Preterm Birth
BS. Nguyễn Hồng Anh
Preterm birth is a substantial (nghiêm trọng) global health issue with significant (đáng kể) consequences to the newborn, family, and society. Preterm delivery affects nearly 15 million births worldwide, is the leading cause of death in children younger than 5 years, and remains a prominent (nổi bật) issue in obstetrics (Chawanpaiboon, 2019). Although the burden of preterm birth is clear, defining the biology of human parturition and identifying strategies to reduce preterm birth rates remain elusive.
DEFINITION OF PRETERM BIRTH
Preterm birth is delivery before 37 completed weeks, that is, before 366/7 weeks. Subdivisions vary among organizations. According to the American College of Obstetricians and Gynecologists (2021b), births occurring between 34 and 36 completed weeks are considered late preterm. The Centers for Disease Control and Prevention recognizes this late preterm definition but also labels births before 336/7 weeks as early preterm (Martin, 2021). Instead, the World Health Organization (2018) defines births before 28 completed weeks as extremely preterm, those from 28 to 32 weeks as very preterm, and from 32 to 37 weeks as moderate to late preterm.
These definitions lack a functional basis and should be distinguished from the concept of prematurity, which represents incomplete development of various organ systems at birth. For example, the lungs are particularly affected and may be susceptible to the respiratory distress syndrome (Chap. 34, p. 615). Similarly, neonates born before term can be small or large for gestational age but are still preterm by definition.
Low birthweight refers to neonates weighing 1500 to 2500 g; very low birthweight describes those between 1000 and 1500 g; and extremely low birthweight refers to those <1000 g (World Health Organization, 2019).
PRETERM BIRTH RATE TRENDS
Preterm birth is delivery before 37 completed weeks, that is, before 366/7 weeks. Subdivisions vary among organizations. According to the American College of Obstetricians and Gynecologists (2021b), births occurring between 34 and 36 completed weeks are considered late preterm. The Centers for Disease Control and Prevention recognizes this late preterm definition but also labels births before 336/7 weeks as early preterm (Martin, 2021). Instead, the World Health Organization (2018) defines births before 28 completed weeks as extremely preterm, those from 28 to 32 weeks as very preterm, and from 32 to 37 weeks as moderate to late preterm.
These definitions lack a functional basis and should be distinguished from the concept of prematurity, which represents incomplete development of various organ systems at birth. For example, the lungs are particularly affected and may be susceptible to the respiratory distress syndrome (Chap. 34, p. 615). Similarly, neonates born before term can be small or large for gestational age but are still preterm by definition.
Low birthweight refers to neonates weighing 1500 to 2500 g; very low birthweight describes those between 1000 and 1500 g; and extremely low birthweight refers to those <1000 g (World Health Organization, 2019).
PRETERM NEWBORN MORBIDITY AND MORTALITY
In 2018 in the United States, 21,498 infants died in their first year of life, and 66 percent of infant deaths were among those born preterm. Gestational age at delivery and the risk of neonatal morbidity and mortality are inversely related. Namely, neonates born in the early-preterm period make up the smallest proportion of births, but these infants experience disproportionately higher rates of prematurity-related complications, including death (Table 45-1) (Ely, 2020). For context, the infant mortality rate in those born at less than 28 weeks’ gestation was 186 times higher than in those born at 37 to 41 weeks in the United States in 2018.
The joint effect of gestational age and infant condition at birth also has been examined. Data from the Swedish Medical Birth Register correlated Apgar scores at 5 and 10 minutes in preterm neonates across gestational ages. The relative risk of death consistently increased with decreased Apgar scores (Cnattingius, 2020). Low Apgar scores in preterm newborns may reflect biological immaturity rather than fetal depression. However, Apgar scores and changes in the score between 5 and 10 minutes were associated with neonatal mortality among preterm newborns. Preterm neonates who survive are at risk for a range of short- and long-term morbidities, largely due to organ system immaturity (Table 45-2) (Eichenwald, 2008). That said, remarkable strides have been made in neonatal survival for those born preterm. In a study of more than 18,000 newborns weighing between 400 and 1500 g or aged between 22 and 32 weeks’ gestation, survival rates were analyzed as a function of both birthweight and gestational age (Fanarof, 2007). After achieving a birthweight ≥1000 g, a gestational age ≥28 weeks for females, or age ≥30 weeks for males, survival rates reach 95 percent.
■ Threshold of Viability
Births once considered to be “abortuses” because the fetus weighed <500 g are now classified as live births. In the United States in 2019, 5189 live births weighed <500 g (Martin, 2021). Fortunately, perinatal and neonatal care has advanced tremendously for these births. As a result, the threshold of viability, which is the lower limit of fetal maturation compatible with extrauterine survival, has been reassessed. Currently, the threshold of viability lies between 200/7 and 256/7 weeks’ gestation. Neonates born in this periviable period are vulnerable because of their immature organ systems. Complications include brain injury and sepsis, both described in Chapter 34, (p. 618). To guide obstetrical decision-making and care of these fetuses, a national perinatal workshop convened in 2013 (Raju, 2014).
The executive summary statement from this meeting served as the foundation for an Obstetric Care Consensus document (American College of Obstetricians and Gynecologists, 2019d).
Periviable Neonatal Survival
Delivery before 23 weeks’ gestation often results in death, and survival rates approximate 5 to 10 percent (Fig. 45-1). Among survivors, morbidity is significant. Practices regarding active resuscitation vary between institutions and may explain the differing perinatal outcomes among these. Neonatal survival rates also vary among international comparisons, and rates at 24 weeks’ gestation range from 35 to 84 percent (Helenius, 2017).
A retrospective analysis of infants born at the University of Iowa from 2006 to 2015 at 22 to 25 weeks’ gestation underscores this issue (Watkins, 2020). After excluding anomalous fetuses, death in the delivery room, and parental request for palliation, the neurodevelopmental outcomes were analyzed. For 169 of 214 survivors at 18 to 22 months. Active management was defined as antenatal corticosteroids and resuscitation when desired by the parents. The survival rate was lower in neonates born at 22 to 23 weeks’ than at 24 to 25 weeks’ gestation. However, mild or no neurodevelopmental impairment was reported in 64 percent of the surviving 22- to 23-week infants.
An important caveat when examining perinatal outcomes, however, is ascertainment bias. For example, the mean survival rate is 45 percent if the denominator is all live births compared with 72 percent if the denominator is only newborns admitted to neonatal intensive care (Guillen, 2011). Another source of bias is use of multicenter datasets with considerable differences in obstetrical and early neonatal interventions (Stoll, 2010). To evaluate contemporaneous outcomes of neonates born at 22 to 24 weeks, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network reported both survival and neurodevelopmental outcomes across consecutive birth-year epochs of 2000 to 2003, 2004 to 2007, and 2008 to 2011 in infants aged 18 to 22 months (Younge, 2017). The percentage of infants who survived rose significantly from 30 percent in 2000 to 2003 to 36 percent in 2008 to 2011. The percentage of infants who survived without neurodevelopmental impairment also significantly grew from 16 percent to 20 percent during the same time period.
Although rates of survival without neurodevelopmental impairment increased over time for those born at 23 and 24 weeks, only 1 percent of infants born at 22 weeks survived without neurodevelopmental impairment (Younge, 2017). Somewhat similar results were published from Sweden. This report details a national population-based study of all neonates born at 22 to 26 weeks. Rates oh survival to 1 year hrom 2004 to 2007 were compared with rates hrom 2014 to 2016. Survival rates at 1 year among live-born neonates at 22 to 26 weeks’ gestation signicantly improved during the later period (Table 45-3) (Norman, 2019).
Clinical Management
The Periviable Birth Obstetric Care Consensus document also addresses management options based on the clinical characteristics of a given pregnancy. Nonmodifable factors are fetal gender, weight, and plurality. Potentially modifable antepartum and intrapartum factors include the location of delivery, intent to intervene by cesarean delivery, and administration of antenatal corticosteroids (Table 45-4). Postnatal management addresses the initiation or withdrawal of intensive care after birth.
Cesarean delivery at the threshold of viability is controversial. If the fetus-neonate is perceived to be too immature for aggressive support, cesarean delivery for common indications such as breech presentation or nonreassuring fetal heart rate patterns might be preempted. Moreover, observational studies have been inconsistent in demonstrating a benefit of cesarean delivery for the sole indication of periviability. Moreover, cesarean delivery may predispose the gravida to adverse intraoperative events and morbidity (Bertholdt, 2018; Blanc, 2019).
In a study of 2906 singletons between 240/7 and 316/7 weeks eligible for attempted vaginal birth, 84 percent of cephalic presenting fetuses were delivered vaginally (Reddy, 2012). Neonatal mortality rates did not differ compared with those associated with planned cesarean delivery. For breech presentations, however, relative risk for mortality was three- fold higher with attempted vaginal delivery. In another study, Werner and colleagues (2013) analyzed 20,231 newborns delivered at 24 to 34 weeks. Cesarean delivery did not protect against poor outcomes such as neonatal death, intraventricular hemorrhage, seizures, respiratory distress, and subdural hemorrhage.
From these findings, the Obstetric Care Consensus proposes that cesarean delivery be considered for fetal indications at 230/7 to 246/7 weeks. However, before 22 weeks, this route is reserved only for maternal indications. As emphasized by the authors of the Iowa report cited earlier, providing active management—such as antenatal corticosteroids—can be uncoupled from the decision of cesarean in the periviable period (Watkins, 2020). That said, the frequency of cesarean in the 23rd week has increased in the United States following publication of the perinatal workshop executive summary in 2014 (Rossi, 2019).
It is difcult to summarize the current practices of obstetrical care in the management of the periviable pregnancy given its continued rapid evolution. Moreover, it appears that maternal and neonatal interventions are shifting during the 22- to 23-week gestational age period. Data from the National Center for Health Statistics show that rates of at least one maternal or neonatal intervention were 38.9 percent and 78.3 percent for 22 and 23 weeks’ gestation, respectively (Hajdu, 2020). In this uncertain environment, individualized, patient-centered care with a multidisciplinary team remains essential. Tis is particularly relevant given that nearly 20 percent of women may have serious morbidity with delivery during the periviable period (Rossi, 2018).
For cases with threatened periviable delivery, neonatal and perinatal consultation aids informed decision-making and helps form expectations for the family. For fetuses with a life-limiting condition, such as extreme prematurity, perinatal palliative care is a strategy that emphasizes comfort (American College of Obstetricians and Gynecologists, 2019c). Care team members can include obstetric and neonatal professionals, chaplaincy, and mental health specialists.
■ Late preterm Birth
As discussed, neonates born between 34 and 36 weeks’ gestation account for more than 70 percent of all preterm births (Fig. 45-2) (Martin, 2021). Most of the increase in the total preterm birth rate for the United States 2018 to 2019 was among neonates born at 34 to 36 weeks. To estimate the risks associated with late-preterm births, investigators analyzed neonatal mortality and morbidity rates at 34, 35, and 36 weeks compared with those of births at term at Parkland Hospital (McIntire, 2008). Approximately 3 percent of all births during the study period were between 24 and 32 weeks, and 9 percent were during the late-preterm period. Thus, and similar to the national rates, late-preterm births accounted for three fourths of all preterm births. Approximately 80 percent of these resulted from idiopathic spontaneous preterm labor or prematurely ruptured membranes (Fig. 45-3). Other obstetrical complications were implicated in the remaining 20 percent of cases. Rates of morbidity and mortality were greater in these late-preterm newborns compared with rates in term ones (Table 45-5) (McIntire, 2008). Similarly, Tomashek (2007) reported higher neonatal mortality rates for late-preterm newborns. Rates of adverse neurodevelopment outcomes also are increased in these latepreterm infants (Petrini, 2009). Taken together, these findings suggest that a health-care focus on prematurity should include these late-preterm births.
