited in the United States. According to Likis and colleagues (2012), the heterogeneity of these first two studies that included women with varied indications for progestogen treatment, combined with the fact that outcomes were not reported by risk factors such as nulliparity, made it impossible to interpret the eicacy of progesterone for speciic indications. The third study randomly assigned administration of 17 -0 HP -C intramuscular injection or placebo between 16 and 223/7 weeks to nulliparas with a singleton gestation and a cervical length < 30 mm detected sonographically (Table 42-8) (Grobman, 2012). Treatment with 17-0HP-C given weekly did not reduce the frequency of preterm birth before 37 weeks. Regardless of cervical length, 17-0 HP -C was inefective.


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Obstentrics_Williams. hus, vaginal progesterone, but not 17 -OHP-C, appears to benefit women with a sonographically measured short cervix. Romero and Stanczyk (2013) provided a review to explain the conlicting evidence and argued that naturally occurring progesterone, which is used in the vaginal preparations, is not the same as synthetic 17-0HP-C. Likewise, Furcron and coworkers (2015) found that 17-0 HP -C did not have local antiinflammatory efects at the maternal-fetal interface or cervix. Further, 17 -OHP-C did not protect against endotoxin-induced preterm birth. From all these studies, the merican College of Obstetricians and Gynecologists (2016c) concluded that universal cervical length screening in women without a prior preterm birth is not mandatory. However, this screening strategy could be considered in the context of treatment with vaginal progesterone.


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Obstentrics_Williams. The OPPTIMUM Study his study of 1228 high-risk women with singleton pregnancies is the largest to date for vaginal progesterone prophylaxis (N orman, 2016). his randomized trial of vaginal progesterone, 200 mg daily from 22-24 weeks to 34 weeks of gestation, was termed the OPPTIMUM study-dQes Erogesterone Erophyxis Io prevent preterm labor prove High-risk women were defined as those with a prior spontaneous birth :;34 weeks or with a cervical length :;25 mm or a positive FN test result combined with other clinical risk factors for preterm birth.


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Obstentrics_Williams. he primary outcomes of OPPTHvIUM were unique in that both immediate obstetrical and childhood outcomes were examined. These were fetal death or birth <34 weeks; a composite of death, brain injury, or bronchopulmonary dysplasia; and a standardized cognitive score at 2 years of age. Contrary to earlier reports, vaginal progesterone was not associated with a lower risk of preterm birth or composite neonatal adverse outcomes. In children at 2 years of age, vaginal progesterone also had no long-term benefit or harm.


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Obstentrics_Williams. hus, evidence is conflicting as to the eicacy of progestogens across the spectrum of the various specific indications. Some have attempted to resolve these issues through systematic review and metaanalysis (Prior, 2017; Romero, 2016, 2017). s outlined in this entire section, virtually all evidence supporting use of progestogens for a specific indication can be challenged in some way. We agree with the conclusions from the OPPTIMUM trial (Norman, 2016) that the results of recent studies should prompt a major review of progesterone use for preterm birth prophylaxis, a search to identiy specific women who might specifically benefit, and a redoubling of eforts to find alternative strategies to prevent preterm birth in women at risk. TABLE 42-8. Comparison of 17-0HP-C versus Placebo to Prevent Preterm Birth at Preterm birth <37 wk: Cervical length, mm Preterm birth <34 wk: Cervical length, mm ap value for Breslow-Day interaction term. Data are presented as n/N (%).


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Obstentrics_Williams. Preterm birth <37 wk: Cervical length, mm Preterm birth <34 wk: Cervical length, mm ap value for Breslow-Day interaction term. Data are presented as n/N (%). CI = confidence interval; RR = relative risk; 17-0HP-C = 17-hydroxyprogesterone caproate. Data from Grobman, 201n2. FIGURE 42-8 Percentage of births before 37 weeks' gestation at Parkland Hospital from 1988 to 2006 compared with that in the United States from 1996 to 2002. Analysis in both cohorts was limited to singleton liveborn infants �500 g who received prenatal care. (Reproduced with permission from with permission from Leveno J, Mcintire DO, Bloom SL, et al: Decreased preterm births in an innercity public hospital, Obstet Gynecol. 2009 Mar;1o13(3):578-584.)


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Obstentrics_Williams. Awell-organized prenatal system lowers the preterm birth rate in high-risk indigent populations (Creasy, 1980). One example is the Parkland Hospital prenatal clinic system (Leveno, 2009). As shown in Figure 42-8, the declining preterm birth rate between 1988 and 2006 coincided with a substantial rise in prenatal care attendance. In the early 1990s, a concerted efort was made to improve access to prenatal care by creating seamless care that began with antenatal enrollment and extended through delivery and the puerperium. Prenatal clinics were placed strategically throughout Dallas County to provide convenient access for our patients. Prenatal protocols are used by nurse practitioners at all clinic sites to guarantee homogeneous care. Women with highrisk pregnancy complications are referred to our hospital-based central clinic system. Here, Maternal-Fetal Medicine clinics operate each weekday and are stafed by residents and midwives and supervised by fellows and faculty.


