Williams Obstetrics, 24th Edition

CHAPTER 42. Preterm Labor

DEFINITION OF PRETERM

TRENDS IN PRETERM BIRTH RATES

MORBIDITY IN PRETERM INFANTS

CAUSES OF PRETERM DELIVERY

ANTECEDENTS AND CONTRIBUTING FACTORS

DIAGNOSIS

PRETERM BIRTH PREVENTION

MANAGEMENT OF PRETERM PREMATURELY RUPTURED MEMBRANES

MANAGEMENT OF PRETERM LABOR WITH INTACT MEMBRANES

CORTICOSTEROIDS FOR FETAL LUNG MATURATION

TOCOLYSIS TO TREAT PRETERM LABOR

MAGNESIUM SULFATE FOR FETAL NEUROPROTECTION

Low birthweight defines neonates who are born too small. Preterm or premature births are terms used to describe neonates who are born too early. With respect to gestational age, a newborn may be preterm, term, or postterm. With respect to size, a newborn may be normally grown and appropriate for gestational age; undersized, thus, small for gestational age; or overgrown and consequently, large for gestational age. In recent years, the term small for gestational age has been widely used to categorize newborns whose birthweight is usually < 10th percentile for gestational age. Other frequently used terms have included fetal-growth restriction or intrauterine growth restriction. The term large for gestational age has been widely used to categorize newborns whose birthweight is > 90th percentile for gestational age. The term appropriate for gestational age designates newborns whose weight is between the 10th and 90th percentiles.

Thus, infants born before term can be small or large for gestational age but still fit the definition of preterm. Low birthweight refers to neonates weighing 1500 to 2500 g; very low birthweight refers to those between 500 and 1500 g; and extremely low birthweight refers to those between 500 and 1000 g. In 1960, a neonate weighing 1000 g had a 95-percent risk of death. Today, a neonate with the same birthweight has a 95-percent chance of surviving (Ingelfinger, 2007). This remarkable improvement in survival is due to the widespread application of neonatal intensive care in the early 1970s.

DEFINITION OF PRETERM

Up until the 15th edition of this textbook (1976), a preterm or premature infant was defined by birthweight < 2500 g. Beginning with the 15th edition, preterm infants were those delivered before 37 completed weeks, that is, ≤ 366/7weeks. This definition, which has now been in use for almost 40 years, was first promulgated in 1976 by the World Health Organization (WHO) and the International Federation of Gynecology and Obstetrics (FIGO). This definition was based on a statistical analysis of gestational age distribution at birth (Steer, 2005). It lacks a specific functional basis and should be clearly distinguished from the concept of prematurity. Prematurity represents incomplete development of various organ systems at birth. The lungs are particularly affected, leading to the respiratory distress syndrome.

Beginning in 2005, in recognition that infants born between 340/7 weeks and 366/7 weeks experience morbidities and mortality characteristic of premature infants, preterm births were subdivided. Those before 336/7 weeks are labeled—early preterm, and those occurring between 34 and 36 completed weeks—late preterm. Most recently, Spong (2013) observed, “it has become apparent that infants born between 37 weeks 0 days and 38 weeks 6 days gestation experience morbidities that are associated with prematurity compared to births at 39 weeks 0 days through 40 weeks 6 days when infant mortality is lower than at any other time in human gestation.” Those births 370/7weeks through 386/7 weeks are now defined as early term and those 39 weeks 0 days through 40 weeks 6 days are defined as term.

In the United States in 2011, 23,910 infants died in their first year of life (Hamilton, 2012). Preterm birth, defined as delivery before 37 completed weeks, has been implicated in approximately two thirds of these deaths (Mathews, 2013). As shown in Table 42-1late preterm births, defined as those 34 to 36 weeks’ gestation, comprised approximately 70 percent of all births before 37 completed weeks. The data in Table 42-1 suggest the possibility of redefining births attributed to short gestation to be those before 39 weeks. Surprisingly, 40 percent of live births in the United States in 2009 were associated with a shortened period of gestation when births 39 to 41 weeks are taken as the reference standard. Moreover, these 40 percent of live births with shortened gestation contributed 80 percent of the infant deaths. Another implication of these data is that only 55 percent of births in the United States occurred during the optimal 39 to 41 weeks’ gestation. Put yet another way, only 55 percent of births were “normal” based on infant outcomes. Does this mean that almost half of pregnancies resulting in live births are “abnormal”? Alternatively, perhaps the adjectives “normal” and “abnormal” should be abandoned and replaced with the realization that fetal maturation in humans is a continuum that is completed later in human pregnancy than previously appreciated.

TABLE 42-1. Infant Mortality Rates in the United States in 2009

image

Steer (2005) observed that signs of immaturity at birth and shorter than average gestational length have an unusually high incidence in Homo sapiens compared with other mammals. This has been attributed to the development of a narrow pelvis for bipedal gait, coupled with evolution toward a large brain and head that is associated with language and social skill acquisition. It is hypothesized that this combination results in a relatively high incidence of obstructed labor, which favors an evolutionary trend toward shorter gestation and thus an earlier birth.

As previously noted, if infant mortality rates are used as the outcome of interest, the data in Table 42-1 suggest that optimal pregnancy outcomes vis-à-vis prematurity are achieved at 39 weeks’ gestation. Is the 39-week threshold correct for defining pathologically shortened human gestation? For example, if neonatal death is used as the outcome of interest, delivery at 380/7 through 386/7 weeks is equivalent to delivery at 39 weeks (McIntire, 2008). Similarly, if respiratory morbidity is used as the outcome of interest, 380/7 through 386/7 weeks is equivalent to 39 weeks (Consortium on Safe Labor, 2010). These examples suggest that shortened human gestation with regard to prematurity is birth before 380/7 weeks rather than before 390/7 weeks.

A consequence of defining optimal pregnancy outcomes to occur at 39 weeks has been the concern that some births before 39 weeks may be unnecessary, that is, intentional deliveries not based on medical indications. Indeed, Bailit (2012) observed, “The dangers of delivering a newborn before 39 weeks for nonmedical reasons have become increasingly clear.” The evidence that unnecessary deliveries are occurring before 39 weeks in the United States is not robust. Martin (2009b) used birth certificate data to analyze late preterm births between 1990 and 2006. The rate of infants born late preterm increased 20 percent during this time period. Moreover, the percentage of late preterm births for which labor was induced more than doubled between 1990 and 2006, climbing from 7.5 to 17.3 percent. The percentage of late preterm births delivered by cesarean also rose substantially, from 23.5 to 34.3 percent. Such increases in obstetrical interventions inevitably raise the specter of medically unnecessary interventions.

Reddy (2009) used 2001 United States birth certificate data to examine delivery indications for late preterm birth. A total of 23 percent of late preterm births had no recorded indication for delivery. Some of the factors significantly increasing the chance of no recorded indication were older maternal age, non-Hispanic white mother, and ≥ 13 years of education. Factors such as these raised the possibility that patient factors—as opposed to medical factors—were playing a role in late preterm births without a specified medical indication in the birth certificate. But Bailit (2012) has described the complexities of ascertaining the indications for delivery.

In contrast, an analysis of the indications for delivery of 21,771 late preterm births at Parkland Hospital using a research data set showed that 99.8 percent of such births were indicated and that 80 percent were due to idiopathic preterm labor or preterm spontaneously ruptured membranes. Indeed, and as shown in Figure 42-1, medically indicated preterm births are largely responsible for the increase in preterm births in the United States.

image

FIGURE 42-1 Rates of births < 37 weeks in the United States from 1989 to 2001. (Redrawn from Ananth, 2005, with permission.)

Undoubtedly, unnecessary obstetrical interventions are occurring before 38 or 39 weeks’ gestation, but the magnitude of this problem is unclear at this time. Caution is urged before assuming that obstetrical interventions before 38 or 39 weeks are unnecessary. For example, Koopmans and colleagues (2009) randomized women with mild preeclampsia or gestational hypertension at 36 weeks’ gestation to induction of labor versus expectant management. This trial showed that delivery at 37 weeks was better for women and their newborns compared with later delivery. The American College of Obstetricians and Gynecologists (2013b) also recommends caution before withholding indicated intervention.

TRENDS IN PRETERM BIRTH RATES

The percentage of preterm births increased 36 percent from 9.4 percent in 1984 to a high of 12.8 percent in 2006 (Mathews, 2013). Since 2006, however, the trend has reversed, and the percentage of preterm births declined to 11.7 percent in 2011 (Figure 42-2). This decline in the percentage of preterm births occurred for both the early—less than 34 weeks—and later preterm periods (Hamilton, 2012). Although the lowest level in more than a decade, the 2011 preterm birth rate is still higher than rates reported during the 1980s and most of the 1990s.

image

FIGURE 42-2 Preterm and low-birthweight rate: United States, final 1990 to 2010 and preliminary 2011. (Redrawn from Hamilton, 2012.)

Is the decrease in preterm births shown in Figure 42-2 real? It could be argued that the decrease since 2006 is a result of changes in the birth certificate that is used to compute United States preterm birth rates. In 2003, a revised birth certificate intended to expand the collection of clinical information was introduced in the United States. Implementation depends on the rapidity with which the various states transitioned to the new version. For example, by 2008, the revised birth certificate had been implemented in 27 states representing 65 percent of all 2008 births (Osterman, 2011). This “trickle in” implementation coincides with the decline in preterm births shown in Figure 42-2.

Importantly, the 2003 version of the birth certificate introduced use of a clinical estimate of gestational age rather than primarily the last menstrual period, which was used in the previous 1989 version of the birth certificate. Joseph and associates (2007) noticed that preterm birth rates were much higher in the United States compared with Canada. This difference, however, was reduced when the United States rate was based on the clinical estimate of gestational age rather than menstrual dating. For example, the preterm birth rate in the United States in 2002 was 12.3 percent if computed using menstrual dating compared with 10.1 percent when a clinical estimate was used. The decrease in preterm births shown in Figure 42-2 from 12.8 percent in 2006 to 11.7 percent in 2011 is well within the range of change to be expected if the change was attributable to the method used for determining gestational age for the 2003 birth certificate.