CAUSES OF PRETERM BIRTH
Four direct causes for preterm births in the United States include (1) spontaneous unexplained preterm labor with intact membranes, (2) idiopathic preterm prelabor rupture of membranes, (3) delivery for maternal or fetal indications, and (4) twins and higher-order multifetal births. Of all preterm births, 30 to 35 percent are indicated, 40 to 45 percent are due to spontaneous preterm labor, and 30 to 35 percent follow preterm membrane rupture (Goldenberg, 2008). More than 98 percent of triplets and 60 percent of twins are born preterm (Martin, 2021).
At term, a common parturition pathway is activated physiologically and leads to labor. For preterm labor, several disease processes are thought to activate one or more of the components of this common pathway (Romero, 2014). Put another way, preterm labor is not simply labor that starts too soon. This paradigm is supported by the rationale that causes of preterm birth have multiple, often interacting, antecedents and contributing factors that lead to a heterogenous syndrome (Deindl, 2020; Esplin, 2016). Analogous to other complex disease processes, multiple coexistent genetic alterations, bacterial and viral colonization, and diverse environmental factors may lead to preterm birth (Bayar, 2020; Mekonnen, 2021; Volozonoka, 2020). These multiple factors continue to pose challenges in identifying predictive biomarkers in blood, urine, or cervicovaginal fluid, despite signifcant technical advances in multiomic approaches (Ghaemi, 2021; Jehan, 2020; Peterson, 2020; Parry, 2020).
■ Spontaneous Preterm Labor
Pregnancies with spontaneous preterm labor yet intact fetal membranes must be distinguished from those complicated by ruptured membranes. Even so, spontaneous preterm labor does not constitute a homogeneous group. Evidence suggests it is a syndrome attributable to multiple pathological processes (Romero, 2014). Among the more common associated findings are multifetal pregnancy, intrauterine infection, bleeding, placental infarction, premature cervical dilation, cervical insufficiency, hydramnios, uterine fundal abnormalities, and fetal anomalies. Severe maternal illness from infections, autoimmune diseases, and gestational hypertension also elevate preterm labor risks.
These processes culminate in a common end point of premature cervical dilation, effacement, and activation of uterine contractions. Importantly, the actual process of preterm labor should be considered a final step stemming from progressive or acute changes that could be initiated days or even weeks before labor onset. Diverse pathways to instigate parturition exist and are dependent on the etiology of preterm birth (Fig. 45-4) (Romero, 2014). Major causes include uterine overdistention, premature cervical changes, infection, and maternal fetal stress. Genetic and environmental factors likely contribute to each mechanism.
Uterine Overdistention
Multifetal pregnancy and hydramnios are well-recognized risks for preterm birth. With these, uterine overdistention imparts greater stress on the myometrium. In nonhuman primates, infation of intraamnionic balloons can stimulate uterine contractility, preterm labor, and an “inflammatory pulse.” Similar inflammatory responses have been observed in the amnion of women with polyhydramnios and twins (Adams Waldor, 2015).
Early uterine overdistention likely acts to initiate expression of contraction-associated proteins in the myometrium. These genes include those coding for gap-junction proteins, oxytocin receptors, and prostaglandin synthase (Korita, 2002; Lyall, 2002; Sooranna, 2004). Excessive uterine distention also leads to early activation of the placental–fetal endocrine cascade (Chap. 21, p. 407). Taken together, mechanical stressinduced distension and activation of endocrine cascades both lead to premature activation of inflammatory responses that result in uterine contractile activation (Gomez-Lopez, 2014; Stephen, 2015). A possible compensatory response to uterine distention is tissue remodeling and muscle growth (Adams Waldor, 2015).
Cervical Dysfunction
In most cases, premature cervical remodeling precedes labor onset. In some instances, cervical dysfunction of the epithelia or its stromal extracellular matrix is the underlying cause(Nallasamy, 2017). Importantly, an intact cervical epithelial barrier is critical to prevent ascending infection. For example, loss of hyaluronan in cervical epithelia or colonization of group B streptococcus (GBS) enhances risk of preterm birth (Akgul, 2014; Coleman, 2021). GBS has the unique ability to synthesize the hyaluronan-degrading enzyme hyaluronidase to aid bacterial ascension (Vornhagen, 2017). Second, the mechanical competence of the cervix can be reduced. Genetic mutations in components of collagen and elastic fibers or proteins required for their assembly can be risk factors for cervical insufficiency and preterm birth (Nallasamy, 2017; Volozonoka, 2020).
Infection
Of all the mechanisms listed in Figure 45-4, only intraamnionic infection has been causally linked to spontaneous preterm delivery (Romero, 2014). Bacteria can gain access to intrauterine tissues through (1) transplacental transfer oh maternal systemic infection, (2) flow of infection 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 orifice, this anatomical arrangement provides a passageway for microorganisms. Ascending infection is considered to be the most common entry route where microorganisms colonize the cervix, decidua, and possibly the membranes, and then may enter the amnionic sac. Colonization with an infectious agent has been detected in 25 to 40 percent of all preterm deliveries (Goldenberg, 2008). In some instances, histological evidence of microbial inflammation is found in the fetal membranes, decidua, or umbilical cord. Other cases are deemed sterile intraamnionic inflammation. Despite the substantial association of infection with preterm birth, the cellular and molecular mechanisms underlying inflammation-driven preterm birth remain undefined (Cappelletti, 2020; Purisch, 2017).
Current data suggest that microbial invasion of the reproductive tract is sufficient to induce infection-mediated preterm birth. The level and kinetics of inflammation can vary between a polymicrobial or single-microbe exposure (ong, 2021). Affected women are more likely to develop clinical chorioamnionitis and rupture of membranes compared with women whose cultures are sterile. Moreover, their neonates are also more likely to have perinatal complications such as neonatal sepsis (Villamor-Martinez, 2020). Although the clinical course is more severe when intraamnionic infection is obvious, inflammation in the absence of detectable intraamnionic microorganisms—termed sterile intraamnionic inflammation—is also a risk factor for an inflammatory response (Motomura, 2021). In sum, the earlier the onset of preterm labor, the greater the likelihood of underlying infection (Goldenberg, 2000; Goncalves, 2002).
Paradoxically, the incidence of culture-positive amnionic fluid collected by amniocentesis during spontaneous labor at term is similar to that with preterm labor (Gomez, 1994; Romero, 1993). It has been suggested that at term, amnionic fluid is infiltrated by bacteria as a consequence of labor, whereas in preterm pregnancies, bacteria represent an inciting cause. Thus, fetal infection, as defined by bacteria detected within amnionic fluid, has differing etiologies and consequences. With chorioamnionitis, microbes may invade only maternal tissue and not amnionic fluid. Despite this, endotoxins can stimulate amnionic cells to secrete cytokines that enter amnionic fluid. This scenario may serve to explain the apparently contradictory observations concerning an association between amnionic fluid cytokines and preterm labor in cases in which microbes are not detected in the amnionic fluid.
Inflammatory Responses. These responses drive the pathogenesis of infection-induced preterm labor. Lipopolysaccharide (LPS) or other toxins elaborated by bacteria are recognized by receptors such as toll-like receptors (TLRs) (Janssens, 2003). These receptors are present on mononuclear phagocytes, decidual cells, cervical epithelia, and trophoblasts (Gonzalez, 2007; Holmlund, 2002). The expression of TLRs on maternal immune cells is necessary to recognize inflammatory stimuli in inflammation-mediated preterm birth (Cappelletti, 2020). Activation of TLRs induces a signaling cascade that activates production of chemokines such as interleukin 8 (IL-8) and cytokines such as IL-1β. 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 itself.
LPS-induced production of IL-1β 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-α); (2) proliferation, activation, and migration of leukocytes; (3) modifications in extracellular matrix proteins; and (4) mitogenic and cytotoxic effects such as fever and acute-phase response (El-Bastawissi, 2000). In many tissues, including myometrium, decidua, and amnion, IL-1β also promotes prostaglandin formation that induces cervical ripening and loss of myometrial quiescence (Challis, 2002; Keelan, 2003). The importance of prostaglandins to infection-mediated preterm birth is supported by the observation that prostaglandin inhibitors can reduce the rate of LPS-induced preterm birth in both the mouse and nonhuman primate (Gravett, 2007; immons, 2014). Inhibition of cyclooxygenase 2 prevents inflammation-mediated preterm labor in the mouse. For these reasons, clinical approaches described on page 806 are being explored.
Proteases such as matrix metalloproteinases (MMPs) also are induced by inflammatory cytokines and function to break down extracellular matrix components such as collagen or elastic fibers. This disrupts the structural integrity of fetal membranes or the cervix. Current evidence from animal and human studies suggests that many aspects of infection-mediated preterm birth differ from pathways that regulate term parturition (Hamilton, 2012; Shynlova, 2013a,b; Willcockson, 2018).
Origin of Cytokines. Secretion of uterine cytokines is likely important for preterm labor. Cytokines produced in maternal decidua and myometrium have effects confined to that side, whereas cytokines produced in the membranes or in cells within the amnionic fluid will not be transferred to maternal tissues. In general, resident and invading leukocytes produce the bulk of cytokines in cases of inflammation resulting from infection. The presence of cytokines in amnionic fluid and their association with preterm labor is well documented. But, their exact cellular origin—with or without recoverable microorganisms— is not well defined. Amnionic fluid cytokines are most likely secreted by mononuclear phagocytes or neutrophils activated and recruited into the amnionic fluid (ong, 2020). Thus, the amount of amnionic fluid IL-1β would be determined by the number of leukocytes recruited, their activational status, or the effect of amnionic fluid constituents on their IL-1β secretion rate.
Microbiota. Mucosal immunity and barrier function of the cervicovaginal epithelia, the vaginal microbiota composition, and their interplay among differing populations are major research topics (Elovitz, 2019; Fettweis, 2019; Serrano, 2019). To explore these, advanced genomic analysis techniques are used and show that the nonpregnant vagina hosts a complex microbial community (Gajer, 2012; White, 2011). And, the vaginal microbiome changes during normal pregnancy (Stout, 2017). Specifically, the diversity of microbe populations are reduced during pregnancy and become more stable.
Some but not all studies report an increased population of certain microbes—for example, Gardnerella vaginalis and Ureaplasma urealyticum—in women with preterm birth (Donders, 2009; Nelson, 2014). In contrast, Schuster and coworkers (2020) reported that asymptomatic vaginal Candida colonization was not associated with preterm birth. Differences in populations studied, preterm birth definitions, and data analysis complicate interpretation of these data. Currently, the strongest evidence for the role of the microbiome in preterm birth relates to the vaginal microbiota. The most consistent finding across almost all studies is the benefit of a vaginal microbiota characterized by Lactobacillus crispatus (Bayar, 2020).
Aagaard and colleagues (2014) suggested that the placenta contains a microbiome akin to the oral microbiome. Subsequent studies, however, have failed to confirm this (Lauder, 2016; Teis, 2019). Recently, de Goau and associates (2019) Found no evidence of bacteria in most of 537 placental samples from both complicated and uncomplicated pregnancies. Almost all samples pointed to acquisition of bacteria during labor and delivery or to contamination of laboratory reagents with the exception of Streptococcus agalactiae. Tus, the human placenta does not appear to have a relevant microbiome (Bayar, 2020).