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Obstentrics_Williams. hus, prenatl care is considered one component of a comprehensive and orchestrated public health-care system that is community-based. We believethat the drop in preterm births experienced at our inner-city hospitl is at least partially attributable to a geographically based public health-care program specifically targeting minority populations ofpregnant women. A similar obstetrical care system for indigent women at the University of Alabama at Birmingham has also produced salutary results (Tita, 2011).


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Obstentrics_Williams. Methods used to diagnose ruptured membranes are detailed in Chapter 22 (p. 435). A history of vaginal leakage of luid, either as a continuous stream or a gush, should prompt a speculum examination to visualize gross vaginal pooling ofamnionic fluid, clear fluid from the cervical canal, or both. Conirmation of PPROM is usually accompanied by sonographic examina tion to assess amnionic fluid volume, to identiY the presenting part, and if not previously determined, to estimate gestational age. Once PPROM is identified, the general scheme shown in Table 42-9 can guide management.


Obstentrics_Williams

Obstentrics_Williams. Table 42-9 can guide management. Cox and associates (1988) describedpregnancy outcomes of298 consecutive womenwho gave birth following spontaneously ruptured membranes between 24 and 34 weeks' gestation at Parkland Hospital. 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, 76 percent of the women were already in labor, and 5 percent were delivered for other complications. Thus, only 19 percent initially were permitted expectant management. Ultimately, deliverywas delayed 48 hours or more ater membrane rupture in only 7 percent of the total study cohort. There was beneit noted from delayed delivery, however, as none of the neonates died in this group. This contrasted with a neonatal death rate of 80 per 1000 in preterm newborns delivered within 48 hours ofmembrane rupture. Nelson and colleagues later (1994) reported similar results.


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Obstentrics_Williams. The time from PPROM to delivery is inversely proportional to the gestational age when rupture occurs (Carroll, 1995). s shown in Figure 42-9, very few days are gained when membranes ruptured during the third trimester compared with midpregnancy. Most clinicians hospitalize women with ruptured membranes. Concerns regarding the costs oflengthy hospitalizations are usually moot, because most women enter labor within a week or less after membrane rupture. Carlan and coworkers (1993) randomly assigned 67 women with ruptured membranes ro home or hospital management. No benefitswere found for hospitalization, and maternal hospital stays were reduced by 50 percent in those sent home-14 versus 7 days. Importantly, the investigators emphasized that this study was too small to conclude that home management was safe in regard to umbilical cord prolapse.


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Obstentrics_Williams. Before the mid-1970s, labor was usually induced in women with preterm ruptured membranes because of fear of sepsis. Maternal infection risk and fetal prematurity risk vary according to the gestational age at membrane rupture, and management decisions hinge on this balance. With regard ro periviable pregnancy, 110rales (1993b) expectantly managed 94 singleton pregnancies with ruptured membranes before 25 weeks. he average time gained was 11 days. Although 41 percent ofinfants survived to age 1 year, only 2 percent of the original cohort were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their colleagues. Management of these early pregnancies is discussed on page 807. For PPROM in general, two randomized trials in the 1990s compared labor induction with expectant management (Cox, 1995; Mercer, 1993). In both of these studies, the balance of risk and beneit was diicult to ascertain, as neither immediate • •I I . .•.,. . .• I · .......


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Obstentrics_Williams. FIGURE 42-9 Relationship of time between preterm membrane rupture and delivery in 172 singleton pregnancies. (Reproduced with permission from Carroll SG, Blott M, Nicolaides KH: of membranes before 37 weeks' gesPreterm prelabor amniorrhexis: Outcome of live births, Obstet Gynecol 1995 Jul;86(1 ):18-25.) tation without contraindications to TABLE 42-9. Management of Preterm Premature Rupture of Membranes 34 weeks or more Plan delivery: labor induction unless contraindicated Group B streptococcal Single corticosteroid course may be considered up to 366/7 weeksb 32 weeks to 33 completed weeks Expectant management Group B streptococcal prophylaxisa Single corticosteroid coursec Antimicrobials to prolong latency 24 weeks to 31 completed weeks Expectant management T ocolytics: no consensus Antimicrobials to prolong latency <24 weeks Expectant management or induction of labore Group B streptococcal prophylaxis is not recommendedf Single corticosteroid course may be considerede,f f


Obstentrics_Williams

Obstentrics_Williams. Group B streptococcal prophylaxis is not recommendedf Single corticosteroid course may be considerede,f f Tocolytics: no consensuse,n Antimicrobials: may be considerede,9 aFigure 64-7 (p. 1222) outlines group B streptococcal prophylaxis for preterm gestations. bMay be considered between 34°17 and 366/7 weeks in those who have not received a previous course of antenatal corticosteroids. (Repeat, or rescue, course of corticosteroids with preterm rupture of membranes is controversial. dMagnesium sulfate for neuroprotection in accordance with one of the larger studies. eSee Periviable Neonatal Survival (p. 806) to aid patient counseling and decision making. flntervention not recommended before viability but may be considered as early as 23°(7 weeks of gestation. 9May be considered as early as 20°/7 weeks of gestation. Data from American College of Obstetricians and Gynecologists 2016a, d, 2017a, e.