A disturbing aspect of the trend in preterm birth rates in the United States is the persistence of racial and ethnic disparity (Fig. 42-3). Indeed, 77 percent of the race/ethnicity-related disparity in infant mortality rates in the United States in 2009 was associated with preterm birth (Mathews, 2013). Some investigators attribute this disparity to socioeconomic circumstances (Collins, 2007). Rates of preterm birth in the United States are also higher compared with those in other industrialized countries (Ananth, 2009; Joseph, 2007). For example, the preterm birth rate was 12.3 percent in the United States in 2003 compared with 7.7 percent in Canada. Indeed, similar differences have been noted in the preterm delivery rates between the United States and virtually all the other industrialized countries.

image

FIGURE 42-3 Preterm births in the United States in 2011 according to maternal race and ethnicity. (Redrawn from Hamilton, 2012.)

MORBIDITY IN PRETERM INFANTS

Various morbidities, largely due to organ system immaturity, are significantly increased in infants born before 37 weeks’ gestation compared with those delivered at term (Table 42-2). For approximately 40 years, complications in infants born before 34 weeks have been the primary focus. Only recently (2005) have late preterm infants—34 to 36 weeks—gained attention because of their increased morbidity. Attention has also been given to increasingly small preterm infants—very low birthweight and extremely low birthweight. These very small infants suffer disproportionately not only the immediate complications of prematurity but also long-term sequelae such as neurodevelopmental disability. Indeed, live births once considered “abortuses” because they weighed < 500 g are now classified as live births. Indeed, there were 6331 live births between 400 and 500 g recorded in the United States in 2009 (Martin, 2011). Remarkable strides have been made in neonatal survival for infants born preterm. This is especially true for those born after 28 weeks. Shown in Figure 42-4 are survival rates for more than 18,000 infants born between 400 and 1500 g or between 22 and 32 weeks’ gestation. Importantly, the results are shown as a function of both birthweight and gestational age. After achieving a birthweight of ≥ 1000 g or a gestational age of 28 weeks for females or 30 weeks for males, survival rates reach 95 percent.

TABLE 42-2. Major Short- and Long-Term Problems in Very-Low-Birthweight Infants

image

image

FIGURE 42-4 Mortality rates by birthweight, gestational age, and gender. The limits of the colored area indicate the upper 95th and lower 5th percentiles of birthweight for each gestational age. The curved lines indicate combinations of birthweight and gestational age with the same estimated probability of mortality from 10 to 90 percent. The gradation of color denotes the change in estimated probability of death. Green indicates infants of lower gestational age and birthweight who are more likely to die, whereas yellow indicates infants of higher gestational age and birthweight who are less likely to die. The methods used underestimate mortality rates in those at 22 and 23 weeks with a birthweight up to 600 g. (Redrawn from Fanaroff, 2007, with permission.)

Resources used to care for low-birthweight infants are a measure of the societal burden of preterm birth. The annual cost of preterm birth in the United States in 2006 was estimated to be $26.2 billion, or $51,000 per premature infant (Institute of Medicine, 2007). The economic consequences of preterm birth that reach beyond the newborn period into infancy, adolescence, and adulthood are difficult to estimate. However, they must be enormous when the effects of adult diseases associated with prematurity, such as hypertension and diabetes, are considered.

image Mortality and Morbidity at the Extremes of Prematurity

The tremendous advances in the perinatal and neonatal care of the preterm infant have been found predominantly in those infants delivered at ≤ 33 weeks. With survival of increasingly very immature infants in the 1990s, there has been uncertainty and controversy as to the lower limit of fetal maturation compatible with extrauterine survival. This has resulted in continual reassessment of the threshold of viability.

Threshold of Viability

Births before 26 weeks are generally considered at the current threshold of viability, and these preterm infants pose various complex medical, social, and ethical considerations. For example, Sidney Miller is a child who was born at 23 weeks, weighed 615 g, and survived but developed severe physical and mental impairment (Annas, 2004). At age 7 years, she was described as a child who “could not walk, talk, feed herself, or sit up on her own … was legally blind, suffered from severe mental retardation, cerebral palsy, seizures, and spastic quadriparesis in her limbs.” An important issue for her family was the need for a lifetime of medical care estimated to cost tens of millions of dollars.

Infants now considered to be at the threshold of viability are those born at 22, 23, 24, or 25 weeks (American College of Obstetricians and Gynecologists, 2012a,b). These infants have been described as fragile and vulnerable because of their immature organ systems. Moreover, they are at high risk for brain injury from hypoxic-ischemic injury and sepsis. In this setting, hypoxia and sepsis start a cascade of events that lead to brain hemorrhage, white-matter injury that causes periventricular leukomalacia, and poor subsequent brain growth eventuating in neurodevelopmental impairment (Chap. 34p. 656). Because active brain development normally occurs throughout the second and third trimesters, those infants born at 22 to 25 weeks are believed especially vulnerable to brain injury.

Until recently, discussion of clinical management and ethical and economic considerations of extremely premature infants were hampered by data compromised by ascertainment bias (American College of Obstetricians and Gynecologists, 2012a,b). For example, the mean survival rate was 45 percent if the denominator was all live births compared with 72 percent if the denominator used was only infants admitted to neonatal intensive care (Guillen, 2011). Another source of ascertainment bias was use of multicenter datasets. There were considerable center differences in obstetrical and early neonatal interventions, particularly at 22 and 23 weeks (Stoll, 2010).

A remarkable report on infants born before 27 weeks was recently published (Serenius, 2013). This report is unique in that it details a national population-based prospective study of all infants born alive or stillborn before 27 weeks in Sweden. This country is a uniform society without extreme poverty, and antenatal care is easily accessible and used by almost 100 percent of mothers. All citizens are covered by health insurance including 480 days of parental leave after childbirth and additional benefits for severely sick children. Active perinatal care in Sweden includes early and free access to specialist perinatal care, centralization of extremely preterm births to level III hospitals, a low threshold to provide life support at birth, and near universal admission of infants born at 23 to 26 weeks for neonatal intensive care. Thus, this report likely describes infant outcomes at the threshold of viability under optimal circumstances.

Shown in Table 42-3 are the survival and disability rates for 707 infants born alive from 22 to 26 weeks between 2004 and 2007 in Sweden. The proportion of children with mild or no disabilities increased from 40 percent at 22 weeks to 83 percent at 26 weeks. Conversely, the number of infants with moderate or severe disabilities decreased with advancing gestational age at birth. Moderate or severe disabilities were found in 31 percent of preterm boys compared with 23 percent of preterm girls. No differences in overall outcomes were noted if singletons and multiple births were compared.

TABLE 42-3. Outcomes at 2½ Years Corrected Age by Gestational Age at Birth in Sweden, 2004–2007

image

The most recent report from the United States concerning survival and morbidity rates for births at 22 to 26 weeks is from the National Institute of Child Health and Human Development (NICHD) Neonatal Network. This dataset includes 5736 live births delivered between 2003 and 2007 at 20 medical centers across the United States. Rates of survival and survival without morbidity in the neonatal period are shown in Table 42-4.

TABLE 42-4. Survival and Disability Rates for 5736 Live Births Born between 22 and 26 Weeks’ Gestation at 20 Medical Centers in the United States During 2003–2007

image

Cesarean delivery at the threshold of viability is controversial. For example, if the fetus-infant is perceived to be too immature for aggressive support, then cesarean delivery for common indications such as breech presentation or nonreassuring fetal heart rate patterns might be preempted. This aside, national data clearly show a high frequency of cesarean delivery for these small infants (Fig. 42-5). Determining the optimal delivery mode for newborns at the threshold of viability is virtually impossible given that randomizing the delivery route has extreme ethical considerations. That said, retrospective, nonrandomized studies have consistently failed to document a benefit of cesarean delivery for the extremely preterm fetus (American College of Obstetricians and Gynecologists, 2012a). Reddy (2012) analyzed 2906 singleton live births between 240/7 and 316/7 weeks selected because they were eligible for attempted vaginal birth after excluding those cases with fetal distress, placenta previa, placental abruption, and anomalies. Attempted vaginal delivery for cephalic presenting fetuses had a high success rate (84 percent), and there was no difference in the neonatal mortality rate compared with that with planned cesarean delivery. For breech presentations, however, there was a threefold increased relative risk in mortality when vaginal delivery was attempted. Werner (2013) analyzed 20,231 preterm infants at 24 to 34 weeks born in New York City between 1995 and 2003. Cesarean delivery was not protective against poor outcomes such as neonatal death, intraventricular hemorrhage, seizures, respiratory distress, and subdural hemorrhage.

image

FIGURE 42-5 United States cesarean delivery rates by birthweight from 1999 to 2000. (Redrawn from Lee, 2006, with permission.)

Threshold of Viability at Parkland Hospital

Policies were developed in conjunction with the Neonatology Service. We must emphasize that the decision not to perform cesarean delivery does not necessarily imply that the fetus is “nonviable” or “written off.” Neonatologists are consulted before delivery, and there is discussion of survival and morbidity with the woman and her family. A neonatologist attends each delivery and determines subsequent management.

From an obstetrical standpoint, all fetal indications for cesarean delivery in more advanced pregnancies are practiced in women at 25 weeks. Cesarean delivery is not offered for fetal indications at 23 weeks. At 24 weeks, cesarean delivery is not offered unless fetal weight is estimated at 750 g or greater. Aggressive obstetrical management is practiced in cases of growth restriction.

image Late Preterm Birth

As shown in Figure 42-6, infants between 34 and 36 weeks account for more than 70 percent of all preterm births. These are the fastest increasing and largest proportion of singleton preterm births in the United States (Raju, 2006). Thus, increased attention is being given to determining optimal obstetrical and neonatal management of late preterm birth.

image

FIGURE 42-6 Distribution in percent of preterm births in the United States for 2004. (Redrawn from Martin, 2006.)