■ Preterm Prelabor Rupture of Membranes
Previously referred to as preterm premature rupture of membranes, preterm prelabor rupture of membranes (PPROM) defines spontaneous membrane rupture before 37 completed weeks and before labor onset (American College of Obstetricians and Gynecologists, 2020g). Such rupture likely has various causes, but intrauterine infection, oxidative stress–induced DNA damage, and premature cellular senescence are major predisposing events (Dutta, 2016; Mercer, 2003). Associated risk factors are similar to those at term and include lower socioeconomical status, low body mass index, nutritional deficiencies, and cigarette smoking. Women with PPROM carry an enhanced risk for recurrence during a subsequent pregnancy (Bloom, 2001). Despite these known risk factors, none are identified in many cases.
Bacterial cultures of amnionic fluid support a role for infection in PPROM. 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). Microbiome-mediated preterm birth and PPROM are current research areas (Bayar, 2020). One goal is to identify early risk markers for PPROM.
Molecular Changes
In pregnancies with PPROM, the amnion exhibits a higher degree of cell death and more apoptosis markers than in term amnion (Arechavaleta-Velasco, 2002; Fortunato, 2003). In vitro studies indicate that apoptosis is likely regulated by bacterial endotoxin, IL-1β, and TNF-α. 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, 2020). With membrane rupture, thrombin activity rises, which activates MMPs and prostaglandin synthesis. Studies by Mogami (2013) provide a mechanism by which bacterial endotoxin or TNF-α elicits release of fetal fibronectin (FN) by amnion epithelial cells. The TFN then binds toll-like receptor 4 in the amnion mesenchymal cells to activate signaling cascades. These result in augmented prostaglandin E (PGE2) synthesis and elevated activity of MMPs. Increasing prostaglandin levels promote cervical ripening and uterine contractions. Greater MMP concentrations allow collagen breakdown in the fetal membranes, resulting in premature rupture. Last, proteins involved in collagen synthesis or promoting its tensile strength are altered in membranes with premature rupture (Wang, 2006).
Recently, Blois and associates (2020) introduced the concept of galectins, a family of glycan-binding proteins. They may serve as a mediator in fetal-maternal immune tolerance and work to prevent microbial infections that lead to preterm birth. Both preterm labor and PPROM arise from distinct pathophysiological pathways but share inflammation as a common underlying mechanism. Excellent reviews are presented by Menon (2020) and Diemert (2020) and their coworkers.
■ MaternalFetal Stress
In this context, stress is defined as a condition that disturbs the normal physiological or psychological functioning of an individual. Since the 1940s, the association of maternal stress with birth outcomes has been explored. Results vary partly because of methodological difference in measuring stress (Hong, 2021). Quantitative measure is difficult, but considerable evidence shows that psychosocial stress in the form of racial discrimination—especially in black populations—results in poor health outcomes, including preterm birth (Salow, 2018). Psychological duress can include childhood stress, depression, or posttraumatic stress syndrome (Gillespie, 2017; Goldstein, 2017; Venkatesh, 2016). In one review of more than 50 studies, a significant link was found between low birthweight and preterm birth in women impacted by intimate partner violence (Donovan, 2016).
One potential mechanism for stress-induced preterm birth is premature activation of the placental–adrenal endocrine axis. 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 release of uterotonic signals for uterine activation at term. The interplay between preterm birth and maternal stress was recently reviewed by Hong and colleagues (2021).
CONTRIBUTING FACTORS
Several factors associated with preterm birth include pregnancy factors, lifestyle and behaviors, genetic and demographic features, and aspects of obstetrical history (Table 45-6). Disentangling association from causation remains a dilemma.
■ Prior Preterm Birth
The most important risk factor for preterm labor is a prior preterm birth. Data from nearly 16,000 women delivered at Parkland Hospital are instructive (Bloom, 2001). 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 first two newborns were preterm subsequently delivered a third preterm newborn. Most—70 percent—of the recurrent births occurred within 2 weeks of the gestational age of the prior preterm delivery. The 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. Expressed another way, 90 percent of the preterm births at Parkland Hospital could not be predicted based on a history of preterm birth. Others have confirmed the importance of prior spontaneous preterm birth (Laughon, 2014). Moreover, prior indicated preterm birth was strongly associated with subsequent spontaneous preterm birth. Variable definitions of spontaneous and indicated may explain this association. 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 influenced 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 is less than that for a woman with a prior term birth followed by preterm birth. Thus, the influence of reproductive history has a profound prognostic significance for risk of recurrence. This may also influence the supposed benefit attributed to interventions described later.
■ Pregnancy Factors
Of these, threatened abortion in early pregnancy is associated with higher rates of later adverse outcomes. Weiss (2004) reported outcomes in nearly 14,000 women with vaginal bleeding at 6 to 13 weeks’ gestation. Both light and heavy bleeding were associated with subsequent preterm labor, placental abruption, and pregnancy loss before 24 weeks. Birth defects in the fetus also may predispose to preterm birth. In a secondary analysis of data from the First- and Second-Trimester Evaluation of Risk (FASER) trial, birth defects were associated with preterm birth and low-birthweight neonates (Dolan, 2007). Multifetal gestation is another well-recognized associate. Importantly, preterm delivery continues to be the major cause of the excessive perinatal morbidity and mortality for these pregnancies.
■ Lifestyle Factors
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; Goldenberg, 2008; Leveno, 2009). Cigarette smoking, inadequate maternal weight gain, and illicit drug use affect the incidence and outcome of low-birthweight neonates (Chap. 47, p. 825). Studies of work and physical activity related to preterm birth have yielded conflicting results (Goldenberg, 2008).
Some evidence suggests that working long hours, fixed night shifts, and hard physical labor are probably linked to a higher risk of preterm birth (Cai, 2020). 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, 2020;
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). Because of the observational nature of many of the studies with the potential for confounding, the American College of Obstetricians and Gynecologists (2020b) has offered guidance for employment considerations during pregnancy. It is emphasized that accommodations that allow a woman to keep working are the most reliable way to guarantee pay, benefits, and job protection.
■ Genetic Factors
Evidence for a genetic component to preterm birth is supported by familial recurrent preterm births (Crider, 2005). Genome-wide studies have identified genetic variants associated with gestational duration and preterm birth (Zhang, 2017). Common variants in EBF1, EEFSEC, and AGR2 genes have an association with preterm birth. Data sets, however, included only women with European ancestry, and thus future efforts will ideally include other populations. Recent large-scale transcriptome studies have identified additional loci associated with gestation length (Marinić, 2021; Sakabe, 2020).
■ Periodontal Disease
Gingivitis is a chronic anaerobic inflammation that affects as many as 50 percent of pregnant women in the United States (Goepert, 2004). One metaanalysis of 17 studies showed that periodontal disease was significantly associated with preterm birth (Vergnes, 2007). To better study this relationship, 813 pregnant women between 13 and 17 weeks’ gestation who had periodontal disease were randomly assigned to treatment during pregnancy or postpartum. Treatment during pregnancy improved periodontal disease, however, it failed to significantly alter preterm birth rates (Michalowicz, 2006). A workshop of the European Federation of Periodontology and the American Academy of Periodontology reafrmed this position (Sanz, 2013).
■ Interpregnancy Interval
In one 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). The causal effect of short interpregnancy intervals, however, has been questioned (Ball, 2014). A recent cohort study of more than three million births across four countries, including the United States, found that associations between interpregnancy intervals and preterm birth are modified by whether the previous pregnancy was preterm (Marinovich, 2021).
■ Infection
Antimicrobial Prophylaxis
As discussed on page 789, a link between some cases of preterm birth and inection seems irreutable (Goldenberg, 2008). In several studies, antimicrobial treatment has been given to prevent preterm labor that was thought to stem rom microbial invasion. Some o these strategies have targeted Mycoplasma species.
First, Andrews and associates (2006) reported results o a randomized trial in which they provided a course o azithromycin plus metronidazole every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery beore 34 weeks. Approximately 80 percent o the women with subsequent pregnancies had received study drug within 6 months o their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate o recurrent preterm birth. From a subgroup analysis o this data, ita and coworkers (2007) concluded that such use o antimicrobials may be harmul. In another randomized study, 2661 women were given placebo or metronidazole plus erythromycin between 20 and 24 weeks’ gestation ollowed by ampicillin plus metronidazole during labor (Goldenberg, 2006). Tis antimicrobial regimen did not reduce the rate o preterm birth or histological chorioamnionitis. As discussed later, antibiotic prophylaxis to prevent preterm birth is not currently recommended in women with preterm labor and intact membranes (Flenady, 2013).
Bacterial Vaginosis
In this condition, normal, hydrogen peroxide–producing, lactobacillus-predominant vaginal ora is replaced with anaerobes. For nearly 40 years, bacterial vaginosis has been recognized to be associated with spontaneous abortion, preterm labor, rupture o membranes, chorioamnionitis, and amnionic uid inection (Gravett, 1986; Hillier, 1995). Unortunately, screening and treatment have not prevented preterm birth (Haahr, 2016). Moreover, microbial resistance or antimicrobial-induced change in the vaginal ora results rom regimens intended to eliminate bacterial vaginosis (Beigi, 2004; Carey, 2005).
COVID-19
Early reports suggested an increase in rates o preterm birth in pregnant women with COVID-19. However, population-level data show conicting results on the changes, i any, in preterm birth rates (Berghella, 2020; Hedermann, 2021; Main, 2021). At Parkland Hospital, Adhikari and colleagues (2020) did not identiy higher rates o preterm birth in 252 women with COVID-19 compared with 3122 gravidas who tested negative. However, women with severe inection are oten delivered preterm or maternal indications (Pierce-Williams, 2020).
DIAGNOSIS
■ Symptoms
Contractions, pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain are typical symptoms o preterm labor. Tese can also be seen with normal pregnancy and may be minimized by patients and providers. Early dierentiation between true and alse labor is difcult—especially beore demonstrable cervical eacement and dilation. Uterine activity alone can be misleading because o Braxton Hicks contractions (Chap. 4, p. 52). Accordingly, the American College o Obstetricians and Gynecologists (2020e) denes preterm labor to be regular contractions accompanied by a change in cervical dilation, eacement, or both or to be regular contractions and cervical dilation o at least 2 cm at initial presentation. Chao (2011) prospectively studied 843 women with a singleton etus who presented to Parkland Hospital with preterm labor symptoms between 240/7 and 336/7 weeks, intact membranes, and cervical dilation <2 cm. Tose whose cervix remained <2 cm were sent home with a diagnosis o alse preterm labor. When analyzed against the general obstetrical population, women sent home had a similar rate o birth beore 34 weeks—2 versus 1 percent. However, these women did have signicantly higher rates o birth between 34 and 36 weeks— 5 percent compared with 2 percent. Women with cervical dilation o 1 cm at discharge were signicantly more likely to deliver beore 34 weeks compared with women without cervical dilation—5 percent versus 1 percent. Almost 90 percent o the 1-cm group delivered within 21 days o the initial presentation.
■ Cervical Change
Asymptomatic cervical dilation ater midpregnancy is suspected to be a preterm delivery risk actor. Multiparity alone is not su- cient to explain cervical dilation discovered early in the third trimester. Cook (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks’ gestation 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 rom Parkland Hospital, routine digital cervical examinations were perormed between 26 and 30 weeks in 185 asymptomatic women. Approximately 25 percent o women whose cervix was dilated 2 or 3 cm delivered beore 34 weeks (Leveno, 1986a). Other investigators have veried cervical dilation as a predictor o increased preterm delivery risk (Copper, 1995).