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Obstentrics_Williams. Data from American College of Obstetricians and Gynecologists 2016a, d, 2017a, e. delivery nor expectant management were proven to be superior prolonged latency after membrane rupture was not associated for neonatal outcomes. Lieman and associates (2005) found that with a greater incidence of fetal neurological damage. n imporneonatal outcomes did not improve with expectant management tant correlate is that infection-specifically chorioamnionitisbeyond 33 weeks. McElrath and coworkers (2003) found that is recognized as a risk factor for development of neonatal neurological injury (Gaudet, 2001; Wu,r2000). •Deaths from prematurity complications recently compared planned early 150 birth with expectant management ..Deaths from pulmonary hypoplasia for women with PPROM before 37 weeks' gestation. They evaluated women and 3628 newborns. No �90 • ..0• clinically important diferences in ..,..0. . D • the incidence of neonatal sepsis


Obstentrics_Williams

Obstentrics_Williams. D • the incidence of neonatal sepsis C .•. • between women who immediately ..0. . . • . . • delivered and those managed expec ..,..0. . tantly were identified. Although the .,incidence of chorioamnionitis was ..,:I · : lower, neonates of women random ized to early birth were more likely to be born at an earlier gestational Gestation at amniorrhexis (weeks) perinatal sequelae. The authors con cluded that in women with rupture continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for both the mother and newborn.


Obstentrics_Williams

Obstentrics_Williams. he American College of Obstetricians and Gynecologists (2016d) has recognized the controversies of immediate deliv ery compared with expectant management. Clearly, gestational age is an important consideration. At 24°/7 to weeks, expectant management in the absence of nonreassuring fetal status, clinical chorioamnionitis, or placental abruption is rec ommended. At 34°/7 weeks of gestation or greater, delivery is still recommended by the College for all women with ruptured membranes. Our current practices at Parkland Hospital are consistent with these recommendations. • Considerations with Expectant Management


Obstentrics_Williams

Obstentrics_Williams. • Considerations with Expectant Management Several scenarios during expectant management merit consideration. One is performance of digital cervical examination. Alexander and colleagues (2000) analyzed findings in women with PPROM expectantly managed between 24 and 32 weeks' gestation. hey compared those who had one or two digital cervical examinations with women who were not examined. Those who were examined had a rupture-to-delivery interval of 3 days compared with 5 days in those not examined. This diference did not worsen maternal or neonatal outcomes.


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Obstentrics_Williams. Rupture of membranes following second-trimester amniocentesis is uncommon (Chap. 14, p. 293). Compared with women with spontaneous rupture during the second trimester, Borgida and associates (2000) found that pregnancies complicated by PPROM after genetic amniocentesis resulted in signiicantly better perinatal outcomes. The perinatal survival rate was 91 percent. After counseling, afected women are typically managed expectantly as outpatients with serial surveillance of amnionic fluid volume (American College of Obstetricians and Gynecologists, 2016d). In the series cited above, the mean time to documentation of a normal amnionic fluid volume after amniocentesis approximated 2 weeks.


Obstentrics_Williams

Obstentrics_Williams. T ocolysis has been used in few studies. In women with ruptured membranes and lack of labor, prophylactic tocolysis does not improve neonatal outcomes but is associated with greater rates of chorioamnionitis (Mackeen, 2014). Similarly, therapeutic tocolysis-for those with ruptured membranes and labor-has also not provided signiicant perinatal beneit (Garite, 1987). There is uncertainty regarding PPROM in the woman who has undergone cervical cerclage. McElrath and associates (2002) studied 114 women with a cerclage in place who later had ruptured membranes before 34 weeks. They were compared with 288 controls. Pregnancy outcomes were equivalent in both groups. Cerclage retention for more than 24 hours after preterm rupture of membranes may be associated with pregnancy prolongation, however, there is risk of intrauterine infection and its consequences (Giraldo-Isaza, 2011r; Laskin, 2012). As discussed in Chapter 18 (p. 357), such management is controversial.


Obstentrics_Williams

Obstentrics_Williams. With PPROM in general, the volume of amnionic luid remaining after rupture appears to have prognostic importance in pregnancies before 26 weeks. Hadi and colleagues (1994) described 178 pregnancies with ruptured membranes between 20 and 25 weeks. Almost 40 percent developed oligohydram nios, defined by the absence of fluid pockets measuring 2 em or more. Virtually all women with oligohydramnios delivered before 25 weeks, whereas 85 percent with adequate amnionic luid volume were delivered in the third trimester. Carroll and coworkers (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 devel opment of lung hypoplasia (Chap. 7, p. 133). Further, when contemplating early expectant management, consideration is also given to oligohydramnios and resultant limb compression deformities (Chap. 11, p. 232).