To estimate the risks associated with late preterm births, we analyzed neonatal mortality and morbidity rates at 34, 35, and 36 weeks compared with those of births at term between 1988 and 2005 at Parkland Hospital (McIntire, 2008). We were particularly interested in obstetrical complications during this time, because if modified, rates of late preterm birth can possibly be decreased. Approximately 3 percent of all births during the study period occurred between 24 and 32 weeks, and 9 percent were during the late preterm weeks. Thus, late preterm births accounted for three fourths of all preterm births. Approximately 80 percent of these were due to idiopathic spontaneous preterm labor or prematurely ruptured membranes (Fig. 42-7). Complications such as hypertension or placental accidents were implicated in the other 20 percent of cases.

image

FIGURE 42-7 Obstetrical complications associated with 21,771 late preterm births at Parkland Hospital. (Adapted from McIntire, 2008.)

Neonatal mortality rates were significantly increased in each late preterm week compared with those at 39 weeks as the referent and as shown in Figure 42-8. Similarly, Tomashek (2007) analyzed all United States births between 1995 and 2002 and also found higher neonatal mortality rates for late preterm infants. Importantly, indices of neonatal morbidity shown in Table 42-5 are increased in these late preterm infants born at Parkland. Fuchs (2008) reported similar results regarding respiratory morbidity in 722 infants. Specifically, the frequency of respiratory morbidity decreased by approximately 50 percent per week from 34 to 37 completed weeks. Increased rates of adverse neurodevelopment have also been found in late preterm infants compared with term newborns (Petrini, 2009).

image

FIGURE 42-8 Neonatal death rates at Parkland Hospital from 34 to 40 weeks’ gestation in singleton infants without malformations. ap < .001 compared with 39 weeks as the referent. bp = .02 compared with 39 weeks as the referent. (Redrawn from McIntire, 2008, with permission.)

TABLE 42-5. Neonatal Morbidity Rates at Parkland Hospital in Live Births Delivered Late Preterm Compared with 39 Weeks

image

These findings suggest that the health-care focus on prematurity should be expanded to include late preterm births. Even so, because approximately 80 percent of these women begin labor spontaneously—similar to births before 34 weeks—attempts to interrupt preterm labor have not been satisfactory. Specifically, the Institute of Medicine (2007) report, Preterm Birth: Causes, Consequences, and Prevention, acknowledges that treatment of preterm labor has not prevented preterm birth. Thus, we are of the view that a national strategy aimed at prevention of late preterm births is unlikely to provide discernible benefit without new developments in the prevention and management of preterm labor. In the meantime, the Maternal-Fetal Medicine Units (MFMU) Network is studying the efficacy of corticosteroids in late preterm births. The American College of Obstetricians and Gynecologists (2013b) has emphasized that intentional late preterm deliveries should occur only when an accepted maternal or fetal indication for delivery exists.

CAUSES OF PRETERM DELIVERY

There are four main direct reasons for preterm births in the United States. These include: (1) spontaneous unexplained preterm labor with intact membranes, (2) idiopathic preterm premature rupture of membranes (PPROM), (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). Indeed, much of the increase in the singleton preterm birth rate in the United States is explained by rising numbers of indicated preterm births (Ananth, 2005).

Reasons for preterm birth have multiple, often interacting, antecedents and contributing factors. This complexity has greatly confounded efforts to prevent and manage this complication. This is particularly true for preterm ruptured membranes and spontaneous preterm labor, which together lead to 70 to 80 percent of preterm births. Last, according to data from Martin (2006), approximately one in six preterm births in the United States is from twins or higher-order multifetal pregnancies (Chap. 45p. 891). For example, in 2004, there were 508,356 preterm births, and of these, 86,116 or 17 percent were from multifetal pregnancies. Many of these pregnancies were achieved using ovulation-inducing drugs and assisted reproductive technologies (ART).

Analogous to other complex disease processes, multiple coexistent genetic alterations and environment may lead to preterm birth (Esplin, 2005; Ward, 2008). There are polymorphisms in genes associated with inflammation and infection and in those associated with collagen turnover (Velez, 2008). Inherited mutations in genes regulating collagen assembly may predispose individuals to cervical insufficiency or prematurely ruptured membranes (Anum, 2009; Wang, 2006; Warren, 2007).

image Basic Science of Spontaneous Preterm Labor

For both clinical and research purposes, pregnancies with intact fetal membranes and spontaneous preterm labor must be distinguished from those complicated by preterm prematurely ruptured membranes. Even so, those with spontaneous preterm labor do not constitute a homogeneous group characterized singularly by early initiation of parturition (American College of Obstetricians and Gynecologists, 2012b). This certainly is one reason why preventative therapies and clinical tools to assess the risks for preterm birth have been difficult to identify. Among the more common associated findings are multifetal pregnancy, intrauterine infection, bleeding, placental infarction, premature cervical dilatation, cervical insufficiency, hydramnios, uterine fundal abnormalities, and fetal anomalies. Severe maternal illness as a result of infections, autoimmune diseases, and gestational hypertension also increases preterm labor risks.

Although there are unique aspects to each cause of preterm labor, these diverse processes culminate in a common end point, which is premature cervical dilatation and effacement and premature activation of uterine contractions. It seems important to emphasize that the actual process of preterm labor should be considered a final step—one that results from progressive or acute changes that could be initiated days or even weeks before labor onset. Indeed, many forms of spontaneous preterm labor that result from premature initiation of phase 2 of parturition may be viewed in this light (Chap. 21p. 410). Although the end result in preterm birth is the same as at term, namely cervical ripening and myometrial activation, recent studies in animal models support the idea that preterm birth is not always an acceleration of the normal process. Diverse pathways to instigate parturition exist and are dependent on the etiology of preterm birth. Identification of both common and uncommon factors has begun to explain the physiological processes of human parturition at term and preterm. Four major causes of spontaneous preterm labor include uterine distention, maternal–fetal stress, premature cervical changes, and infection.

Uterine Distention

There is no doubt that multifetal pregnancy and hydramnios lead to an increased risk of preterm birth (Chap. 45p. 913). It is likely that early uterine distention acts to initiate expression of contraction-associated proteins (CAPs) in the myometrium. The CAP genes that are influenced by stretch include those coding for gap-junction proteins such as connexin 43, for oxytocin receptors, and for prostaglandin synthase (Korita, 2002; Lyall, 2002; Sooranna, 2004). Recent reports suggest that gastrin-releasing peptides (GRPs) are increased with stretch to promote myometrial contractility and that GRP antagonists can inhibit uterine contractility (Tattershell, 2012). There is also a stretch-induced potassium channel—TREK-1—that is upregulated during gestation and downregulated in labor. This pattern of expression is consistent with a potential role in uterine relaxation during pregnancy (Buxton, 2010). Expression of TREK-1 splice variants that block function of the full-length TREK-1 have been recently identified in myometrium from women with preterm labor. This further implicates a role for TREK-1 in uterine quiescence (Wu, 2012). Although these and other regulatory factors remain to be validated, it is clear that excessive uterine stretch causes premature loss of myometrial quiescence.

Excessive uterine stretch also leads to early activation of the placental–fetal endocrine cascade shown in Figure 21-17 (p. 425). The resulting early rise in maternal corticotropin-releasing hormone and estrogen levels can further enhance the expression of myometrial CAP genes (Warren, 1990; Wolfe, 1988). Finally, the influence of uterine stretch should be considered with regard to the cervix. For example, cervical length is an important risk factor for preterm birth in multifetal pregnancies (Goldenberg, 1996). Prematurely increased stretch and endocrine activity may initiate events that shift the timing of uterine activation, including premature cervical ripening.

Maternal–Fetal Stress

Stress is defined as a condition or adverse circumstance that disturbs the normal physiological or psychological functioning of an individual. But the complexities of measuring “stress” are what cause difficulty in defining its exact role (Lobel, 1994). That said, considerable evidence shows a correlation between some sort of maternal stress and preterm birth (Hedegaard, 1993; Hobel, 2003; Ruiz, 2003). Moreover, there is a correlation between maternal psychological stress and the placental–adrenal endocrine axis that provides a potential mechanism for stress-induced preterm birth (Lockwood, 1999; Petraglia, 2010; Wadhwa, 2001).

As discussed earlier, the last trimester is marked by rising maternal serum levels of placental-derived corticotropin-releasing hormone (CRH). This hormone works with adrenocorticotropic hormone (ACTH) to increase adult and fetal adrenal steroid hormone production, including the initiation of fetal cortisol biosynthesis. Rising levels of maternal and fetal cortisol further increase placental CRH secretion, which develops a feed-forward endocrine cascade that does not end until delivery (Fig. 21-17p. 425). Rising levels of CRH further stimulate fetal adrenal dehydroepiandrosterone sulfate (DHEA-S) biosynthesis, which acts as substrate to increase maternal plasma estrogens, particularly estriol.

It has been hypothesized that a premature rise in cortisol and estrogens results in an early loss of uterine quiescence. A number of studies have reported that spontaneous preterm labor is associated with an early rise in maternal CRH levels and that CRH determination may be a useful biomarker for preterm birth risk assessment (Holzman, 2001; McGrath, 2002; McLean, 1995; Moawad, 2002). Because of large variations in CRH levels among pregnant women, however, a single CRH measurement has low sensitivity (Leung, 2001; McGrath, 2002). It may be that the rate of increase in maternal CRH levels is possibly a more accurate predictor of preterm birth. Confounding factors include CRH variability among ethnic groups. Another is that placental CRH enters the fetal circulation—albeit at lower levels than in the maternal circulation. In vitro studies have shown that CRH can directly stimulate fetal adrenal production of DHEA-S and cortisol (Parker, 1999; Smith, 1998). Thus, current studies do not support the idea that CRH levels alone have a positive-predictive value for preterm birth risk.