Although women with dilation and eacement in the third trimester are at greater risk or preterm birth, detection does not necessarily improve pregnancy outcome. In one randomized study, 2719 women undergoing routine cervical examinations at each prenatal visit were compared with 2721 gravidas in whom serial examinations were not perormed. Knowledge o antenatal cervical dilation did not aect any pregnancy outcome related to preterm birth or the requency o interventions or preterm labor (Buekens, 1994). Tus, it seems that prenatal cervical examinations in asymptomatic women are neither benecial nor harmul. Numerous cervical imaging technologies are under investigation or early, accurate prediction o cervical changes associated with preterm birth (Pizzella, 2020).
■ Ambulatory Uterine Monitoring
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 U.S. Food and Drug Administration (FDA) prompted its widespread clinical use. Subsequently, it was proven that this expensive and time-consuming system did not reduce preterm birth rates (Collaborative Home Uterine Monitoring Study Group, 1995; Iams, 2002). Despite technology improvements, use of such monitoring is discouraged (American College of Obstetricians and Gynecologists, 2021c).
■ Biomarkers
Because clinical symptoms alone are not predictive of preterm birth, surrogate biomarkers have been evaluated. These include fetal fibronectin (TFN), phosphorylated insulin-like growth factor–binding protein 1 (phIGFBP-1), and placental alpha microglobulin 1 (PAMG-1). Their performance varies between studies and is influenced by demographic and other factors (Melchor, 2018).
Fetal Fibronectin
This glycoprotein is produced in 20 different molecular forms by various cell types, including hepatocytes, fibroblasts, endothelial cells, and fetal amnion cells. Present in high concentrations in maternal blood and amnionic fluid, FN is thought to function in intercellular adhesion during implantation and in maintenance o placental adherence to uterine decidua (Leeson, 1996). Detected in cervicovaginal secretions in women who have normal pregnancies with intact membranes at term, FN appears to reect stromal remodeling o the cervix beore 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 uid and maternal blood should be avoided. Interventional studies based on FN screening results in asymptomatic women have not demonstrated improved perinatal outcomes (Andrews, 2003; Esplin, 2017). Te American College o Obstetricians and Gynecologists (2021c) does not recommend screening with FN tests. In one review o 16 trials involving management based upon FN results, the low quality o existing evidence and need or cost-eectiveness analyses were noted (Berghella, 2019).
■ Cervical Length Measurement
Progressively shorter cervical canals assessed sonographically are associated with increased rates of preterm birth (Iams, 1996). Te sonographic technique is described in Chapter 14 (p. 254). Te Society for Maternal-Fetal Medicine (2016b) has provided guidance or proper cervical length measurement and recommends that sonographers and practitioners obtain specic training through accreditation programs in the acquisition and interpretation o cervical length images. ransvaginal cervical sonography is not aected by maternal obesity, cervix position, or shadowing rom the etal presenting part. Because o the inability to easily distinguish the lower uterine segment rom the cervix in early gestation, transvaginal cervical length assessment is typically perormed ater 16 weeks’ gestation. Such interrogation is currently limited to singleton gestations and not recommended or multietal gestations outside o research trials (American College o Obstetricians and Gynecologists, 2021c).
Indications or cervical length measurement are controversial. For those women with a history o prior spontaneous preterm birth, the Society or Maternal-Fetal Medicine (2016b) recommends transvaginal cervical length screening. And, the American College o Obstetricians and Gynecologists (2021c) now also recommends screening or this indication. In women with singleton pregnancies but without a history o prior preterm birth, the Society or Maternal-Fetal Medicine and the College view cervical length screening as reasonable yet acknowledges that this remains an area o debate. Biomarkers have been incorporated with hopes to improve screening perormance. Esplin and colleagues (2017) prospectively studied 9410 nulliparas with singleton pregnancies. Universal screening o sonographically measured cervical length and quantitative measurement o vaginal FN levels were evaluated as predictors o women who would spontaneously deliver beore 37 weeks. Tese measures had poor predictive perormance as a screening test. Based on these ndings, routine use o these screening tests in a low-risk population is not recommended. O other markers, PAMG-1 has emerged as superior to predict potential preterm birth compared with FN, particularly among symptomatic women (Nikolova, 2018; Pirjani, 2019; Wing, 2017). Incorporating results o cervicovaginal uid proteomic markers and microRNAs obtained rom peripheral blood also has been assessed (Parry, 2020; Winger, 2020). Although evidence seems promising, any rm recommendations should await larger clinical trials (Jones, 2020).
Tis is particularly important given the challenges with accuracy and utility o screening, especially in low-risk women, who represent most o the population with preterm birth. A second concern with screening is the efcacy o interventions to improve perinatal outcomes once cervical length screening, biomarkers, or both have isolated at-risk women. Cervical cerclage or vaginal progesterone have been evaluated, and their efcacy is described in the next section. Bloom and Leveno (2017) subsequently critiqued the use o transvaginal cervical length screening in low-risk women and the promulgation o consensus guidelines. Tey highlighted the staggering costs encumbering the healthcare system in the United States as a result o such strategies. Similar concerns were raised by Kuusela and associates (2021) who evaluated cervical length screening among 11,456 asymptomatic gravidas.
PRETERM BIRTH PREVENTION
Prevention o preterm birth remains an elusive goal. Yet, experts continue to debate the optimal strategies to prevent or manage preterm birth (Medley, 2018). Dietary supplementations, or example, have not shown benet (Makrides, 2019; Palacios, 2019). Still, recent reports suggest that prevention in selected populations may be achievable (Breslin, 2020; Good- ellow, 2021).
■ Cervical Cerclage
Cerclage placement may be used to prevent preterm birth in at least three circumstances. First, the procedure may benet women who have a history o recurrent second-trimester loss and who are diagnosed with cervical insufciency. A second instance is the woman identied during sonographic examination to have a short cervix. Te third indication is a “rescue” cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor. Cerclage placement in twin pregnancies or clinical indications is an evolving area (Li, 2019; Roman, 2020). In this chapter, however, cerclage placement will be in the context o a singleton pregnancy. An accurate history is critical or management decisions.
For recurrent abortion rom cervical incompetence, historical clues are outlined in Chapter 11 (p. 205). For women with a short cervix incidentally detected by sonography, the benet o cerclage placement appears directly related to whether the woman has a history o prior preterm birth. In those without a prior preterm birth, cerclage or a sonographically detected short cervix alone oers no advantage (Berghella, 2017). o and associates (2004) screened 47,123 women and randomly assigned the 253 women with a cervix measuring <15 mm, with or without a history o preterm birth, to cerclage or no cerclage groups. Te requency o preterm delivery beore 33 weeks did not dier signicantly between the two cohorts.
In contrast, women with a sonographically diagnosed short cervix and a history o preterm birth may benet. Owen and colleagues (2009) randomly assigned 302 women with prior preterm birth plus a short cervix—dened as length <25 mm— to cerclage or no-procedure groups. Te primary study outcome was not supported by the intervention. However, women with a cervical length <15 mm delivered beore 35 weeks signicantly less oten ollowing cerclage compared with women with no cerclage—30 versus 65 percent. Tis study suggested that recurrent preterm birth could be prevented in a subset o women with asymptomatic singleton gestations with both previous preterm birth and short cervical length.
Tese ndings prompted a reassessment by Berghella and coworkers (2011), who perormed a metaanalysis using individual patient data (Fig. 45-5). Te primary outcomes rom the included trials did not support cerclage placement. However, these investigators concluded that cerclage signicantly prevented preterm birth and improved composite perinatal mortality and morbidity outcomes in women with prior spontaneous preterm birth, singleton gestation, and cervical length <25 mm.
One caveat in the interpretation o this cerclage data is the inuence o obstetrical history. For example, all o the trials comprising the metaanalysis included preterm birth as early as 16 to 17 weeks’ gestation. Dening these early second-trimester losses as preterm births, rather than cervical incompetence, is problematic. Tus, it is difcult to distinguish whether these women were treated in the context o cervical incompetence or o preterm labor at 16 weeks. Nonetheless, based on these ndings, the American College o Obstetricians and Gynecologists (2021c) concluded that in women with a singleton pregnancy, prior spontaneous preterm birth, cervical length <25 mm, and gestational age <24 weeks, cerclage placement may be considered versus vaginal progesterone (p. 797).
Technique
Te operative placement o cervical cerclage is shown in Chapter 11 (p. 206). Several emerging trends, however, merit comment. For example, indication or cerclage placement may inuence selection o suture material (Battarbee, 2019). ocolysis and antibiotics with cerclage placement is another controversy (Eleje, 2020). In a retrospective report o 142 cases, 72 received perioperative prophylaxis, which consisted o perioperative ceazolin and indomethacin, during physical examination–indicated cerclage placement. Tis practice was associated with a signicant prolongation in gestational latency (Premkumar, 2020). At Parkland Hospital, we have not adopted such practices. Last, or women with a history o a ailed cerclage, transabdominal cerclage appears to be superior to vaginal cerclage (Shennan, 2020).
■ Prophylaxis with Progestogen Compounds
In most mammals, progesterone withdrawal is considered to be a parturition-triggering event. During human parturition, however, maternal, etal, and amnionic uid progesterone levels remain elevated. It has been proposed that human parturition involves unctional progesterone withdrawal mediated by decreased activity o progesterone receptors (Chap. 21, p. 406). It ollows conceptually that progesterone administration may prevent preterm labor. Tis hypothesis has stimulated several studies o both 17-alpha hydroxyprogesterone caproate and vaginally administered progesterone in women with varying risks or preterm birth.
At present, reported benets o either progestogen therapy are largely limited to women with singleton pregnancies. Progestogen prophylaxis specically in multietal gestations has not lowered preterm birth rates (Caritis, 2009; Dodd, 2019; Rehal, 2020; Rouse, 2007). Accordingly, both the American College o Obstetricians and Gynecologists (2021c) and the Society or Maternal-Fetal Medicine (2020b) support the use o progestogen therapy or prevention o preterm birth in select women with singleton pregnancies despite the challenges chronicled (Nelson, 2021). Either a history o prior preterm birth or no prior preterm birth but a sonographically identied short cervix is a criterion.
■ Prior Preterm Birth and Progestogen
Compounds
Te synthetic progestogen 17-alpha-hydroxyprogesterone caproate (17-OHPC) is the ocus o current controversy. It remains the rst, and only, drug approved by the FDA or prevention o recurrent preterm birth. Tis therapy was originally approved in 2011 through an accelerated process or orphan drugs and based on the ndings o Maternal-Fetal Medicine Units (MFMU) Network study, described next. However, this approval and justication or continued use is now disputed (Chang, 2020; Food and Drug Administration, 2019, 2020; Greene, 2020; Nelson, 2021).
Maternal-Fetal Medicine Units Network Trial
In the MFMU Network trial, 463 women with a prior preterm birth were randomly assigned to receive weekly intramuscular injections o inert oil placebo or 17-OHPC rom 16 through 36 weeks’ gestation (Meis, 2003). Recurrence o preterm birth rates were 36 percent in women receiving 17-OHPC and 55 percent in those given placebo. Tis study was challenged because o the unexpectedly high preterm delivery rate in the placebo arm (Romero, 2013). One explanation or this high rate was asymmetry in the risks o recurrence. Indeed, 41 percent o the placebo group had ≥2 prior preterm births compared with only 28 percent in the 17-OHPC group. Another concern was that the injection dosage o 17-OHPC, which was 250 mg weekly, was empirically chosen (Caritis, 2012, 2014).