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Obstentrics_Williams. Other risk factors have also been evaluated. First, in neo nates born to women with active herpetic lesions who were expectantly managed, the infectious morbidity risk appeared to be outweighed by risks associated with preterm delivery (Major, 2003). Second, Lewis and associates (2007) found that expectant management of women with PPROM and nonce phalic presentation was associated with a higher rate of umbili cal cord prolapse, especially before 26 weeks.


Obstentrics_Williams

Obstentrics_Williams. As discussed, infection is a major concern with membrane rupture. While some cases remain subclinical, if chorioamnionitis is diagnosed, prompt eforts to efect delivery, preferably vaginally, are initiated. Because maternal leukocytosis alone is not a consistent inding, ever is the ony reliable indicator or the diagnosis of chorioamnionitis. Institutional practices and protocols vary in deining the temperature threshold. T raditionally, a temperature �38°C (100.4°F) accompanying ruptured membranes has implied infection. At Parkland Hospital, we still adhere to this criterion.


Obstentrics_Williams

Obstentrics_Williams. In 2015, a workshop sponsored by the NICHD was convened and suggested renaming this condition "intraamnionic infection and inflammation" (Higgins, 2016). The merits and clinical utility of this novel "triple I" terminology have been questioned (Barth, 2016). Nonetheless, the American College of Obstetricians and Gynecologists (20 17b) recently revised both the definitions and temperature thresholds for intraamnionic infection. Using these new deinitions, the diagnosis of suspected intraamniotic infection is made when the maternal temperature is �39.0°C or when the maternal temperature is 38.0 to 38.9°C and one additional clinical risk factor is present. Suggested factors include low parity, multiple digital examinations, use of internal uterine and fetal monitors, meconiumstained amnionic fluid, and the presence of certain genital tract pathogens. Examples are group B streptococcus and sexually transmitted agents. Isolated maternal fever is deined as any maternal temperature between


Obstentrics_Williams

Obstentrics_Williams. fluid, and the presence of certain genital tract pathogens. Examples are group B streptococcus and sexually transmitted agents. Isolated maternal fever is deined as any maternal temperature between 38.0°C and 38.9°C with no additional risk factors present, and with or without persistent temperature elevation.


Obstentrics_Williams

Obstentrics_Williams. With chorioamnionitis, fetal and neonatal morbidity are substantively increased. lexander and colleagues (1998) studied 1367 very-Iow-birthweight neonates delivered at Parkland Hospital. Approximately 7 percent were born to women with overt chorioamnionitis, and their outcomes were compared with similar newborns without clinical infection. Those in the infected group had higher incidences of sepsis, RDS, earlyonset seizures, intraventricular hemorrhage, and periventricular leukomalacia. The investigators concluded that these very-Iowbirthweight newborns were vulnerable to neurological injury attributable to chorioamnionitis. Yoon and colleagues (2000) found that intraamnionic infection in preterm neonates was related to increased rates of cerebral palsy. Petrova and associates (2001) studied more than 11 million singleton live births in the United States from 1995 to 1997. During labor, 1.6 percent of all women had fever, and this was a strong predictor of infection-related death in


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Obstentrics_Williams. more than 11 million singleton live births in the United States from 1995 to 1997. During labor, 1.6 percent of all women had fever, and this was a strong predictor of infection-related death in both term and preterm neonates.


Obstentrics_Williams

Obstentrics_Williams. The proposed microbial pathogenesis for spontaneous preterm labor or ruptured membranes has prompted investigators to give various antimicrobials to forestall delivery. Mercer and associates (1995) reviewed 13 randomized trials performed before 35 weeks. heir metaanalysis indicated that only three of 10 outcomes werepossiby beneited: (1) fewer women developed chorioamnionitis, (2) fewer newborns developed sepsis, and (3) pregnancy was more often prolonged 7 days in women given antimicrobials. Rates of neonatal survival, necrotizing enterocolitis, RDS, or intracranial hemorrhage, however, were unafected.


Obstentrics_Williams

Obstentrics_Williams. To further address this issue, the MFMU Network designed a trial to study expectant management combined with placebo or with a 7 -day antibiotic regimen. Treatment included intravenous ampicillin plus erythromycin every 6 hours for 48 hours, which was followed by oral amoxicillin plus erythromycin, every 8 hours for 5 days. The women had membrane rupture between 24 and 32 weeks' gestation. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had signiicantly fewer newborns with RDS, necrotizing enterocolitis, and composite adverse outcomes (Mercer, 1997). The latency period was also 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. lso, a significantly greater number of treated pregnancies were undelivered at 14 and 21 days. Cervico vaginal group B streptococcal colonization did not alter these results.


Obstentrics_Williams

Obstentrics_Williams. Other studies have examined the eicacy of shorter treatment lengths and diferent antimicrobial combinations. hreeday treatments compared with 7 -day regimens using either ampicillin or ampicillin-sulbactam appear equally efective in regard to perinatal outcomes (Lewis, 2003; Segel, 2003). Similarly, erythromycin compared with placebo ofered a range of significant neonatal benefits. The amoxicillin-clavulanate regimen was not recommended, however, because of its association with an increased incidence of neonatal necrotizing enterocolitis (Kenyon, 2004).