If preterm delivery is associated with early activation of the fetal adrenal–placental endocrine cascade, maternal estrogen levels would likely be prematurely elevated. This is indeed the case. An early rise in serum estriol concentrations is noted in women with subsequent preterm labor (Heine, 2000; McGregor, 1995). Physiologically, this premature rise in estrogen levels may alter myometrial quiescence and accelerate cervical ripening.

Taken together, these observations suggest that preterm birth is associated, in many cases, with a maternal–fetal biological stress response. The stressors that activate this cascade likely are broad, and the stress response is dependent on the stressor. For example, CRH or estriol levels are prematurely elevated in preterm birth due to infection and multifetal pregnancies but not in pregnant women with perceived stress (Gravett, 2000; Himes, 2011; Warren, 1990). Chronic, psychological stress—resulting for example from racial discrimination—appears to promote impaired cellular immune competence (Christian, 2012b). A growing body of work in the area of psychoneuroimmunology will perhaps enhance the understanding of pathways that link stress with adverse birth outcomes (Christian, 2012a).

Infection

There is great interest in the role of infection as a primary cause of preterm labor in pregnancies with intact membranes (Goncalves, 2002; Iams, 1987). In some cases, there is histological evidence of inflammation in the fetal membranes, decidua, or umbilical cord, whereas other cases are deemed “subclinical.” More recently, new technologies based on genomic analysis of a mixed population of microorganisms have shown that the nonpregnant vaginal tract hosts a complex microbial community that can differ widely between women who are all healthy (Gajer, 2012; White, 2011). The application of the field of metagenomics to understanding microbiome complexity in term and preterm birth and to identifying microbe populations that may mediate subclinical infection holds great promise. Aagaard and coworkers (2012) used metagenomics to determine how the vaginal microbiome changes during normal pregnancy. They reported that the diversity and richness of microbes is reduced through pregnancy. Compared with nonpregnant controls, there is an increased dominance of Lactobacillus species. These findings lay the foundation for future studies to identify microbial populations associated with “subclinical” infection-induced preterm birth.

Current data suggest that microbial invasion of the reproductive tract is sufficient to induce infection-mediated preterm birth—more specifically, there is ongoing “subclinical” infection. However, microorganisms certainly are not ubiquitous in the amnionic fluid of all women with preterm labor, and indeed, positive cultures are found in only 10 to 40 percent (Goncalves, 2002). This minority of women with amnionic fluid bacteria are more likely to develop clinical chorioamnionitis and preterm ruptured membranes compared with women with sterile cultures. Moreover, their neonates are also more likely to have complications (Hitti, 2001). Although infection is more severe when there is clinically obvious intraamnionic infection, inflammation in the absence of detectable microorganisms is also a risk factor for a fetal inflammatory response (Lee, 2007, 2008). The earlier the onset of preterm labor, the greater the likelihood of documented infection (Goldenberg, 2000; Watts, 1992). It is enigmatic that the incidence of culture-positive amnionic fluids collected by amniocentesis during spontaneous term labor is similar to that with preterm labor (Gomez, 1994; Romero, 1993). It has been suggested that at term, amnionic fluid is infiltrated by bacteria as a consequence of labor, whereas in preterm pregnancies, bacteria represent an important cause of labor. If true, this explanation questions the contribution of fetal infection as a major cause of preterm labor and delivery.

Despite these observations, there are considerable data that associate chorioamnionitis with preterm labor (Goldenberg, 2002; Üstün, 2001). In such infections, the microbes may invade maternal tissue only 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 which microbes were not detectable in the amnionic fluid.

Sources for Intrauterine Infection. The patency of the female reproductive tract, although essential for achievement of pregnancy and delivery, is theoretically problematic during phase 1 of parturition. It has been suggested that bacteria can gain access to intrauterine tissues through: (1) transplacental transfer of maternal systemic infection, (2) retrograde flow of infection into the peritoneal cavity via the fallopian tubes, or (3) ascending infection with bacteria from the vagina and cervix. The lower pole of the fetal membrane–decidual junction is contiguous with the cervical canal orifice, which is patent to the vagina. This anatomical arrangement provides a passageway for microorganisms, and ascending infection is considered to be the most common. A thoughtful description of the potential degrees of intrauterine infection has been provided by Goncalves and associates (2002). They categorize intrauterine infection into four stages of microbial invasion that include bacterial vaginosis—stage I, decidual infection—stage II, amnionic infection—stage III, and finally, fetal systemic infection—stage IV. As expected, progression of these stages is thought to increase rates of preterm birth and neonatal morbidity.

Based on these insights, it is straightforward to construct a theory for the pathogenesis of infection-induced preterm labor. Ascending microorganisms colonize the cervix, decidua, and possibly the membranes, where they then may enter the amnionic sac. Lipopolysaccharide (LPS) or other toxins elaborated by bacteria induce immune-cell recruitment into the reproductive tract and cytokine production by immune cells and by cells within the cervix, decidua, membranes, or fetus itself. Both LPS and cytokines then provoke prostaglandin release from the membranes, decidua, or cervix. These influence both cervical ripening and loss of myometrial quiescence (Challis, 2002; Keelan, 2003; Olson, 2003). Current evidence based on animal and human studies suggests that many aspects of infection-mediated preterm birth differ from pathways that regulate term parturition (Hamilton, 2012; Holt, 2011; Shynlova, 2013a,b).

Microbes Associated with Preterm Birth. Some micro-organisms—examples include Gardnerella vaginalis, Fusobacterium, Mycoplasma hominis, and Ureaplasma urealyticum—are detected more frequently than others in amnionic fluid of women with preterm labor (Gerber, 2003; Hillier, 1988; Yoon, 1998). This finding was interpreted by some as presumptive evidence that specific microorganisms are more commonly involved as pathogens in the induction of preterm labor. Another interpretation, however, is that given direct access to the membranes after cervical dilatation, selected microorganisms, such as fusobacteria, that are more capable of burrowing through these exposed tissues will do so. Fusobacteria are found in the vaginal fluid of only 9 percent of women but in 28 percent of positive amnionic fluid cultures from pregnancies with preterm labor and intact membranes (Chaim, 1992). Knowledge from metagenomic studies will better define these interactions in the future. In addition, host responses to pathogens with respect to mucosal immunity, barrier protection of cervical and vaginal epithelia, and expression of antimicrobial peptides is likely to provide insights. Specifically, the mechanisms that render some women more susceptible to infection-mediated preterm birth may be found.

Intrauterine Inflammatory Response. The initial inflammatory response elicited by bacterial toxins is mediated, in large measure, by specific receptors on mononuclear phagocytes, decidual cells, cervical epithelia, and trophoblasts. These Toll-like receptors represent a family that has evolved to recognize pathogen-associated molecules (Janssens, 2003). Toll-like receptors are present in the placenta on trophoblast cells, in the cervical epithelia, and on fixed and invading leukocytes (Chuang, 2000; Gonzalez, 2007; Holmlund, 2002). Loss of specific Toll-like receptors results in delayed parturition in mouse models (Montalbano, 2013).

Under the influence of ligands such as bacterial LPS, these receptors increase chemokine, cytokine, and prostaglandin release as part of an inflammatory response. One example is interleukin-1β (IL-1β), which is produced rapidly after LPS stimulation (Dinarello, 2002). This cytokine in turn acts to promote 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). Also, IL-1 promotes prostaglandin formation in many tissues, including myometrium, decidua, and amnion (Casey, 1990). 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; Gross, 2000). Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. And immunomodulators plus antibiotics delay preterm delivery after experimental intraamnionic infection in a nonhuman primate model. Thus, there appears to be a cascade of events once an inflammatory response is initiated that can result in preterm labor.

Origin of Cytokines. Cytokines within the normal term uterus are likely important for normal and preterm labor. The transfer of cytokines such as IL-1 from decidua across the membranes into amnionic fluid appears to be severely limited. It is reasonable that cytokines produced in maternal decidua and myometrium will have effects on that side, whereas cytokines produced in the membranes or in cells within the amnionic fluid will not be transferred to maternal tissues. The human myometrium expresses chemokine receptors that decline during labor (Hua, 2013). Macrophages are reported to infiltrate the human and rat decidua before labor onset and may be important for decidual activation (Hamilton, 2012). Still, the requirement of leukocytes for initiation of term labor in women remains inconclusive. In most cases of inflammation resulting from infection, resident and invading leukocytes produce the bulk of cytokines. Indeed, with infection, leukocytes—mainly neutrophils, macrophages, and T lymphocytes—infiltrate the cervix, lower uterine segment, fundus, and membranes at the time of labor. Thus, invading leukocytes may be the major source of cytokines in preterm labor. Along with proinflammatory cytokines, studies in women and animal models highlight the importance of the antiinflammatory limb of the immune response in parturition (Gotsch, 2008; Timmons, 2009).

Immunohistochemical studies in the term laboring uterus have shown that both invading leukocytes and certain parenchymal cells produce cytokines. These leukocytes appear to be the primary source of myometrial cytokines, including IL-1, IL-6, IL-8, and TNF-α (Young, 2002). By contrast, in the decidua, both stromal cells and leukocytes are likely to contribute because they have been shown to produce these same cytokines. In the cervix, glandular and surface epithelial cells appear to produce IL-6, IL-8, and TNF-α. Of these, IL-8 is considered a critical cytokine in cervical dilation, and it is produced in both cervical epithelial and stromal cells.

The presence of cytokines in amnionic fluid and their association with preterm labor has been well documented. But their exact cellular origin—with or without recoverable microorganisms—has not been well defined. Although the rate of IL-1 secretion from forebag decidual tissue is great, Kent (1994) found that there is negligible in vivo transfer of radiolabeled IL-1 across the membranes. Amnionic fluid IL-1 probably does not arise from amnion, fetal urine, or fetal lung secretions. It most likely is secreted by mononuclear phagocytes or neutrophils activated and recruited into the amnionic fluid. Therefore, IL-1 in amnionic fluid likely is generated in situ from newly recruited cells (Young, 2002). Thus, the amount of amnionic fluid IL-1 would be determined by the number of leukocytes recruited, their activational status, or the effect of amnionic fluid constituents on their IL-1 secretion rate.