Because o these reported challenges, the FDA granted approval but called or a conrmatory randomized clinical trial beore nal FDA approval (Food and Drug Administration, 2019). Te multicenter, international, randomized trial was launched in 2009 but required 9 years to complete (Blackwell, 2020).
Pricing Concerns
Following the accelerated approval, drug-overpricing claims prompted concern (Cohen, 2011; Romero, 2013). In 2011, the FDA gave temporary approval to KV Pharmaceutical to market 17-OHPC under the brand name Makena. Because regulations prohibited compounding, there was no competitor or this relatively inexpensive drug, and Makena was priced at $1500 per injection. Tis caused widespread concern because the cumulative cost o Makena would be more than $30,000 per pregnancy.
Parkland Hospital, given these pricing concerns, contracted a local compounding pharmacy to provide 250-mg, singledose vials o 17-OHPC in sesame oil at a cost o $25 per dose. Nelson and colleagues (2017) reported their ndings rom this program in a prospective study o 430 women given this compounded 17-OHPC. It was ineective or prevention o recurrent preterm birth at 35 weeks or less compared with a historical cohort rom Parkland Hospital. Moreover, 17-OHPC did not signicantly reduce the rates o recurrent preterm birth regardless o prior preterm birth number or sequence. Moreover, plasma concentrations o 17-OHPC were not dierent at 24 weeks or 32 weeks between women delivered at ≤35 weeks and those delivered later.
Metabolism
Despite its widespread use, the mechanism o action or 17-OHPC remains unknown. Sharma and associates (2008) reported that the metabolism o 17-OHPC was predominantly mediated by the CYP3A enzymatic system. Tus, other agents that induce or inhibit this system or hepatic impairment may alter drug levels. Tey also showed that 17-OHPC is not converted ater administration to the progesterone metabolite 17α-hydroxyprogesterone. Te relative binding afnity o 17-OHPC to progesterone receptors approximates only 30 percent o that by progesterone (Attardi, 2007). Caritis and colleagues (2012) examined 61 women receiving 17-OHPC therapy and ound that the hal-lie was relatively long (median 16.2 days). Pharmacokinetic parameters were aected by maternal body habitus and varied widely between subjects. In addition, 17-OHPC 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-OHPC is sae or the etus (Food and Drug Administration, 2019). No abnormalities, including abnormal genitalia, were ound in a 48-month ollow-up study o inants exposed in the 2003 MFMU Network trial (Northen, 2007). Simons and coworkers (2021) also reported no eect o progestogens on child development in a systematic review comprising numerous developmental measurements.
PROLONG Trial
Te FDA-required conrmatory trial was the PROLONG trial and completed in October 2018. A total o 1708 women were randomly assigned in a 2:1 ratio to receive 17-OHPC or placebo. Tis trial had two primary endpoints, which were birth <35 weeks’ gestation and a neonatal composite. Data were analyzed or 1651 o the liveborn neonates (Table 45-7) (Blackwell, 2020). Progesterone was not eective in preventing recurrent preterm birth. In the analysis o various secondary outcomes, 17-OHPC treatment also lacked efcacy. FDA Recommendations In October 2019, the FDA convened an Advisory Committee meeting to review 17-OHPC and the new data. Efcacy, side eects, and several subgroup analyses were studied, and none supported 17-OHPC efcacy (Fig. 45-6). Te FDA concluded that the PROLONG trial did not demonstrate a treatment benet o 17-OHPC in reducing the neonatal composite index or the rate o spontaneous preterm birth prior to 35 weeks’ gestation. Te Advisory Committee recommended to withdraw approval. In November 2020, the Center or Drug Evaluation and Research proposed that Makena (17-OHPC) be withdrawn rom the market (Food and Drug Administration, 2020).
Response to the FDA position has been mixed. Both the American College o Obstetricians (2019a, 2021a) and Society or Maternal-Fetal Medicine (2020b) have issued statements endorsing continued use o 17-OHPC or prevention o recurrent preterm birth in women with singleton pregnancies. Endorsements by these organizations continue ater publication o a metaanalysis by the Evaluating Progestogens or Preventing Preterm birth International Collaborative (EPPPIC) Group (2021). Tese investigators summarized that vaginal progesterone and 17-OHPC both reduced birth rates beore 34 weeks’ gestation in high-risk singleton pregnancies. Notably, the ndings or 17-OHPC did not reach statistical signicance. Moreover, this metaanalysis grouped together trials o patients with diering risk proles. It combined women with and without a prior preterm birth as well as women with and without a short cervix. Tese positions have stimulated several dueling commentaries regarding its use (Chang, 2020; Godlewski, 2020; Greene, 2020; Sibai, 2020). At this time, the FDA has not withdrawn the accelerated approval. I ormally withdrawn, however, a consequence may be continued “o-label” use, with the caveat that insurers may not provide payment coverage.
■ Progesterone Prophylaxis with Shortened Cervix
Tree randomized trials are at the center o whether progestogen therapy should be used in women without prior preterm births but who have a shortened cervix (Table 45-8). In the rst trial, 250 women with short cervices measuring ≤15 mm identied during routine prenatal care were nightly given 200-mg micronized progesterone vaginal capsules or placebo rom 24 to 34 weeks’ gestation (Fonseca, 2007). Te rate o spontaneous delivery <34 weeks was signicantly reduced by progesterone therapy. Importantly, this trial included nulliparas and also those with twins or prior preterm birth. In the second trial, 465 women with a short cervix—10 to 20 mm—were given vaginal progesterone gel, 90 mg daily, or placebo (Hassan, 2011). Tose receiving progesterone had signicantly lower rates o preterm birth <33 weeks. Tis trial also included nulliparas and women with prior preterm births. According to Likis and colleagues (2012), the heterogeneity o these rst two studies that included women with varied indications or progestogen treatment, combined with the act that outcomes were not reported by risk actors such as nulliparity, made it impossible to interpret the efcacy o progesterone or specic indications.
Te third study randomly assigned administration o 17-OHPC intramuscular injection or placebo between 16 and 223/7 weeks’ gestation to nulliparas with a singleton gestation and a cervical length <30 mm detected sonographically (Grobman, 2012). reatment with 17-OHPC did not reduce the requency o preterm birth <37 weeks. Regardless o cervical length, 17-OHPC was ineective. From these, vaginal progesterone, but not intramuscular 17-OHPC, appears to benet women with a sonographically measured short cervix. Romero and Stanczyk (2013) provided a review to explain the conicting evidence and argued that naturally occurring progesterone, which is used in the vaginal preparations, is not the same as synthetic 17-OHPC. Likewise, Furcron and coworkers (2015) ound that 17-OHPC did not have local antiinammatory eects at the maternal-etal inter- ace or cervix. Further, 17-OHPC did not protect against endotoxin-induced preterm birth. From all these studies, the American College o Obstetricians and Gynecologists (2021c) 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 o treatment with vaginal progesterone. Because o the preliminary results suggesting success o vaginally administered progesterone, the OPPIMUM study was carried out—does progesterone prophylaxis to prevent preterm labor improve outcome? (Norman, 2016). High-risk women were dened 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 actors or preterm birth.
Te primary outcomes o OPPIMUM were unique in that both immediate obstetrical and childhood outcomes were examined. Tese were etal death or birth <34 weeks; a composite o death, brain injury, or bronchopulmonary dysplasia; and a standardized cognitive score at age 2 years. Contrary to earlier reports, vaginal progesterone was not associated with a lower risk o preterm birth or composite neonatal adverse outcomes. In children at 2 years, vaginal progesterone had no long-term benet or harm.
■ Progestogens Summary
Tus, evidence remains conicting as to the efcacy o progestogens across various indications. Some have attempted to resolve these issues through systematic review and metaanalysis (Conde-Agudelo, 2018; da Fonseca, 2020; Jarde, 2019; Prior, 2017; Romero, 2018). However, virtually all evidence supporting progestogen use or a specic indication can be challenged in some way. At this time, we agree with Norman and colleagues (2016) that the results o recent studies should prompt a major review o progesterone use or preterm birth prophylaxis, a search to identiy specic women who might benet, and a redoubling o eorts to nd alternative strategies to prevent preterm birth in women at risk.
■ Geographybased Public Healthcare Programs
A well-organized prenatal system can lower preterm birth rates in high-risk indigent populations (Creasy, 1980). For example, in the Parkland Hospital prenatal clinic system, a declining preterm birth rate between 1988 and 2006 coincided with a substantial rise in prenatal visit attendance (Fig. 45-7) (Leveno, 2009). In the early 1990s, a concerted eort was made to improve access 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 or patients. Prenatal protocols are used by nurse practitioners at all clinic sites to guarantee homogeneous care. Women with highrisk pregnancy complications are reerred to a hospital-based central clinic system. Here, maternal-etal medicine clinics operate each weekday and are staed by residents and midwives who are supervised by ellows and aculty.
A similar obstetrical care system or indigent women at the University o Alabama at Birmingham also has produced salutary results (ita, 2011). Given the recent emphasis on access to care, especially among underserved minorities, these experiences remain relevant (United States Congress, 2019). Prenatal care is an important component o a comprehensive public health-care system that at least partially aects the preterm birth rate.
■ Aspirin
Acetylsalicylic acid (ASA) is a cyclooxygenase inhibitor with antiin- ammatory and antiplatelet properties that has been used in pregnancy most commonly to prevent or delay onset o preeclampsia (Chap. 41, p. 705). Data now suggest that low-dose aspirin may also reduce spontaneous preterm birth rates (Andrikopoulou, 2018). In one randomized study o 11,976 nulliparas in six lowand middle-income countries, women were randomly assigned to receive low-dose aspirin (81 mg) or placebo initiated between 60/7 and 136/7 weeks’ gestation (Homan, 2020). Low-dose aspirin decreased the incidence o birth <37 weeks and reduced the perinatal mortality rate. Although this trial did not dierentiate spontaneous rom indicated preterm birth, it requires replication in high-resource settings. Te American College o Obstetricians and Gynecologists (2020c) does not recommend low-dose aspirin prophylaxis to prevent spontaneous preterm birth in the absence o preeclampsia risk actors.
MANAGEMENT OF PRETERM PRELABOR RUPTURE OF MEMBRANES
Methods used to diagnose ruptured membranes are detailed in Chapter 22 (p. 426). A history o vaginal leakage o uid, either as a continuous stream or a gush, should prompt a speculum examination to visualize gross vaginal pooling o amnionic uid, clear uid rom the cervical canal, or both. Conrmation o rupture o membranes is usually accompanied by sonographic examination to assess amnionic uid volume, to identiy the presenting part, and i not previously determined, to estimate gestational age. Once PPROM is identied, the general scheme shown in Table 45-9 can guide management.