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Obstentrics_Williams. Some predicted that prolonged antimicrobial therapy in such pregnancies might have unwanted consequences (Carroll, 1996; Mercer, 1999). Stoll and associates (2002) studied 4337 neonates weighing from 400 to 1500 g and born from 1998 to 2000. Their outcomes were compared with those of 7606 neonates of similar birthweight born from 1991 to 1993 and prior to the practice of antibiotic prophylaxis. The overall rate of early-onset sepsis did not change between these two epochs. But, the rate of group B streptococcal sepsis dropped from 5.9 per 1000 births in the 1991 to 1993 group to 1.7 per 1000 births in the 1998 to 2000 group. Comparing these same epochs, the rate of Escherichia coli sepsis, however, rose from 3.2 to 6.8 per 1000 births. Almost 85 percent of coliform isolates from the more recent cohort were resistant to ampicillin. Neonates with early-onset sepsis were more likely to die, especially if they were infected with coliforms. Long term, Kenyon and coworkers (2008a) found


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Obstentrics_Williams. recent cohort were resistant to ampicillin. Neonates with early-onset sepsis were more likely to die, especially if they were infected with coliforms. Long term, Kenyon and coworkers (2008a) found that antimicrobials given for women with PPROM had no efect on the health of children at age 7 years .


Obstentrics_Williams

Obstentrics_Williams. • Corticosteroids to Accelerate The use of antenatal corticosteroids in the setting of PPROM was once considered controversial as the magnitude of the beneits was not as great as when the membranes were intact. A single course of corticosteroids, however, is now recommended for pregnant women with ruptured membranes between 24°/7 and 34°17 weeks' gestation (American College of Obstetricians and Gynecologists, 2017 a). As with periviability (p. 807), a single course of corticosteroids as early as 23°/7 weeks in those who are at risk for preterm delivery within 7 days may be considered (American College of Obstetricians and Gynecologists, 2017e). A similar controversy is found at the other end of the gestational age spectrum, wherein corticosteroid administration in the late-pre term period is also under consideration (p. 823).


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Obstentrics_Williams. Tissue sealants are used for various purposes in medicine, including achieving surgical hemostasis. As discussed in Chap. 18 (p. 351), there are limited reports of sealants in the repair of fetal membranes. Crowley and coworkers (2016) recently reviewed the available evidence and concluded that data are currently insuicient to evaluate sealing procedures for ruptured membranes. At Parkland Hospital, we do not currently use these agents for this indication. Women with signs and symptoms of preterm labor with intact membranes are managed similarly to those with PPROM. If possible, delivery before 34 weeks' gestation is delayed. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed. • Amniocentesis to Detect Infection


Obstentrics_Williams

Obstentrics_Williams. • Amniocentesis to Detect Infection Several tests have been used to diagnose intraamnionic infection (Andrews, 1995; Romero, 1993; Yoon, 1996). Although such infection can be conirmed with a positive test result, there is little utility for routine amniocentesis (American College of Obstetricians and Gynecologists (2017b). Because glucocorticosteroids were found to accelerate lung maturation in preterm sheep fetuses, Liggins and Howie (1e972) evaluated them to treat women. Corticosteroid therapy was efective in lowering the incidence of RDS and neonatal initiation of betamethasone. Infants exposed to corticosteroids in these early studies have now been followed to age 31 years with no ill efects detected. In 1995, a National Institutes of ened preterm birth. In a subsequent meeting, another NIH


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Obstentrics_Williams. Conference (2000) concluded that data were insuicient to by hypertension, diabetes, multifetal gestation, fetal-growth restriction, or fetal hydrops. It was concluded, however, that it was reasonable to administer corticosteroids to these women. A recent metaanalysis by Roberts and associates (20e17) of 30 studies totaling 7774 women and 8158 infants quantiied the beneit of a single course of corticosteroids. Treatment was associated with lower rates of perinatal death, neonatal death, RDS, intraventricular hemorrhage, necrotizing enterocolitis, need for mechanical ventilation, and systemic infection in the first 48 hours of life. No obvious beneits were gained for chronic lung disease, death in childhood, or neurodevelopmental delay in childhood. Therapy was not associated with chorioamnionitis. Parenthetically, corticosteroids given prophylactically to women at risk of preterm birth in low-and middle-income countries actually increase perinatal mortality rates (Althabe, 2015).


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Obstentrics_Williams. A single course of corticosteroids is currently recommended by the American College of Obstetricians and Gynecologists (2017a) for women between 24 and 34 weeks who are at risk for delivery within 7 days. This recommendation for premature twins has been challenged (Viteri, 20e16). Boundaries of gestational age for corticosteroid administration are also now being explored. For pregnancies at 23 weeks and at risk of delivery within 7 days, a single course of corticosteroids may be considered (p. 807). Administration of corticosteroids during the periviable period is linked to a family's decision regarding resuscitation and should be considered in that context (American College of Obstetricians and Gynecologists, 20e1e7e).