Leukocyte infiltration may be regulated by fetal membrane synthesis of specific chemokines. In term labor, there are increased amnionic fluid concentrations of the potent chemoattractant and monocyte-macrophage activator monocyte chemotactic protein-1 (MCP-1), which is also called chemokine (C-C motif) ligand 2 (CCL2). As is true for prostaglandins and other cytokines, the levels of MCP-1 are much higher in the forebag compared with the upper compartment (Esplin, 2003). Levels in preterm labor were significantly higher than those found in normal term amnionic fluid (Jacobsson, 2003). MCP-1 may initiate fetal leukocyte infiltration of the placenta and membranes, and its production may act as a marker for intraamnionic infection and inflammation.

image Preterm Premature Rupture of Membranes

This term defines spontaneous rupture of the fetal membranes before 37 completed weeks and before labor onset (American College of Obstetricians and Gynecologists, 2013d). Such rupture likely has various causes, but intrauterine infection is believed by many to be a major predisposing event (Gomez, 1997; Mercer, 2003). There are associated risk factors that include low socioeconomic status, body mass index ≤ 19.8, nutritional deficiencies, and cigarette smoking. Women with prior preterm premature rupture of membranes (PPROM) are at increased risk for recurrence during a subsequent pregnancy (Bloom, 2001). Despite these known risk factors, none is identified in most cases of preterm rupture.

Molecular Changes

Preterm membrane rupture pathogenesis may be related to increased apoptosis of membrane cellular components and to increased levels of specific proteases in membranes and amnionic fluid. Most tensile strength of the membranes is provided by the amnionic extracellular matrix and interstitial amnionic collagens—primarily type I and III—which are produced in mesenchymal cells (Casey, 1996). For that reason, collagen degradation has been a focus of research. The matrix metalloproteinase (MMP) family is involved with normal tissue remodeling and particularly with collagen degradation. The MMP-1, MMP-2, MMP-3, and MMP-9 members of this family are found in higher concentrations in amnionic fluid from pregnancies with preterm prematurely ruptured membranes (Maymon, 2000; Park, 2003; Romero, 2002). MMP activity is in part regulated by tissue inhibitors of matrix metalloproteinases—TIMPs. Several of these inhibitors are found in lower concentrations in amnionic fluid from women with ruptured membranes. Elevated MMP levels found at a time when protease inhibitor expression decreases supports further that their expression alters amnionic tensile strength. Studies of amniochorion explants have demonstrated that the expression of MMPs can be increased by treatment with IL-1, TNF-α, and IL-6 (Fortunato, 1999a,b, 2002). Recent studies by Mogami (2013) provide a mechanism by which bacterial endotoxin or TNF-α elicits release of fetal fibronectin (fFN) by amnion epithelial cells. The fFN then binds Toll-like receptor 4 in the amnion mesenchymal cells to activate signaling cascades. These result in increased prostaglandin E (PGE2) synthesis and elevated activity of MMP-1, MP-2, and MMP-9. Increased prostaglandin levels promote cervical ripening and uterine contractions. Increased MMPs allow collagen breakdown in the fetal membranes resulting in premature rupture.

In pregnancies with PPROM, the amnion exhibits a higher degree of cell death and more apoptosis markers than that in term amnion (Arechavaleta-Velasco, 2002; Fortunato, 2003). In vitro studies indicate that apoptosis is likely regulated by bacterial endotoxin, IL-1, and TNF-α. Last, there are proteins involved in the synthesis of mature cross-linked collagen or matrix proteins that bind collagen and thereby promote tensile strength. These proteins are altered in membranes with premature rupture (Wang, 2006). Taken together, these observations suggest that many PPROM cases result from collagen degradation, altered collagen assembly, and cell death, which all lead to a weakened amnion.

Infection

Several studies have been done to ascertain the incidence of infection-induced premature membrane rupture. Bacterial cultures of amnionic fluid support a role for infection in a significant proportion. A review of 18 studies comprising almost 1500 women with PPROM found that in a third, bacteria were isolated from amnionic fluid (Goncalves, 2002). Accordingly, some have given prophylactic antimicrobial treatment to prevent premature rupture (Miyazaki, 2012; Phupong, 2012).

Overall, there is compelling evidence that infection causes a significant proportion of PPROM cases. The inflammatory response that leads to membrane weakening is currently being defined. Research is focused on mediators of this process with a goal to identify early risk markers for PPROM.

image Multifetal Gestation

Twins and higher-order multifetal births account for approximately 3 percent of infants born in the United States (Martin, 2009a). The majority—95 percent—of these births are twins. Compared with 1980, the rates of multiple births increased steadily and peaked in 1998. Current rates have declined since then, but remain higher than the 1980s. The increased rate of multifetal births is due to the increased number of women having babies after the age of 30, at which time the risk to conceive multiples rises. In addition, the use of fertility treatments has contributed to the elevated rates of multifetal pregnancies. Preterm delivery continues to be the major cause of the excessive perinatal morbidity and mortality with multifetal pregnancies. The effects of uterine stretch discussed on page 837 are obvious in these pregnancies, and this likely is related to the increased incidence of preterm cervical dilatation. Many of these interrelationships are discussed in Chapter 45.

image Summary of Preterm Labor Pathophysiology

Preterm labor is a pathological condition with multiple etiologies. Romero (2006) termed it the preterm parturition syndrome. Most research in this field has been focused on the role of infection in mediating preterm birth. It is possible that intrauterine infection causes some cases currently categorized as idiopathic spontaneous preterm labor. There are various sites for intrauterine infection—maternal, fetal, or both—and increasing evidence that the inflammatory response may have distinct and compartment-specific functions that differ between uterus, fetal membranes, and cervix in normal birth. Thus, determining the proportion of pregnancies that end prematurely because of infection is difficult.

Infection does not explain all causes of preterm birth. In recent years, our understanding of other influences on the parturition process, such as maternal nutrition before or during pregnancy, genetics, the vaginal microbiome, and dynamic regulation of the extracellular matrix, has led to new avenues of research and a broader understanding of this complicated and multifactorial process. The current and future application of genomic and bioinformatics as well as molecular and biochemical studies will shed light on pathways involved in term and preterm labor and identify processes critical to all phases of cervical remodeling and uterine function.

ANTECEDENTS AND CONTRIBUTING FACTORS

Myriad genetic and environmental factors affect the frequency of preterm labor.

image Threatened Abortion

Vaginal bleeding in early pregnancy is associated with increased adverse outcomes later. Weiss (2004) reported outcomes with vaginal bleeding at 6 to 13 weeks in nearly 14,000 women. Both light and heavy bleeding were associated with subsequent preterm labor, placental abruption, and subsequent pregnancy loss before 24 weeks.

image Lifestyle Factors

Cigarette smoking, inadequate maternal weight gain, and illicit drug use have important roles in both the incidence and outcome of low-birthweight neonates (Chap. 12p. 253). Overweight and obese mothers have an elevated risk of preterm birth (Cnattingius, 2013). Other maternal factors implicated include young or advanced maternal age, poverty, short stature, and vitamin C deficiency (Casanueva, 2005; Gielchinsky, 2002; Kramer, 1995; Meis, 1995; Satin, 1994).

As discussed on page 837, psychological factors such as depression, anxiety, and chronic stress have been reported in association with preterm birth (Copper, 1996; Li, 2008; Littleton, 2007). Neggers and coworkers (2004) found a significant link between low birthweight and preterm birth in women injured by physical abuse (Chap. 47p. 951).

Studies of work and physical activity related to preterm birth have produced conflicting results (Goldenberg, 2008). There is some evidence, however, that working long hours and hard physical labor are probably associated with increased risk of preterm birth (Luke, 1995).

image Genetic Factors

The recurrent, familial, and racial nature of preterm birth has led to the suggestion that genetics may play a causal role. An accumulating literature on genetic variants buttresses this concept (Gibson, 2007; Hampton, 2006; Li, 2004; Macones, 2004). As discussed on page 839, several such studies have also implicated immunoregulatory genes in potentiating chorioamnionitis in cases of preterm delivery due to infection (Varner, 2005).

Birth Defects

In a secondary analysis of data from the First- and Second-Trimester Evaluation of Risk (FASTER) Trial, it was found that birth defects were associated with preterm birth and low birthweight (Dolan, 2007).

image Periodontal Disease

Gum inflammation is a chronic anaerobic inflammation that affects as many as 50 percent of pregnant women in the United States (Goepfert, 2004). Vergnes and Sixou (2007) performed a metaanalysis of 17 studies and concluded that periodontal disease was significantly associated with preterm birth—odds ratio 2.83. The researchers concluded, however, that the data were not robust enough to recommend screening and treatment of pregnant women (Stamilio, 2007).

To better study the relationship with periodontitis, Michalowicz (2006) randomly assigned 813 pregnant women between 13 and 17 weeks’ gestation who had periodontal disease to treatment during pregnancy or postpartum. They found that treatment during pregnancy improved periodontal disease and that it is safe. However, treatment failed to significantly alter preterm birth rates.

image Interval between Pregnancies

Short intervals between pregnancies have been known for some time to be associated with adverse perinatal outcomes. In a metaanalysis, Conde-Agudelo and colleagues (2006) reported that intervals < 18 months and > 59 months were associated with increased risks for both preterm birth and small-for-gestational age newborns.

image Prior Preterm Birth

A major risk factor for preterm labor is prior preterm delivery (Spong, 2007). Shown in Table 42-6 is the incidence of recurrent preterm birth in nearly 16,000 women delivered at Parkland Hospital. The recurrent preterm delivery risk for women whose first delivery was preterm was increased threefold compared with 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 in this study occurred within 2 weeks of the gestational age of the prior preterm delivery. Importantly, the causes of prior preterm delivery also recurred.