■ Natural History
Te time rom PPROM to delivery is inversely related to the gestational age at which rupture occurs. Very ew days are gained i membranes rupture during the third trimester compared with midpregnancy (Fig. 45-8) (Carroll, 1995). In an earlier study rom Parkland Hospital, 298 consecutive women with spontaneously ruptured membranes between 24 and 34 weeks’ gestation were analyzed (Cox, 1988). PPROM constituted 1.7 percent o pregnancies during the study period. At the time they presented, 76 percent o the women were already in labor, and 5 percent were delivered or other complications. Tus, only 19 percent initially were suitable or expectant management. Ultimately, delivery was delayed 48 hours or more ater membrane rupture in only 7 percent o the total study cohort. None o the neonates in this group died. Tis contrasted with a neonatal death rate o 8 percent in preterm newborns delivered within 48 hours o membrane rupture. Others have reported similar results (Nelson, 1994)
■ Hospitalization
Most clinicians hospitalize women with PPROM. Concerns regarding the costs o lengthy hospitalizations are usually moot, because most women enter labor within a week or less ate membrane rupture. Carlan and coworkers (1993) randomly assigned 67 women with PPROM at <37 weeks’ gestation to home or hospital management. Te mean gestational age was 31 weeks. No benets were ound or 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 sae in regard to umbilical cord prolapse. I hospitalization is chosen, no consensus guides the optimal requency o inpatient assessment. Te American College o Obstetricians and Gynecologists (2020g) notes that an acceptable strategy would include periodic sonograms or etal growth, etal heart rate monitoring, and clinical surveillance or maternal inection—particularly ever. During the periviable period and at gestation ages beore interventions would be planned, a short period o initial observation and consideration o outpatient monitoring in select cases is reasonable. Hospitalization would then be practiced at the time o viability
■ Intentional Delivery
Beore the mid-1970s, labor was usually induced in women with PPROM because o sepsis ears. Maternal inection risk and etal prematurity risk vary according to the gestational age at membrane rupture, and management decisions incorporate this data. With periviable pregnancy, Morales (1993b) expectantly managed 94 singleton pregnancies with PPROM beore 25 weeks. Te average time gained was 11 days. Although 41 percent o inants survived to age 1 year, only 27 percent o the original cohort were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their colleagues. Management o these early pregnancies is discussed on page 785.
For PPROM in general, two randomized trials in the 1990s compared labor induction with expectant management (Cox, 1995; Mercer, 1993). In both o these studies, the balance o risk and benet was difcult to ascertain, as neither immediate delivery nor expectant management was superior or neonatal outcomes. Lieman and associates (2005) ound that neonatal outcomes did not improve with expectant management beyond 33 weeks. McElrath and coworkers (2003) ound that prolonged latency ater membrane rupture was not associated with a greater incidence o etal neurological damage. An important correlate is that inection—specically chorioamnionitis—is a recognized risk actor or neonatal neurological injury (Gaudet, 2001; Wu, 2000). Bond and colleagues (2017) compared planned early birth with expectant management or women with PPROM beore 37 weeks’ gestation. Tey evaluated 12 randomized trials totaling 3617 women and 3628 newborns. No clinically important di- erences in the incidence o neonatal sepsis between women who immediately delivered and those managed expectantly were identied. Although the incidence o chorioamnionitis was lower, neonates o women randomized to early birth were more likely to be born at an earlier gestational age and encountered attendant perinatal sequelae. Te authors concluded that in women with rupture o membranes beore 37 weeks’ gestation without contraindications to continuing the pregnancy, a policy o expectant management with careul monitoring was associated with better outcomes or both the mother and newborn. A subsequent metaanalysis o late-preterm prelabor rupture o membranes by Quist-Nelson and coworkers (2018) noted that immediate delivery and expectant management resulted in comparable rates o the composite o adverse neonatal outcomes.
Because o conicting data and the controversies o immediate delivery compared with expectant management, the American College o Obstetricians and Gynecologists (2020g) cannot make rm recommendations. Clearly, gestational age is an important consideration. At 240/7 to 336/7 weeks, expectant management in the absence o nonreassuring etal status, clinical chorioamnionitis, or placental abruption is recommended. At 340/7 to 366/7 weeks’ gestation, delivery was once recommended, however, it is now considered reasonable to oer either expectant management or immediate delivery ollowing consideration o risks and benets, counseling, and shared decision-making. Expectant management should not go beyond 370/7 weeks’ gestation. Based upon limitations o access to care and resources, our current practices at Parkland Hospital continue to avor immediate delivery ater 34 weeks’ gestation.
■ Expectant Management
Several considerations arise during expectant management o PPROM (Boettcher, 2020; Shaddeau, 2020). One is digital cervical examination. Alexander and colleagues (2000) analyzed ndings in women with membrane rupture expectantly managed between 24 and 32 weeks’ gestation. Tey compared those who had one or two digital cervical examinations with women who were not examined. Tose who were examined had a rupture-to-delivery interval o 3 days compared with 5 days in those not examined. Tis dierence did not worsen maternal or neonatal outcomes. At Parkland Hospital, digital cervical examination is used judiciously in PPROM cases. Rupture o membranes ollowing second-trimester amniocentesis is uncommon (Chap. 17, p. 345). Compared with women with spontaneous rupture during the second trimester, Borgida and associates (2000) ound that pregnancies complicated by PPROM ater genetic amniocentesis resulted in signicantly better perinatal outcomes. Te perinatal survival rate was 91 percent. Ater counseling, aected women are typically managed expectantly as outpatients with serial surveillance o amnionic uid volume and sel-assessment o temperature (American College o Obstetricians and Gynecologists, 2020g). In the series cited above, the mean time to documentation o a normal amnionic uid volume ater amniocentesis approximated 2 weeks. ocolysis given with PPROM has been reported in ew studies. In women with ruptured membranes and lack o labor, prophylactic tocolysis does not improve neonatal outcomes but is associated with greater chorioamnionitis rates (Mackeen, 2014). Similarly, therapeutic tocolysis—or those with ruptured membranes and labor—has not provided signicant perinatal benet (Garite, 1987).
Management o PPROM in the woman who has undergone cervical cerclage is complex (American College o Obstetricians, 2020g). McElrath and associates (2002) studied 114 women with a cerclage in place who later had ruptured membranes beore 34 weeks. Tey were compared with 288 controls. Pregnancy outcomes were equivalent in both groups. Cerclage retention or more than 24 hours ater PPROM may be associated with pregnancy prolongation, however, intrauterine inection and its consequences are risks (Giraldo-Isaza, 2011; Laskin, 2012). At Parkland Hospital, cerclage retention in the absence o inection or labor is currently practiced with close clinical surveillance in those with PPROM.
With PPROM in pregnancies beore 26 weeks, the volume o amnionic uid remaining ater rupture appears to have prognostic importance (Carroll, 1995; Hadi, 1994). Although varied by report, current rates o pulmonary hypoplasia with PPROM beore 24 weeks among surviving neonates can be as high as 30 percent (Kiver, 2018). Tis suggests that 23 weeks reects a threshold or lung hypoplasia development (Chap. 7, p. 131). Further, when contemplating early expectant management, oligohydramnios and resultant limb compression deormities are inuencing considerations.
For neonates born to women who have active herpetic lesions and who are expectantly managed, the inectious morbidity risk appears to be outweighed by risks associated with preterm birth (Chap. 68, p. 1216) (Major, 2003). Lewis and associates (2007) ound that expectant management o women with PPROM and noncephalic presentation was associated with a higher rate o umbilical cord prolapse, especially beore 26 weeks. issue sealants are oten used to gain surgical hemostasis. Limited reports describe their use or repair o etal membranes (Chap. 11, p. 203). Crowley and coworkers (2016) concluded that available data are currently insufcient to assess the value o sealing procedures or PPROM. We do not use these agents or this indication.
■ Clinical Chorioamnionitis
Inection is a major concern with membrane rupture. Although some cases remain subclinical, i chorioamnionitis is diagnosed, prompt eorts to eect delivery, preerably vaginally, are initiated. Because maternal leukocytosis alone is not a consistent nding, ever is the only reliable indicator or the diagnosis o chorioamnionitis. Institutional practices and protocols vary in dening the temperature threshold. raditionally, a temperature ≥38°C (100.4°F) accompanying ruptured membranes has implied inection. At Parkland Hospital, we still adhere to this criterion. In 2015, a workshop sponsored by the NICHD was convened and suggested renaming this condition intraamnionic inection and inammation—triple I (Higgins, 2016). Te merits o this terminology have been questioned (Barth, 2016). Nonetheless, the American College o Obstetricians and Gynecologists (2019b) revised both the denitions and temperature thresholds or intraamnionic inection. Using these new denitions, the diagnosis o suspected intraamnionic inection 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 actor is present. Te latter include low parity, multiple digital examinations, internal uterine and etal monitors, meconium-stained amnionic uid, and the presence o certain genital tract pathogens, such as group B streptococcus (GBS) and sexually transmitted agents. Isolated maternal ever is dened as any maternal temperature between 38.0°C and 38.9°C with no additional risk actors present, and with or without persistent temperature elevation.
With chorioamnionitis, etal and neonatal morbidity are substantively increased. Alexander and colleagues (1998) studied 1367 very-low-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 inection. Tose in the inected group had higher incidences o sepsis, respiratory distress, early-onset seizures, intraventricular hemorrhage, and periventricular leukomalacia. Yoon and colleagues (2000) ound that intraamnionic inection in preterm neonates was associated with increased rates o cerebral palsy. In one study o more than 11 million singleton live births in the United States rom 1995 to 1997, 1.6 percent o gravidas had ever during labor. Tis was a strong predictor o inection-related death in both term and preterm neonates (Petrova, 2001).
■ Antimicrobial Therapy
Various antimicrobials have been evaluated to orestall preterm delivery. Mercer and associates (1995) reviewed 13 randomized trials that evaluated antibiotics or PPROM beore 35 weeks. Teir metaanalysis indicated that only three o 10 outcomes were possibly beneted: (1) ewer women developed chorioamnionitis, (2) ewer newborns developed sepsis, and (3) pregnancy was more oten prolonged 7 days in women given antibiotics. However, rates o other neonatal outcomes, including survival and respiratory distress, were unaected.
In an MFMU Network trial, women with membrane rupture between 24 and 32 weeks’ gestation were randomly assigned to expectant management combined with placebo or to a 7-day antibiotic regimen. reatment included intravenous ampicillin plus erythromycin every 6 hours or 48 hours, which was ollowed by oral amoxicillin plus erythromycin, every 8 hours or 5 days. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had signicantly ewer newborns with respiratory distress, necrotizing enterocolitis, and composite adverse outcomes (Mercer, 1997). Te latency period was also signicantly longer. Specically, 50 percent o women given an antimicrobial regimen remained undelivered ater 7 days o treatment compared with only 25 percent o those given placebo. Also, a signicantly greater number o treated pregnancies were undelivered at 14 and 21 days. Cervicovaginal GBS colonization did not alter these results.
Other studies have examined the efcacy o shorter treatment lengths and dierent antimicrobial combinations. Tree-day treatments compared with 7-day regimens using either ampicillin or ampicillin-sulbactam appear equally eective in regard to perinatal outcomes (Lewis, 2003; Segel, 2003). Similarly, erythromycin compared with placebo oered a range o signicant neonatal benets. Te substitution o azithromycin or erythromycin does not appear to impact maternal or neonatal outcomes, and the ormer has an improved side-eect prole (Dotters-Katz, 2020). An amoxicillin-clavulanate regimen is not recommended, however, because o its association with an increased incidence o neonatal necrotizing enterocolitis (Kenyon, 2004).
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 rom 400 to 1500 g and born rom 1998 to 2000. Teir outcomes were compared with those o 7606 neonates o similar birthweight born rom 1991 to 1993 and prior to the practice o antibiotic prophylaxis. Te overall rate o early-onset sepsis did not change between these two epochs. But, the rate o GBS sepsis dropped rom 5.9 per 1000 births in the earlier group to 1.7 per 1000 births in the later group. Comparing these same epochs, the rate o Escherichia coli sepsis, however, rose rom 3.2 to 6.8 per 1000 births. Almost 85 percent o isolates rom the more recent cohort were resistant to ampicillin. Neonates with early-onset sepsis were more likely to die, especially i they were inected with coliorms. Long term, Kenyon and coworkers (2008a) ound that antimicrobials given or women with PPROM had no eect on the health o children at age 7 years.