Obstentrics_Williams

Obstentrics_Williams. Betamethasone and dexamethasone appear to be equivalent for fetal lung maturation (Murphy, 2007). These two drugs are comparable in reducing rates of major neonatal morbidities in preterm newborns (Elimian, 2007). A treatment course may be two 12-mg doses of betamethasone, and each dose is given intramuscularly 24 hours apart. With dexamethasone, 6-mg doses are given intramuscularly every 12 hours for four doses. Because treatment for less than 24 hours may be beneicial and reduce neonatal morbidity and mortality rates, a first dose of antenatal corticosteroids is administered regardless of the ability to complete additional doses before delivery (American College of Obstetricians and Gynecologists, 20e1e7a). The MFMU Network conducted a randomized trial to assess whether administration of antenatal betamethasone to women who were likely to deliver in the late-pre term period would


Obstentrics_Williams

Obstentrics_Williams. The MFMU Network conducted a randomized trial to assess whether administration of antenatal betamethasone to women who were likely to deliver in the late-pre term period would Bannerman, 2016). Even though only 60 percent of the study cohort of 283e1 women received both injections, the rate of respiratory complications measured as a composite outcome was lower with corticosteroid use compared with placebo-1 1.6 versus 14.4 percent. Because of these indings, consideration for administration of a single course of betamethasone for women the American College of Obstetricians and Gynecologists (2017a) and the Society for Maternal-Fetal Medicine (2016a).


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Obstentrics_Williams. Adoption of this practice has not been universal. Both shortand long-term neonatal safety are concerns (Crowther, 2016; Kamath-Rayne, 2016). Specifically, in the newborns receiving betamethasone, rates of hypoglycemia were signiicantly greater (Gyami-Bannerman, 20e16) . Neonatal hypoglycemia is particularly worrisome for possible adverse long-term consequences that include developmental delay (Kerstjens, 2012). Another caveat is that the largest efects of betamethasone included a reduction in transient tachypnea of the newborn-a self-limited condition with little clinical signiicance (KamathRayne, 2016). Speciically, the rates of transient tachypnea of the newborn were 6.7 and 9.9 percent in those given betamethasone and placebo, respectively. These rates are three-to fourfold higher than those reported by the Consortium on Safe Labor (20e10), which was a retrospective, observational study that abstracted detailed labor and delivery information from 19 hospitals across the United


Obstentrics_Williams

Obstentrics_Williams. than those reported by the Consortium on Safe Labor (20e10), which was a retrospective, observational study that abstracted detailed labor and delivery information from 19 hospitals across the United States on 233,844 deliveries. Because of these issues, we do not provide corticosteroids beyond 34 weeks at Parkland Hospital at this time.


Obstentrics_Williams

Obstentrics_Williams. Single versus additional courses of intramuscular corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneicial in reducing neonatal respiratory morbidity rates, the long-term consequences were much diferent. In one randomized study by Crowther and associates (2007), all women at risk for preterm birth were given a primary course of betamethasone. Women were then given serial weekly doses of 11e.4 mg of betamethasone for persistent risk or were given placebo. hese investigators found no adverse efects in the infants followed to age 2 years. Wapner and coworkers (2007) studied infants born to 495 women who were randomly assigned to receive a single corticosteroid course that contained two doses or assigned to repeated courses that were given weekly. A nonsignificant rise in the cerebral palsy rate was identified in infants exposed to repeated courses. The doubled betamethasone dose in this study was worrisome because


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Obstentrics_Williams. that were given weekly. A nonsignificant rise in the cerebral palsy rate was identified in infants exposed to repeated courses. The doubled betamethasone dose in this study was worrisome because some experimental evidence supports the view that adverse efects are dose dependent (Bruschettini, 2006). Stiles (2007) summarized these two studies as "early gain, long-term questions." We agree, and at Parkland Hospital, we follow the recommendation by the American College of Obstetricians and Gynecologists (2017a) for singlecourse therapy.


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Obstentrics_Williams. his refers to administration of a second corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. In one randomized trial, 326 women received placebo or a single 12-mg dose of betamethasone (Peltoniemi, 2007). Paradoxically, the rescue dose of betamethasone increased the risk of RDS. In another randomized study of 437 women with gestations <33 weeks, Garite and associates (2009) reported significantly lower rates of respiratory complications and neonatal composite morbidity with rescue corticosteroids versus placebo. Rates of perinatal mortality and other morbidities, however, did not difer. Last, McEvoy and colleagues (2010) found that treated infants had improved respiratory compliance.