TABLE 42-6. Recurrent Spontaneous Preterm Births According to Prior Outcome

image

Although women with prior preterm births are clearly at risk for recurrence, they contributed only 10 percent of the total preterm births in this study. Expressed another way, 90 percent of the preterm births at Parkland Hospital cannot be predicted based on a history of preterm birth. Extrapolating data from the 2003 revised birth certificates, it is estimated that approximately 2.5 percent of women delivered in 2004 had a history of prior preterm birth (Martin, 2007).

image Infection

As discussed, a link between preterm birth and infection seems irrefutable. Goldenberg and coworkers (2008) have reviewed this association. Intrauterine infections are believed to trigger preterm labor by activation of the innate immune system. In this hypothesis, microorganisms elicit release of inflammatory cytokines such as interleukins and TNF-α, which in turn stimulate the production of prostaglandin and/or matrix-degrading enzymes. Prostaglandins stimulate uterine contractions, whereas degradation of extracellular matrix in the fetal membranes leads to preterm rupture of membranes. It is estimated that 25 to 40 percent of preterm births result from intrauterine infection. The basic science of preterm birth due to infection is discussed at length beginning on page 838.

In several studies, antimicrobial treatment has been given to prevent preterm labor due to microbial invasion. Based on available data, these strategies especially targeted mycoplasma species. Morency and colleagues (2007) performed a metaanalysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth. Andrews and associates (2006) reported results of a double-blind interconceptional trial in which they gave a course of azithromycin plus metronidazole every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery before 34 weeks. Approximately 80 percent of the women with subsequent pregnancies had received study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth. Tita and coworkers (2007) performed a subgroup analysis of these same data and concluded that such use of antimicrobials may be harmful. In another study, Goldenberg and colleagues (2006) randomized 2661 women at four African sites to placebo or metronidazole plus erythromycin between 20 and 24 weeks’ gestation followed by ampicillin plus metronidazole during labor. This antimicrobial regimen did not reduce the rate of preterm birth or that of histological chorioamnionitis.

Bacterial Vaginosis

In this condition, normal, hydrogen peroxide-producing, lactobacillus-predominant vaginal flora is replaced with anaerobes that include Gardnerella vaginalis, Mobiluncus species, and Mycoplasma hominis(Hillier, 1995; Nugent, 1991). Its diagnosis and management are discussed in Chapter 65 (p. 1276). Using Gram staining, relative concentrations of the bacterial morphotypes characteristic of bacterial vaginosis are determined and graded as the Nugent score.

Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, PPROM, chorioamnionitis, and amnionic fluid infection (Hillier, 1995; Kurki, 1992; Leitich, 2003a,b). Environmental factors appear to be important in bacterial vaginosis development. Exposure to chronic stress, ethnic differences, and frequent or recent douching have all been associated with increased rates of the condition (Culhane, 2002; Ness, 2002). A gene-environment interaction has been described (Macones, 2004). Women with bacterial vaginosis and a susceptible TNF-α genotype had a ninefold increased incidence of preterm birth. From all of these studies, there seems no doubt that adverse vaginal flora is associated in some way with spontaneous preterm birth. Unfortunately, to date, screening and treatment have not been shown to prevent preterm birth. Indeed, microbial resistance or antimicrobial-induced change in the vaginal flora has been reported as a result of regimens intended to eliminate bacterial vaginosis (Beigi, 2004; Carey, 2005). Okun and associates (2005) performed a systematic review of antibiotics given for bacterial vaginosis and for Trichomonas vaginalis. They found no evidence to support such use for the prevention of preterm birth in either low-risk or high-risk women.

DIAGNOSIS

Preterm labor is primarily diagnosed by symptoms and physical examination. Sonography is used to identify asymptomatic cervical dilation and effacement.

image Symptoms

Early differentiation between true and false labor is difficult before there is demonstrable cervical effacement and dilatation. Uterine activity alone can be misleading because of Braxton Hicks contractions, which are discussed in detail in Chapter 21 (p. 409). These contractions, described as irregular, nonrhythmical, and either painful or painless, can cause considerable confusion in the diagnosis of true preterm labor. Not infrequently, women who deliver before term have uterine activity that is attributed to Braxton Hicks contractions, prompting an incorrect diagnosis of false labor. Accordingly, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2012) define preterm labor to be regular contractions before 37 weeks that are associated with cervical change.

In addition to painful or painless uterine contractions, symptoms such as pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain have been empirically associated with impending preterm birth. Such complaints are thought by some to be common in normal pregnancy and are therefore often dismissed by patients, clinicians, and nurses.

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

Chao (2011) prospectively studied 843 women with singletons who presented to Parkland Hospital with preterm labor symptoms, between 240/7 and 336/7 weeks, intact membranes, and cervical dilation < 2 cm. These women underwent electronic fetal and uterine contraction monitoring for 2 hours. Those whose cervix remained < 2 cm were sent home with a diagnosis of false preterm labor. When analyzed compared with the general obstetrical population, women sent home had a similar and nonsignificant rate of birth before 34 weeks—2 versus 1 percent. However, these women had a significantly higher rate of birth between 34 and 36 weeks—5 percent compared with 2 percent. Women with cervical dilation of 1 cm at discharge were significantly more likely to deliver before 34 weeks compared with women without cervical dilatation—5 percent versus 1 percent. Importantly, almost 90 percent of the 1-cm group delivered > 21 days after the initial presentation.

image Cervical Change

Dilatation

Researchers have evaluated asymptomatic cervical changes that may presage and thus predict preterm labor. Asymptomatic cervical dilatation after midpregnancy is suspected to be a risk factor for preterm delivery, although some clinicians consider it to be a normal anatomical variant. Moreover, study results have suggested that parity alone is not sufficient to explain cervical dilatation discovered early in the third trimester. Cook (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks in both nulliparous and parous women who all subsequently gave birth at term. Cervical length and diameter were identical in both groups throughout these critical weeks. In a study from Parkland Hospital, routine digital cervical examinations were performed between 26 and 30 weeks in 185 women. Approximately 25 percent of women whose cervix was dilated 2 or 3 cm delivered before 34 weeks. Other investigators have verified cervical dilatation as a predictor of increased preterm delivery risk (Copper, 1995; Pereira, 2007).

Although women with dilatation and effacement in the third trimester are at increased risk for preterm birth, detection does not improve pregnancy outcome. Buekens and associates (1994) randomly assigned 2719 women to undergo routine cervical examinations at each prenatal visit and compared them with 2721 women in whom serial examinations were not performed. Knowledge of antenatal cervical dilatation did not affect any pregnancy outcome related to preterm birth or the frequency of interventions for preterm labor. The investigators also reported that cervical examinations were not related to preterm membrane rupture. At this time, it seems that prenatal cervical examinations are neither beneficial nor harmful.

Length

Vaginal-probe sonographic cervical assessment has been evaluated extensively during the past two decades. When performed by trained operators, cervical length analysis using transvaginal sonography is safe, highly reproducible, and more predictive than transabdominal sonographic screening (American College of Obstetricians and Gynecologists, 2012b). Unlike the transabdominal approach, transvaginal cervical sonography is not affected by maternal obesity, cervix position, or shadowing from the fetal presenting part. Technique is important, and Yost and colleagues (1999) have cautioned that special expertise is needed. Iams and coworkers (1996) measured cervical length at approximately 24 weeks’ gestation and again at 28 weeks in 2915 women not at risk for preterm birth. The mean cervical length at 24 weeks was approximately 35 mm, and those women with progressively shorter cervices experienced increased rates of preterm birth.

Until recently, routine cervical length evaluation in women at low risk was not advocated because, like other factors associated with potentially higher preterm birth risk, no effective treatments were available. Randomized trials done to investigate vaginal progesterone use in women with short cervix diagnosed during screening have stimulated consideration of whether or not such screening is warranted (Fonseca, 2007; Hassan, 2011). These trials are discussed subsequently on page 844.

image 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 Food and Drug Administration (FDA) prompted its widespread clinical use. Subsequently, the American College of Obstetricians and Gynecologists (1995) concluded that the use of this expensive, bulky, and time-consuming system does not reduce preterm birth rates. A subsequent study by the Collaborative Home Uterine Monitoring Study Group (1995) confirmed these conclusions. And Iams and associates (2002) analyzed data from almost 35,000 hours of daily home monitoring and verified that no contraction pattern efficiently predicted preterm birth. The American College of Obstetricians and Gynecologists (2012a) does not recommend home uterine activity monitoring.

image Fetal Fibronectin

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

Lockwood (1991) reported that fibronectin detection in cervicovaginal secretions before membrane rupture was a possible marker for impending preterm labor. Fetal fibronectin is measured using an enzyme-linked immunosorbent assay, and values exceeding 50 ng/mL are considered positive. Sample contamination by amnionic fluid and maternal blood should be avoided. Interventional studies based on the use of fetal fibronectin screening in asymptomatic women have not demonstrated improved perinatal outcomes (Andrews, 2003; Grobman, 2004). The American College of Obstetricians and Gynecologists (2012b) does not recommend screening with fetal fibronectin tests.

PRETERM BIRTH PREVENTION

Prevention of preterm birth has been an elusive goal. Recent reports, however, suggest that prevention in selected populations may be achievable.

image Cervical Cerclage

There are at least three circumstances when cerclage placement may be used to prevent preterm birth. Two are done prophylactically, and a third is done for treatment. The first prophylactic cerclage is used in women who have a history of recurrent midtrimester losses and who are diagnosed with cervical insufficiency (Chap. 18p. 360). The second prophylactic cerclage is for women identified during sonographic examination to have a short cervix. The third indication is “rescue” cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor.

For women with a short cervix detected by sonography, Berghella and colleagues (2005) reviewed several small trials of cerclage in this group and concluded that cerclage may reduce preterm birth rates in those women with a prior preterm birth. Owen (2009) randomly assigned 302 women with prior preterm birth from 16 centers with a short cervix—defined as length < 25 mm—to cerclage or no procedure. Women with a cervical length < 15 mm delivered before 35 weeks significantly less often following cerclage compared with women with no cerclage—30 versus 65 percent. This study suggests that recurrent preterm birth can be prevented in a subset of women who have a history of prior preterm births.