■ Corticosteroid Therapy
A single course o corticosteroids is recommended or pregnant women with PPROM between 240/7 and 340/7 weeks’ gestation (American College o Obstetricians and Gynecologists, 2020g). A single course o corticosteroids as early as 230/7 weeks in those at risk or preterm delivery within 7 days may be considered. A similar controversy is ound at the other end o the gestational age spectrum, 340/7 to 366/7 weeks’ gestation and with rescue therapy (p. 803). Tese issues were summarized by Battarbee (2020) in a recent review.
MANAGEMENT OF PRETERM LABOR WITH INTACT MEMBRANES
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
One of every 10 women with preterm labor and intact membranes will have intraamnionic infection that is largely subclinical (Yoon, 2019). Because of this, several tests have been used to diagnose intraamnionic infection (Andrews, 1995; Romero, 1993; Yoon, 1996). Although such infection can be identified with a positive test result, routine amniocentesis others little value.
■ Corticosteroid Therapy
Glucocorticosteroids were found to accelerate lung maturation in preterm sheep fetuses, and Liggins and Howie (1972) evaluated them to treat women with preterm labor. Corticosteroid therapy was effective in lowering the incidence of respiratory distress syndrome (RDS) and neonatal mortality rates if birth was delayed for at least 24 hours after initiation of betamethasone. Infants exposed to corticosteroids in these early studies have now been followed into adulthood with no ill effects detected.
In 1995, a National Institutes of Health (NIH) Consensus Development Conference panel recommended corticosteroids for fetal lung maturation in threatened preterm birth. A subsequent NIH Conference (2000) summarized that data were insufcient to assess corticosteroid effectiveness in pregnancies complicated by hypertension, diabetes, multifetal gestation, fetal-growth restriction, or fetal hydrops. It was concluded, however, that administering corticosteroids to these women is reasonable.
One metaanalysis of 30 studies totaling 7774 women and 8158 infants quantified the benefit of a single course of corticosteroids (Roberts, 2017). Treatment was associated with lower rates of perinatal death, neonatal death, RDS, intraventricular hemorrhage, necrotizing enterocolitis, mechanical ventilation, and systemic infection in the first 48 hours of life. No obvious benefits 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 increased perinatal mortality rates (Althabe, 2015). Because o this unexpected finding, a multicountry randomized trial comparing dexamethasone to placebo and involving pregnant women between 260/7 and 336/7 weeks’ gestation was recently completed (WHO ACION Trials Collaborators, 2020). The trial was stopped early due to benefits of dexamethasone, which resulted in a significantly lower risk of stillbirth or neonatal death. The discrepancy between the two reports was attributed to inaccuracies in gestational age assessment (Rohwer, 2020).
A single course of corticosteroids is currently recommended for women between 24 and 34 weeks’ gestation who are at risk for delivery within 7 days (American College of Obstetricians and Gynecologists (2020a). This recommendation for premature twins has been challenged (Viteri, 2016). For pregnancies at 23 weeks and at risk of delivery within 7 days, a single course of corticosteroids may be considered (p. 785). Administration of corticosteroids during the periviable period is linked to parental decisions regarding resuscitation and should be considered in that context (American College of Obstetricians and Gynecologists, 2019d).
Agent Selection
Betamethasone and dexamethasone are glucocorticoids that appear equivalent in stimulating fetal lung maturation (Murphy, 2007). Reduced rates of major preterm neonatal morbidities and increased rates of survival without neurosensory disability at age 2 years do not differ between them (Crowther, 2019; 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 beneficial 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, 2020a).
Late-preterm Delivery
Antenatal betamethasone has been compared against placebo for neonates that are likely to deliver in the late-preterm period (Gyam-Bannerman, 2016). Although only 60 percent of 2831 women received both injections, the rate of respiratory complications measured as a composite outcome was significantly lower with corticosteroid use compared with placebo—11.6 versus 14.4 percent. Because of these findings, consideration for administration of a single course of betamethasone for women between 340/7 and 366/7 weeks is advocated by both the American College of Obstetricians and Gynecologists (2020a) and the Society for Maternal-Fetal Medicine (2016a).
Adoption of this practice has not been universal because of both short- and long-term neonatal safety concerns (Crowther, 2016; Kamath-Rayne, 2016). Specifically, in the newborns receiving betamethasone, rates of hypoglycemia were significantly greater (Gyam-Bannerman, 2016). Neonatal hypoglycemia is particularly worrisome for possible adverse long-term consequences that include developmental delay (Kerstjens, 2012). Another caveat is that the largest effects of betamethasone included a reduction in transient tachypnea of the newborn (TTN), which is a self-limited condition with little clinical significance (Kamath-Rayne, 2016). Specifically, the rates of TTN 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 (2010). The latter was a retrospective, observational study from 19 hospitals across the United States that included 233,844 deliveries. Because of these issues, we do not provide corticosteroids beyond 34 weeks at Parkland Hospital at this time.
Repeated Courses
A single dose of intramuscular corticosteroids has been compared with repeated courses for lung maturation in two major randomized trials. Both found that repeated courses reduced neonatal respiratory morbidity rates, but the longterm consequences were much different. In one study, all women were given a primary course of betamethasone. If the preterm delivery risk persisted, they were assigned to serial weekly doses of betamethasone or placebo. These investigators found no adverse effects in the infants followed to age 2 years (Crowther, 2007).
In the second study, 495 women were randomly assigned to receive a single corticosteroid course that contained two doses or assigned to repeated courses that were given weekly (Wapner, 2007). In infants exposed to repeated courses, a nonsignificant rise in the cerebral palsy rate was identified. Still, exposure to the doubled betamethasone dose was worrisome because some experimental evidence supports the view that adverse effects are dose dependent (Bruschettini, 2006). We agree with Stiles (2007) who summarized these two studies as “early gain, longterm questions.” At Parkland Hospital, our practice is to follow the recommendations of the American College of Obstetricians and Gynecologists (2020a) or single-course therapy.
Rescue Therapy
This 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 differ. Another study found that treated infants had improved respiratory compliance (McEvoy, 2010). In a metaanalysis, Crowther and colleagues (2011) concluded that a single rescue 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 (2020a) notes that a single rescue course of antenatal corticosteroids should be considered in women with fetuses <34 weeks’ gestation whose prior course was administered at least 7 days previously. Effects of rescue therapy beyond 34 weeks are unknown. At Parkland Hospital, we currently do not provide additional courses of corticosteroids beyond the initial single-course therapy.
■ Magnesium Sulfate for Neuroprotection
Very-low-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether, 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’ gestation 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. However, this study was not sufciently powered. The multicenter French trial reported by Marret and associates (2008) had similar problems.
More convincing evidence for magnesium neuroprotection came from the randomized MFMU Network study—Beneficial Efects of Antenatal Magnesium Sulfate—BEAM—study (Rouse, 2008). In the study, 2241 women at imminent risk for preterm birth between 24 and 31 weeks’ gestation were assigned to magnesium sulfate or placebo. Magnesium sulfate was given as a 6-g bolus over 20 to 30 minutes and was followed with a maintenance infusion of 2 g/hr. Magnesium sulfate was actually infusing at the time of delivery in approximately half of the treated women. Infusion continuation protocols vary by institution, including ours. In the BEAM study, after 12 hours with no signs of imminent delivery, the infusion was stopped and resumed if delivery again seemed imminent. If >6 hours had passed since discontinuation, another loading dose was given.
A 2-year assessment was available for 96 percent of the children in the BEAM trial (Table 45-10) (Rouse, 2008). The results can be interpreted differently depending on statistical methodologies employed. Some interpret these findings to mean that magnesium sulfate infusion prevents cerebral palsy regardless of the gestational age at which therapy is given. Those with a differing view conclude that this trial only supports use of magnesium sulfate for prevention of cerebral palsy potentially before 28 weeks. Subsequently, Doyle and associates (2009) reviewed five randomized trials to assess neuroprotective effects. A total of 6145 infants were studied, and these reviewers concluded that magnesium sulfate exposure compared with no exposure significantly lowered risks for cerebral palsy. Rates of other neonatal morbidities did not differ significantly. It was calculated that treatment given to 63 women would prevent one case of cerebral palsy.
Controversy surrounding magnesium sulfate efficacy for neuroprotection prompted a debate at the 2011 annual meeting of the Society for Maternal-Fetal Medicine. Rouse (2011) spoke for the benefits of magnesium sulfate, whereas Sibai (2011) challenged that the reported benefits were falsely positive due to random statistical error in the metaanalysis by Doyle (2009). Another peculiarity is the apparent lack of doseresponse for efcacy (McPherson, 2014). Because none of the individual studies found a benefit from magnesium sulfate for fetal neuroprotection, the American College of Obstetricians and Gynecologists (2020d,g) concluded that those electing prophylaxis should develop specific guidelines, and this includes those with PPROM. In a recent prospective observational study of infants born at 220/7 to 266/7 weeks’ gestation, exposure to both corticosteroids and magnesium sulfate was associated with lower rates of neurodevelopmental impairment and death compared with corticosteroids alone (Gentle, 2020). At Parkland Hospital, for the periviable fetus, we individualize management as shown in Table 45-4.
■ Antimicrobial Treatment
Results have been disappointing in studies of antibiotics given to arrest preterm labor. From one Cochrane metaanalysis, antimicrobial prophylaxis given to women with intact membranes did not reduce preterm birth rates or affect 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.
In the ORACLE Collaborative Group study of 6295 women with spontaneous preterm labor, intact membranes, but without evidence of infection, women were randomly assigned to receive antimicrobial or placebo therapy (Kenyon, 2001). 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 setting was associated with an increased cerebral palsy rate at age 7 years compared with that in children without fetal exposure (Kenyon, 2008b). Moreover, although preterm birth is associated with bacterial vaginosis, treatment with clindamycin in more recent randomized trials has failed to lower preterm birth rates (Bellad, 2018; Subtil, 2018). Importantly, antimicrobial use described here is distinct from that given for GBS prophylaxis (Chap. 67, p. 1195).
■ Bed Rest
This has been one of the most often prescribed interventions, yet one of the least supported by evidence (McCall, 2013). An earlier systematic review concluded that evidence neither supported nor refuted bed rest for preterm birth prevention (Sosa, 2004). Moreover, possible harms are thromboembolic events, deconditioning, and bone loss (Kovacevich, 2000; Promislow, 2004). Grobman and associates (2013) reported that women with activity restriction were nearly 2.5 times more likely to have a preterm birth before 34 weeks. This finding, however, may reflect ascertainment bias. That is, women with restricted activity may have been assigned to bed rest because they were viewed to have a greater risk for preterm delivery. The Society for Maternal-Fetal Medicine (2020a) and the American College of Obstetricians and Gynecologists (2020) recommend against activity restriction to reduce preterm birth rates.
■ Cervical Pessaries
Silicone rings, such as the Arabin pessary, have been used to support the cervix in women with a sonographically short cervix. In one study, 385 women with a cervical length ≤25 mm were provided a silicone pessary or expectant management (Goya, 2012). Newborns spontaneously delivered before 34 weeks’ gestation in 6 percent of women in the pessary group compared with 27 percent in the expectant management group. In another randomized trial, almost 100 women with a cervical length <25 mm at 20 to 24 weeks’ gestation received either pessaries or expectant management (Hui, 2013). The pessary did not lower the rate of delivery <34 weeks. Others have reported similar findings (Nicolaides, 2016). Moreover, authors of a recent systematic review totaling 4687 women and 7167 infants found that current evidence does not support pessary use to prevent preterm birth or improve perinatal outcomes in singleton or twin gestations with a short cervix or in unselected twin gestations (Conde-Agudelo, 2020). The Society for Maternal-Fetal Medicine (2017) currently recommends pessary prophylaxis only within research protocols.