Obstentrics_Williams

Obstentrics_Williams. Garite and coworkers (2009) randomly assigned 437 women with singletons or twins <33 weeks' gestation and with intact membranes to one rescue course of either betamethasone or dexamethasone or placebo. These women had all previously completed a single course of corticosteroids before 30 weeks' gestation and at least 14 days before the rescue course. RDS developed in 41 percent of the newborns given rescue corticosteroids compared with 62 percent of those randomized to placebo. Rates of other morbidities attributable to prematurity did not difer. In a metaanalysis, Crowther and colleagues (201e1) concluded that a single course of corticosteroids should be considered in women whose prior course was administered at least 7 days previously and who were <34 weeks' gestation. The American College of Obstetricians and Gynecologists (2017 a) has taken the position that a single rescue course of antenatal corticosteroids be considered in women before 34 weeks whose prior course was


Obstentrics_Williams

Obstentrics_Williams. College of Obstetricians and Gynecologists (2017 a) has taken the position that a single rescue course of antenatal corticosteroids be considered in women before 34 weeks whose prior course was administered at least 7 days previously. Efects of rescue therapy beyond 34 weeks are currently unknown. At Parkland Hospital, we currently do not provide additional courses of corticosteroids beyond the initial single-course therapy.


Obstentrics_Williams

Obstentrics_Williams. Very-Iow-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, 2000; Nelson, 1995). Because of this, randomized trials were designed to investigate this hypothesis. In one trial, 1063 women at risk of delivery before 30 weeks were given magnesium sulfate or placebo (Crowther, 2003). Magnesium exposure improved some perinatal outcomes. Namely, rates of both neonatal death and cerebral palsy were lower in the magnesium-treated group-but this study was not suiciently powered. The multicenter French trial reported by Marret and associates (2008) had similar problems.


Obstentrics_Williams

Obstentrics_Williams. More convincing evidence for magnesium neuroprotection came from the MFMU Network study-Beneicial Eects of Antenatal Magnesium Suote-BM-Study (Rouse, 2008). This was a placebo-controlled trial in 224e1 women at imminent risk for preterm birth between 24 and 31 weeks. Women randomized to magnesium sulfate were given a 6-g bolus over 20 to 30 minutes followed by a maintenance infusion of 2 g per hour. Magnesium sulfate was actually infusing at the time of delivery in approximately half of the treated women. A 2-year follow-up was available for 96 percent of the children. Results are shown in Table 42-10. his trial can be interpreted diferently depending on statistical methodologies employed. Some interpret these indings to mean that magnesium infusion prevents cerebral palsy regardless of the gestational age at which therapy is given. Those with a difering view conclude that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks.


Obstentrics_Williams

Obstentrics_Williams. Subsequent to these studies, Doyle and associates (2009) reviewed five randomized trials to assess neuroprotective efects. A total of 6145 infants were studied, and these reviewers concluded that magnesium exposure compared with no exposure significantly lowered risks for cerebral palsy. Rates of other neonatal morbidity did not difer significantly. It was calculated that treatment given to 63 women would prevent one case of cerebral plsy.


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Obstentrics_Williams. Controversy surrounding magnesium eicacy for neuroprotection prompted a debate at the 20e11 annual meeting of the Society for Maternal-Fetal Medicine. Rouse (2011) spoke for the beneits of magnesium sulfate, whereas Sibai (2011) challenged that the reported benefits were false positive due to random statistical error in the metaanalysis by Doyle (2009). Another peculiarity is the apparent lack of dose-response for eicacy (McPherson, 2014). Because none of the individual studies found a benefit from magnesium sulfate for fetal neuroprotection, the American College of Obstetricians and Gynecologists (20e1e6a) concluded that those electing prophylaxis should develop specific guidelines. To guide such therapy, the American College of Obstetricians and Gynecologists (20e12) TABLE 42-10. Magnesium Sulfate for the Prevention of Cerebral Palsya Infants with 2-year follow-up


Obstentrics_Williams

Obstentrics_Williams. TABLE 42-10. Magnesium Sulfate for the Prevention of Cerebral Palsya Infants with 2-year follow-up Moderate or severe cerebral palsy: aSelected results from the Beneficial Efects of Antenatal Magnesium Sulfate (BEAM) Study. bWeeks' gestation at randomization. CI = confidence index. Data from Rouse, 2008. issued a Patient Saey Checklist for use of magnesium sulfate for neuroprotection. For those with PPROM, prophylaxis may similarly be considered. At Parkland Hospital, we provide magnesium sulfate for neuroprotection with threatened preterm delivery from 24°/7 to 276/7 weeks.


Obstentrics_Williams

Obstentrics_Williams. Results have been disappointing in studies of antimicrobials given to arrest preterm labor. From one Cochrane metaanalysis, antimicrobial prophylaxis given to women with intact membranes did not reduce preterm birth rates or afect other clinically important short-term outcomes (Flenady, 2013). However, rates of short-and longer-term harm were higher for children of mothers exposed to antibiotics. Kenyon (2001) reported the ORACLE Collaborative Group study of 6295 women with spontaneous preterm labor and intact membranes, but without evidence of infection. Women were randomly assigned to receive antimicrobial or placebo therapy. The primary outcomes of neonatal death, chronic lung disease, and major cerebral abnormality were similar in both groups. In a follow-up of the ORACLE II trial, fetal exposure to antimicrobials in this clinical setting was associated with an increased cerebral palsy rate at age 7 years compared with that in children without fetal exposure (Kenyon, 2008b).