In a multinational study, To and associates (2004) screened 47,123 women and randomized the 253 women with cervices < 15 mm to cerclage or no cerclage. The frequency of preterm delivery < 33 weeks was not significantly different between the treatment groups. Thus, cerclage for sonographically detected short cervix alone has not been found to be beneficial. In contrast, women with a very short cervix, that is, < 15 mm, and a history of prior preterm birth may benefit.

image Prophylaxis with Progestin Compounds

Progesterone levels in most mammals fall rapidly before the onset of labor. This is termed progesterone withdrawal and is considered to be a parturition-triggering event. During human parturition, however, maternal, fetal, and amnionic fluid progesterone levels remain elevated with no decline. It has been proposed that human parturition involves functional progesterone withdrawal mediated by decreased progesterone activity of progesterone receptors (Ziyan, 2010). It follows conceptually that the administration of progesterone to maintain uterine quiescence may block preterm labor. This hypothesis has stimulated several studies in the past half century.

image Prior Preterm Birth and Progestin Compounds

Initial Studies

Studies in the past 15 years have included several investigations to evaluate progestin compounds given prophylactically. A pivotal study was done by the MFMU Network to evaluate prophylactic progestin treatment for women at high-risk for recurrent preterm birth (Meis, 2003). In this trial, 310 women with a prior preterm birth were randomized to receive 17-hydroxyprogesterone caproate (17-OHPC)(Romero, 2013). Another 153 women received placebo, and these were administered as weekly intramuscular injections of either inert oil or 17-OHPC from 16 through 36 weeks’ gestation. Delivery rates before 37, 35, and 32 weeks were all significantly reduced by 17-OHPC therapy. At the same time, however, similar studies of 17-OHPC in both twins and triplets done by the Network showed no improvement in preterm birth rates (Caritis, 2009; Rouse, 2007).

The 17-OHPC study by Meis and colleagues (2003) has been challenged because of the unexpectedly high preterm delivery rate in the placebo arm of the trial. Fifty-five percent delivered rather than the expected rate of 36 percent, which was derived from a pretrial cohort (Romero, 2013). The criticism is that 17-OHPC may have been shown to be effective only because the placebo group was distorted by this high 55-percent preterm delivery rate. This compared with the 36-percent rate, which was actually observed when women were treated with 17-OHPC in the trial. To further elucidate this disparity, a confirmation trial by the Network is underway.

Also in contrast to the 17-OHPC study by Meis and coworkers (2003), O’Brien and associates (2007) randomly assigned 659 women with a prior preterm birth to treatment with daily vaginal progesterone gel (90 mg) or placebo. They found no differences in preterm birth rates.

Subsequent Studies

Perhaps no other topic in contemporary obstetrics has generated as much interest and debate since the 23rd edition of Williams Obstetrics as has the use of progestins to prevent preterm birth. At the center of the controversy is whether or not progestins prevent preterm birth in women with a singleton pregnancy but without prior preterm birth—especially nulliparous women. If progestins are effective in women at low risk for preterm birth, this would justify sonographic screening of all pregnant women to detect short cervices (Silver, 2011).

Three randomized trials are at the center of the controversy, and these are summarized in Table 42-7. Fonseca and colleagues (2007) randomly assigned 250 women with sonographically short cervices—15 mm or less—identified during routine prenatal care. Women were given nightly 200-mg micronized progesterone vaginal capsules or placebo from 24 to 34 weeks’ gestation. As shown in Table 42-7, spontaneous delivery before 34 weeks was significantly reduced by progesterone therapy. Importantly, this trial included not only nulliparous women but also those with twins or prior preterm birth.

TABLE 42-7. Randomized Trials of Progestin Compounds Given Prophylactically to Prevent Preterm Labor

image

Hassan and coworkers (2011) randomly assigned 465 women with a sonographically short cervix—10 to 20 mm—to vaginal progesterone gel, 90 mg daily or placebo. As shown in Table 42-7, this trial also included nulliparous women as well as women with prior preterm births. Unlike the Fonseca (2007) trial, however, twin gestations were excluded. This trial was performed in 44 hospitals located in 10 countries including the United States. The FDA rejected progesterone gel for use in the United States because the results did not meet the level of statistical significance required to show efficacy in the subjects recruited in this country. Neither the Fonseca (2007) nor the Hassan (2011) studies report subset analyses exclusive to nulliparas (Parry, 2012). According to Likis and colleagues (2012), the heterogeneity of these two studies that included women with varied indications for progestin treatment, combined with the fact that outcomes were not reported by risk factors such as nulliparity, makes it impossible to interpret the efficacy of progesterone for specific indications. Based on these studies, the American College of Obstetricians and Gynecologists (2012a,b) concluded that it could not “mandate universal cervical length screening in women without a prior preterm birth, but that this screening strategy may be considered.”

The most recently published study that addresses use of progestins to prevent preterm birth in nulliparas included 657 randomly assigned to 17-OHPC or placebo (Grobman, 2012). This study was limited to women with singletons and sonographic cervical length < 30 mm detected between 16 and 223/7 weeks. Treatment with 17-OHPC given weekly did not reduce the frequency of preterm birth before 37 weeks. Subgroup analyses by cervical length and gestational age at delivery are summarized in Table 42-8. Regardless of cervical length, 17-OHPC was ineffective.

TABLE 42-8. Comparison of 17-OHPC versus Placebo to Prevent Preterm Birth at < 37 and < 34 Weeks

image

Another interesting development vis-à-vis progestin therapy for preterm birth since the last edition of Williams Obstetrics was the marketing of 17-OHPC by KV Pharmaceuticals under the brand name Makena. The original retail price was $1500 per 250-mg injectable dose. Thus, a 20-week course for one woman would cost $30,000. This caused an uproar among the leadership of organizations in obstetrics and gynecology. The United States Congress became involved, and the FDA permitted continued availability of 17-hydroxyprogesterone compounded by pharmacies as an alternative to Makena. In Dallas in 2013, a 250-mg injectable dose of compounded 17-OHPC cost about $18. KV Pharmaceuticals filed for Chapter 11 bankruptcy 4 in August 2012. The company cited that it had been unable to realize the full value of its most important drug, Makena (St Louis Business Journal, 2012).

So, how does the clinician reconcile the conflicting evidence as to the efficacy of progestins across the spectrum of the various specific indications? Romero and Stanczyk (2013) argue that one explanation for the conflicting evidence is that progesterone is not the same as 17-hydroxyprogesterone caproate (Figure 42-9). Progesterone is a natural steroid produced by the corpus luteum and the placenta, whereas 17-hydroxyprogesterone caproate is a synthetic steroid. These authors reviewed the basic science of natural and synthetic progestins vis-à-vis effects on the uterus and cervix in pregnant women, animals, and in vitro experiments. For example, natural progesterone suppresses myometrial contractility in strips that were obtained at cesarean delivery, whereas synthetic 17-OHPC did not. This report is an excellent source of information on the issues involved with progestin use in preterm birth.

image

FIGURE 42-9 Chemical structure of progesterone and 17α-hydroxyprogesterone caproate.

The evidence for or against the preventive efficacy of progestins for preterm birth is clearly complex. As outlined in this section, virtually all evidence supporting use for a specific indication can be challenged in some way. Currently, at Parkland Hospital, we are prescribing weekly injections of 17-hydroxyprogesterone compounded by a local pharmacy for women with a prior preterm birth. In our view, all other indications for the use of progestin in the prevention of preterm birth are investigational.

image Geographic-Based Public Health-Care Programs

A well-organized prenatal system results in a decreased preterm birth rate in high-risk indigent populations. The decreasing preterm birth rate at Parkland Hospital between 1988 and 2006 shown in Figure 42-10 coincided with a substantial increase in prenatal care utilization. In the early 1990s, a concerted effort was made to improve access to and use of prenatal care. The intention was to develop a program of seamless care beginning with enrollment during the prenatal period and extending through delivery and into the puerperium. Prenatal clinics are placed strategically throughout Dallas County to provide convenient access for indigent women. When possible, these clinics were colocated with comprehensive medical and pediatric clinics that enhance patient use. Because the entire clinic system is operated by Parkland Hospital, administrative and medical oversight is seamless. For example, prenatal protocols are used by nurse practitioners at all clinic sites to guarantee homogeneous care. Women with high-risk pregnancy complications are referred to the hospital-based central clinic system. Here, high-risk pregnancy clinics operate each weekday, with specialty clinics for women with prior preterm birth, gestational diabetes, infectious diseases, multifetal pregnancy, and hypertensive disorders. Clinics are staffed by residents and midwives supervised by maternal-fetal medicine fellows and faculty. Because Parkland Hospital has a closed medical staff, all attending physicians are employed by the University of Texas Southwestern Department of Obstetrics and Gynecology. These faculty members adhere to agreed-upon practice guidelines using an evidence-based outcomes approach. Thus, prenatal care is considered one component of a comprehensive and orchestrated public health care system that is community-based. Putting this together, we hypothesize that the decrease in preterm births experienced at our inner-city hospital was attributable to a geographically based public health-care program specifically targeting minority populations of pregnant women. A similar obstetrical care system for indigent women at the University of Alabama at Birmingham has also produced salutary results (Tita, 2011).

image

FIGURE 42-10 Percentage of births before 37 weeks’ gestation at Parkland Hospital from 1988 to 2006 compared with that in the United States from 1996 to 2002. Analysis in both cohorts was limited to singleton live births ≥ 500 g who received prenatal care. (Redrawn from Leveno, 2009, with permission.)