■ Emergency or Rescue Cerclage
Some evidence supports the concept that cervical incompetence and preterm labor lie along a spectrum leading to preterm delivery. Consequently, cerclage placement after preterm labor begins to manifest clinically has been studied. Importantly, for women with labor and active cervical change, cerclage is contraindicated. In one study, 23 women with cervical incompetence beore 27 weeks’ gestation were randomly assigned to bed rest, with or without an adjunctive emergency McDonald cerclage (Althuisius, 2003). Delivery delay was significantly greater in the cerclage group compared with those assigned to bed rest alone—54 versus 24 days, respectively. erkildsen 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’ gestation were associated with a significantly lower chance of significant pregnancy continuation. More recently, a multicenter randomized trial assessed women with twin pregnancies and asymptomatic cervical dilation of 1 to 5 cm between 160/7 and 236/7 weeks’ gestation (Roman, 2020). From a total of 30 enrolled women, 17 women received physical examination-indicated cerclage, and 13 women received no cerclage. Of note, all women who underwent cerclage received indomethacin and antibiotics.
In the cerclage group, the preterm birth rate was significantly decreased at all evaluated gestational ages, and specifically, cerclage lowered the birth rate for those <28 weeks by 50 percent. From these limited reports, for women facing a poor pregnancy prognosis due to cervical dilation at midgestation, emergency or rescue cerclage with appropriate counseling is reasonable. At this time, however, it is unclear if such interventions truly con-fer a benefit or merely increase the risk of membrane rupture and infection (Hawkins, 2017).
■ Tocolysis
Although several drugs have been used to prevent or inhibit preterm labor, none is completely effective. The American College of Obstetricians and Gynecologists (2020e) 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, evidence does not support that tocolytic therapy has any direct favorable effect on neonatal outcomes or that any prolongation of pregnancy afforded by tocolytics alone translates into statistically significant neonatal benefit.
Beta-adrenergic agonists, magnesium sulfate, calcium-channel blockers, or indomethacin are the recommended tocolytic agents for short-term use. The gestational age range for tocolytic use is debatable (Mendez-Figueroa, 2020). But, because the perinatal outcomes in preterm neonates are generally good after 34 weeks’ gestation, most do not recommend use of tocolytics after 33 weeks. In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. Moreover, the American College of Obstetricians and Gynecologists (2020e) has concluded that maintenance therapy with tocolytics is ineffective for preventing preterm birth. No trial has ever convincingly shown reduced rates of any important adverse outcome by a tocolytic drug compared with placebo (Walker, 2016).
β-Adrenergic Receptor Agonists
Several compounds stimulate β-adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (Chap. 21, p. 403). Of β-mimetic drugs in the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine is FDAapproved for preterm labor. Ritodrine was voluntarily withdrawn from the United States market in 2003, but a discussion of ritodrine is included here to present issues with β-mimetic drug use. In a randomized trial at Parkland Hospital, intravenous ritodrine delayed delivery for 24 hours but without other benefits (Leveno, 1986b). Additional studies confirmed a delivery delay up to 48 hours (Canadian Preterm Labor Investigators Group, 1992). Importantly, β-agonist infusion resulted in serious and even fatal maternal side effects. Pulmonary edema is a special concern, and its cause is multifactorial. Risk factors include tocolytic therapy with β-agonist drugs, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and intravenous infusion of large volumes of crystalloid. β-Agonist agents cause retention of sodium and water, and with time—usually 24 to 48 hours—these can cause volume overload (Hankins, 1988). The drugs have been implicated in increased capillary permeability, cardiac rhythm disturbances, and myocardial ischemia. For example, in an earlier study, tocolysis was the third most common cause of acute respiratory distress and death in pregnant women during a 14-year period in Mississippi (Perry, 1998).
Terbutaline is commonly used in the United States to forestall preterm labor. Like ritodrine, it may cause pulmonary edema (Angel, 1988). Low-dose terbutaline can be administered long-term by subcutaneous pump, but randomized trials fail to show benefit for such therapy (Guinn, 1998; Wenstrom, 1997). Oral terbutaline also is ineffective (How, 1995; Parilla, 1993). In one trial, 203 women with arrested preterm labor at 24 to 34 weeks’ gestation were randomly assigned to receive 5-mg terbutaline tablets or placebo every 4 hours (Lewis, 1996). Of outcomes, delivery rates at 1 week, median days of pregnancy extension, mean gestational age at delivery, and incidence of preterm labor relapse were similar in both groups. Because of serious maternal side effects, the FDA (2011) issued a warning regarding terbutaline use for preterm labor. The American College of Obstetricians and Gynecologists (2020e) recommends only short-term inpatient use of terbutaline as a tocolytic or as acute therapy for uterine tachysystole. Subcutaneous dosages of 0.25 mg are commonly used for the latter indication.
Magnesium Sulfate
Ionic magnesium in a sufciently high concentration can alter myometrial contractility. It functions as a calcium antagonist, and when given in pharmacological doses, it may inhibit labor. Magnesium sulate treatment has been associated with pulmonary edema (Samol, 2005). As discussed in Chapter 41 (p. 720), this has not been our experience at Parkland Hospital with treatment of tens of thousands of preeclamptic women with intramuscular or intravenous magnesium sulfate.
In one randomized trial, 54 women with preterm labor received magnesium sulfate, ritodrine, or placebo. Few differences in outcomes were identified (Cotton, 1984). Cox and coworkers (1990) randomly assigned 156 women to receive magnesium sulfate or infusions of normal saline. Magnesium sulfate–treated women and their neonates had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital. Similarly, Crowther and associates (2014) concluded that magnesium sulfate to treat preterm labor was ineffective and potentially harmful. Last, the FDA (2013) has warned against prolonged use of magnesium sulfate given to arrest preterm labor because of bone thinning and fractures in fetuses exposed for more than 5 to 7 days. This was attributed to low calcium levels in the fetus. Yule and associates (2020) demonstrated the influence of magnesium sulfate on maternal serum calcium levels.
Prostaglandin Inhibitors
Tese compounds are intimately involved in the contractions of normal labor (Chap. 21, p. 413). Antagonists act by inhibiting prostaglandin synthesis or by blocking their action on target organs.
Indomethacin, a nonselective cyclooxygenase inhibitor, was first used as a tocolytic in one study of 50 women (Zuckerman, 1974). Studies that followed reported the efcacy of indomethacin in halting contractions and delaying preterm birth (Muench, 2003; Niebyl, 1980). Morales and coworkers (1989, 1993a), however, compared indomethacin with either ritodrine or magnesium sulfate and found no difference in their efcacy to forestall preterm delivery. Berghella and associates (2006) reviewed four trials of indomethacin given to women with a sonographically determined short cervix and found such therapy to be ineffective to halt labor. But, as discussed earlier, its use with cerclage is gaining favor.
Most studies have limited indomethacin use to 24 to 48 hours because of concerns for oligohydramnios, which can develop with therapeutic doses. If amnionic fluid is monitored, oligohydramnios can be detected early, and it is reversible with drug discontinuation. There has also been considerable debate on the association of necrotizing enterocolitis or early ductus arteriosus closure and use of indomethacin (Doni, 2020; Hammers, 2015; Muench, 2001). Two metaanalyses of the effects of antenatal indomethacin on neonatal outcomes had conflicting findings (Amin, 2007; Loe, 2005). In one review of 20 studies, cyclooxygenase inhibitors, including indomethacin, provided no clear benefit compared with placebo or any other tocolytic agent (Reinebrant, 2015).
Calcium-channel Blockers
Myometrial activity is directly related to cytoplasmic free calcium, and reduced calcium concentrations inhibit contractions. Calcium-channel blockers inhibit, by various mechanisms, calcium entry through cell membrane channels. From study results, calcium-channel blockers, especially nifedipine, are safer and more effective tocolytic agents than β-agonist drugs (King, 2003; Papatsonis, 1997). Comparing magnesium sulfate and nifedipine, one study of 192 women at 24 to 33 weeks’ gestation found no substantial differences in efcacy or adverse effects (Lyell, 2007). Comparing nifedipine and atosiban in 145 women with preterm labor between 24 and 33 weeks, another randomized study showed that neither agent was superior to delay delivery. Neonatal morbidity rates were equivalent (Salim, 2012). Flenady and coworkers (2014b) reviewed 38 trials of calcium-channel blockers for preterm labor and concluded that these agents have benefits compared with placebo. It is problematic, however, that this conclusion stemmed from a trial with unclear risk of selection bias and a three-arm study of 84 women that was not blinded (Ara, 2008; Zhang, 2002). More recently, Hawkins and associates (2021) performed a randomized, placebo-controlled trial of nifedipine for acute tocolysis of preterm labor at Parkland Hospital. Acute tocolysis with nifedipine did not affect preterm birth rates. However, the study results were obtained following an interim analysis demonstrating futility for study continuation.
Importantly, the combination of nifedipine and magnesium sulfate for tocolysis is potentially dangerous. Ben-Ami (1994) and Kurtzman (1993) and their coworkers reported that nifedipine enhances the neuromuscular blocking effects of magnesium, which can interfere with pulmonary and cardiac function. In one small study of 54 women with preterm labor who received either magnesium sulfate plus nifedipine or no tocolytic, neither benefit nor harm was found (How, 2006).
Other Agents
Atosiban is a nonapeptide oxytocin analogue and an oxytocinreceptor antagonist that is used in European countries to forestall labor. In randomized trials, atosiban failed to improve relevant neonatal outcomes and was linked with significant neonatal morbidity (Flenady, 2014a; Moutquin, 2000; Romero, 2000). The FDA has denied approval of atosiban for use in the United States because of these findings. Nitric oxide donors are potent smooth-muscle relaxants that affect the vasculature, gut, and uterus. In randomized clinical trials, nitroglycerin administered orally, transdermally, or intravenously was ineffective or showed no superiority compared with other tocolytics. In addition, maternal hypotension is a common side effect (Bisits, 2004; Lees, 1999).
■ Labor and Delivery
Fetal heart rate and uterine contractions are monitored with preterm labor. We prefer continuous electronic monitoring. Fetal tachycardia, especially with ruptured membranes, suggests sepsis. Some evidence supports that intrapartum acidemia may intensify some of the neonatal complications usually attributed to preterm delivery. For example, Morgan and associates (2017) found that metabolic acidemia significantly raised the risks related to prematurity in neonates delivered <34 weeks’ gestation. Low and colleagues (1995) observed that intrapartum acidosis—umbilical artery blood pH <7.0—had an important role in neonatal complications. GBS infections are common and dangerous in the preterm neonate, and antimicrobial prophylaxis should be provided (Chap. 67, p. 1195).
For delivery, perinatal outcome data do not support routine episiotomy or forceps delivery to protect the “fragile” preterm fetal head. Staff proficient in resuscitative techniques commensurate with the gestational age and fully oriented to any specific problems should be present at delivery. The importance of specialized personnel and facilities for preterm newborn care is underscored by the improved survival rates of these neonates when delivered in tertiary-care centers. For community-based hospitals, multidisciplinary team-based simulation for preterm delivery can improve performance (Barbato, 2020).
Preterm newborns frequently have intracranial germinal matrix bleeding that can extend to more serious intraventricular hemorrhage. It was hypothesized that cesarean delivery to obviate trauma from labor and vaginal delivery might prevent these complications. This has not been validated by subsequent studies (Malloy, 1991). At Parkland Hospital, cesarean delivery is reserved for usual obstetrical indications.
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