Obstentrics_Williams

Obstentrics_Williams. fetal exposure to antimicrobials in this clinical setting was associated with an increased cerebral palsy rate at age 7 years compared with that in children without fetal exposure (Kenyon, 2008b). Importantly, antimicrobial use described here is distinct from that given for group B streptococcal prophylaxis (Chap. 64, p. 1222).


Obstentrics_Williams

Obstentrics_Williams. This is one of the most often prescribed interventions during pregnancy, yet one of the least studied. One systematic review concluded that evidence neither supported nor refuted bed rest for prevention of preterm birth (Sosa, 2004). Goulet and coworkers (2001) randomly assigned 250 Canadian women to either home care or hospitalization after treatment of an acute episode of preterm labor and found no beneits. There have, however, been reports of possible harm. Kovacevich and associates (2000) reported that bed rest for 3 days or more increased thromboembolic complications to 16 per 1000 women compared with only 1 per 1000 with normal ambulation. Promislow and colleagues (2004) observed significant bone loss in pregnant women prescribed outpatient bed rest. More recently, Grobman and associates (20e13) noted that women with activity restriction were nearly 2.5 times more likely to have a preterm birth before 34 weeks. his finding, however, may reflect ascertainment bias. hat is, women


Obstentrics_Williams

Obstentrics_Williams. (20e13) noted that women with activity restriction were nearly 2.5 times more likely to have a preterm birth before 34 weeks. his finding, however, may reflect ascertainment bias. hat is, women with restricted activity may have been assigned to bed rest because they were viewed to be at more imminent risk of preterm delivery. McCall and coworkers (2013) summarized the literature on bed rest, and they found insuicient evidence to support its use. The American College of Obstetricians and Gynecologists (20e17 d) suggests that, although frequently prescribed, bed rest is only rarely indicated, and ambulation should be considered in most cases.


Obstentrics_Williams

Obstentrics_Williams. Silicone rings, such as the Arabin pessay, are being used to support the cervix in women with a sonographically short cervix. For 385 Spanish women with a cervical length ;25 mm, Goya and associates (2012) provided a silicone pessary or expectant management. Newborns spontaneous delivered before 34 weeks' gestation in 6 percent of women in the pessary group compared with 27 percent in the expectant management group. Another trial randomly assigned almost 100 women with a cervix <25 mm at 20 to 24 weeks to silicone pessaries or expectant management (Hui, 2013). The pessary did not lower the rate of delivery < 34 weeks. Similar indings were reported by Nicolaides and colleagues (2016). he Society for Maternal-Fetal Medicine (2017b) recently recognized the conflicting published reports and lack of an FDA-approved pessary for the indication of preterm birth prevention. They currently recommend pessary prophylaxis only within research protocols.


Obstentrics_Williams

Obstentrics_Williams. Some evidence supports the concept that cervical incompetence and preterm labor lie along a spectrum leading to preterm delivery. Consequently, investigators have evaluated cerclage placement after preterm labor begins to manifest clinically. Althuisius and colleagues (2003) randomly assigned 23 women with cervical incompetence before 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with those assigned to bed rest-54 versus 24 days, respectively. Terkildsen and coworkers (2003) studied 116 women who underwent second-trimester emergency cerclage. Nulliparity, membranes extending beyond the external cervical os, and cerclage before 22 weeks were associated with a signiicantly decreased chance of signiicant pregnancy continuation. For women facing a poor pregnancy prognosis due to cervical dilation at midgestation, it seems reasonable to ofer emergency or rescue cerclage with appropriate counseling.


Obstentrics_Williams

Obstentrics_Williams. pregnancy continuation. For women facing a poor pregnancy prognosis due to cervical dilation at midgestation, it seems reasonable to ofer emergency or rescue cerclage with appropriate counseling. However, it is unclear if such interventions truly confer a beneit or merely increase the risk of membrane rupture and infection (Hawkins, 2017).


Obstentrics_Williams

Obstentrics_Williams. • Tocolysis to Treat Preterm Labor Although several drugs and other interventions have been used to prevent or inhibit preterm labor, none is completely efective. The American College of Obstetricians and Gynecologists (2016b) has concluded that tocolytic agents do not markedly prolong gestation but may delay delivery in some women for up to 48 hours. This may allow transport to an obstetrical center with higher-level neonatal care and permit time for a course of corticosteroid therapy. Although delivery may be delayed to administer corticosteroids, treatment has not improved perinatal outcome rates (Gyetvai, 1999).


Obstentrics_Williams

Obstentrics_Williams. Beta-adrenergic agonists, magnesium sulfate, calciumchannel blockers, or indomethacin are the recommended tocolytic agents for this short-term use. The gestational age range for tocolytic use is debatable. But, because corticosteroids are not generally used after 34 weeks, and because the perinatal outcomes in preterm neonates are generally good after this time, most do not recommend use of tocolytics after 33 weeks' gestation (Goldenberg, 2002). In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. he College (2016b) notes that maintenance therapy with tocolytics is inefective for preventing preterm birth. Importantly, no trial has ever convincingly shown reductions in rates of any important adverse outcome by a tocolytic drug compared with placebo (Walker, 2016). Maintenance tocolysis after acute therapy is not recommended.