MANAGEMENT OF PRETERM PREMATURELY RUPTURED MEMBRANES

Methods used to diagnose ruptured membranes are detailed in Chapter 22 (p. 448). A history of vaginal leakage of fluid, either as a continuous stream or as a gush, should prompt a speculum examination to visualize gross vaginal pooling of amnionic fluid, clear fluid from the cervical canal, or both. Confirmation of ruptured membranes is usually accompanied by sonographic examination to assess amnionic fluid volume, to identify the presenting part, and if not previously determined, to estimate gestational age. Amnionic fluid is slightly alkaline (pH 7.1–7.3) compared with vaginal secretions (pH 4.5–6.0). This is the basis of frequently used pH testing for ruptured membranes. Blood, semen, antiseptics, or bacterial vaginosis, however, are all also alkaline and can give false-positive results.

image Natural History

Cox and associates (1988) described pregnancy outcomes of 298 consecutive women who gave birth following spontaneously ruptured membranes between 24 and 34 weeks at Parkland Hospital. Although this complication was identified in only 1.7 percent of pregnancies, it contributed to 20 percent of all perinatal deaths. By the time they presented, 75 percent of the women were already in labor, 5 percent were delivered for other complications, and another 10 percent delivered within 48 hours. In only 7 percent was delivery delayed 48 hours or more after membrane rupture. This last subgroup, however, appeared to benefit from delayed delivery because there were no neonatal deaths. This contrasted with a neonatal death rate of 80 per 1000 in preterm newborns delivered within 48 hours of membrane rupture. Nelson (1994) reported similar results.

The time from PPROM to delivery is inversely proportional to the gestational age when rupture occurs (Carroll, 1995). As shown in Figure 42-11, very few days were gained when membranes ruptured during the third trimester compared with midpregnancy.

image

FIGURE 42-11 Relationship of time between preterm membrane rupture and delivery in 172 singleton pregnancies. (Redrawn from Carroll, 1995, with permission.)

image Hospitalization

Most clinicians hospitalize women with PPROM. Concerns regarding the costs of lengthy hospitalizations are usually moot, because most women enter labor within a week or less after membrane rupture. Carlan and coworkers (1993) randomly assigned 67 women with ruptured membranes to home or hospital management. No benefits were found for hospitalization, and maternal hospital stays were reduced by 50 percent in those sent home—14 versus 7 days. Importantly, the investigators emphasized that this study was too small to conclude that home management was safe vis-à-vis umbilical cord prolapse.

image Intentional Delivery

Before the mid-1970s, labor was usually induced in women with preterm ruptured membranes because of fear of sepsis. Two randomized trials compared labor induction with expectant management in such pregnancies. Mercer and associates (1993) randomly assigned 93 women with pregnancies between 32 and 36 weeks to undergo delivery or expectant management. Fetal lung maturity, as evidenced by mature surfactant profiles, was present in all cases. Intentional delivery reduced the length of maternal hospitalization and also reduced infection rates in both mothers and neonates. Cox and coworkers (1995) similarly apportioned 129 women between 30 and 34 weeks. Fetal lung maturity was not assessed. One fetal death resulted from sepsis in the pregnancies managed expectantly. Among those intentionally delivered, there were three neonatal deaths—two from sepsis and one from pulmonary hypoplasia. Thus, neither management approach proved to be superior for perinatal outcomes.

image Expectant Management

Despite extensive literature concerning expectant management of PPROM, tocolysis has been used in few studies. In randomized studies, women were assigned to receive either tocolysis or expectant management. The investigators concluded that active interventions did not improve perinatal outcomes (Garite, 1981, 1987; Nelson, 1985).

Other considerations with expectant management involve the use of digital cervical examination and cerclage. Alexander and colleagues (2000) analyzed findings in women expectantly managed between 24 and 32 weeks’ gestation. They compared those who had one or two digital cervical examinations with women who were not examined digitally. Women who were examined had a rupture-to-delivery interval of 3 days compared with 5 days in those who were not examined. This difference did not worsen maternal or neonatal outcomes.

There is uncertainty regarding ruptured membranes in the woman who has undergone cervical cerclage. McElrath and associates (2002) studied 114 women with cerclage in place who later had ruptured membranes before 34 weeks. They were compared with 288 controls who had not received a cerclage. Pregnancy outcomes were equivalent in both groups. As discussed in Chapter 18 (p. 363), such management is controversial.

Risks of Expectant Management

Maternal and fetal risks vary with the gestational age at membrane rupture. Morales (1993b) expectantly managed 94 singleton pregnancies with ruptured membranes before 25 weeks. The average time gained was 11 days. Although 41 percent of infants survived to age 1 year, only 27 percent were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their colleagues. Lieman and associates (2005) found no improved neonatal outcomes with expectant management beyond 33 weeks. In contrast, McElrath and coworkers (2003) found that prolonged latency after membrane rupture was not associated with an increased incidence of fetal neurological damage.

The volume of amnionic fluid remaining after rupture appears to have prognostic importance in pregnancies before 26 weeks. Hadi and colleagues (1994) described 178 pregnancies with ruptured membranes between 20 and 25 weeks. Forty percent of women developed oligohydramnios, defined by the absence of fluid pockets 2 cm or larger. Virtually all women with oligohydramnios delivered before 25 weeks, whereas 85 percent with adequate amnionic fluid volume were delivered in the third trimester. Carroll and coworkers (1995) observed no cases of pulmonary hypoplasia in fetuses born after membrane rupture at 24 weeks or beyond. This suggests that 23 weeks or less is the threshold for development of lung hypoplasia. Further, when contemplating early expectant management, consideration is also given to oligohydramnios and resultant limb compression deformities (Chap. 11p. 237).

Other risk factors have also been evaluated. In neonates born to women with active herpetic lesions who were expectantly managed, the infectious morbidity risk appeared to be outweighed by risks associated with preterm delivery (Major, 2003). Lewis and associates (2007) found that expectant management of women with preterm ruptured membranes and noncephalic presentation was associated with an increased rate of umbilical cord prolapse, especially before 26 weeks.

image Clinical Chorioamnionitis

Most authors report that prolonged membrane rupture is associated with increased fetal and maternal sepsis (Ho, 2003). If chorioamnionitis is diagnosed, prompt efforts to effect delivery, preferably vaginally, are initiated. Fever is the only reliable indicator for this diagnosis, and temperature of 38°C (100.4°F) or higher accompanying ruptured membranes implies infection. Maternal leukocytosis alone has not been found to be reliable. During expectant management, monitoring for sustained maternal or fetal tachycardia, for uterine tenderness, and for a malodorous vaginal discharge is warranted.

With chorioamnionitis, fetal and neonatal morbidity is 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 infection. Those in the infected group had a higher incidence of sepsis, respiratory distress syndrome, early-onset seizures, intraventricular hemorrhage, and periventricular leukomalacia. The investigators concluded that these very-low-birthweight neonates were vulnerable to neurological injury attributable to chorioamnionitis.

Although Locatelli and coworkers (2005) have challenged this finding, there is other evidence that very small newborns are at increased risk for sepsis. Yoon and colleagues (2000) found that intraamnionic infection in preterm neonates was related to increased rates of cerebral palsy. Petrova and associates (2001) studied more than 11 million singleton live births in the United States from 1995 to 1997. During labor, 1.6 percent of all women had fever, and this was a strong predictor of infection-related death in both term and preterm neonates. Bullard and colleagues (2002) reported similar results.

image Accelerated Pulmonary Maturation

Various clinical events—some well defined—were once proposed to accelerate fetal surfactant production (Gluck, 1979). These included chronic renal or cardiovascular disease, hypertensive disorders, heroin addiction, fetal-growth restriction, placental infarction, chorioamnionitis, and preterm ruptured membranes. Although this view was widely held for many years, subsequent observations do not support this association (Hallak, 1993; Owen, 1990).

image Antimicrobial Therapy

The proposed microbial pathogenesis for spontaneous preterm labor or ruptured membranes has prompted investigators to give various antimicrobials in an attempt to forestall delivery. Mercer and associates (1995) reviewed 13 randomized trials performed before 35 weeks. Metaanalysis indicated that only three of 10 outcomes were possibly benefited: (1) fewer women developed chorioamnionitis, (2) fewer newborns developed sepsis, and (3) pregnancy was more often prolonged 7 days in women given antimicrobials. Neonatal survival, however, was unaffected, as was the incidence of necrotizing enterocolitis, respiratory distress, or intracranial hemorrhage.

To further address this issue, the MFMU Network designed a trial to study expectant management combined with a 7-day treatment with ampicillin, amoxicillin plus erythromycin, or placebo. The women had membrane rupture between 24 and 32 weeks. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had significantly fewer newborns with respiratory distress syndrome, necrotizing enterocolitis, and composite adverse outcomes (Mercer, 1997). The latency period was significantly longer. Specifically, 50 percent of women given an antimicrobial regimen remained undelivered after 7 days of treatment compared with only 25 percent of those given placebo. There was also significant prolongation of pregnancy at 14 and 21 days. Cervicovaginal group B streptococcal colonization did not alter these results.

More recent studies have examined the efficacy of shorter treatment lengths and other antimicrobial combinations. Three-day treatment compared with 7-day regimens using either ampicillin or ampicillin-sulbactam appeared equally effective in regard to perinatal outcomes (Lewis, 2003; Segel, 2003). Similarly, erythromycin compared with placebo offered a range of significant neonatal benefits. The amoxicillin-clavulanate regimen was not recommended, however, because of its association with an increased incidence of necrotizing enterocolitis (Kenyon, 2004).

Some predicted that prolonged antimicrobial therapy in such pregnancies might have unwanted consequences. Carroll (1996) and Mercer (1999) and their coworkers cautioned that such therapy potentially increased the risk for resistant bacteria. Stoll and associates (2002) studied 4337 neonates weighing from 400 to 1500 g and born from 1998 to 2000. Their outcomes were compared with those of 7606 neonates of similar birthweight born from 1991 to 1993. The overall rate of early-onset sepsis did not change between these two epochs. But the rate of group B streptococcal sepsis decreased from 5.9 per 1000 births in the 1991 to 1993 group to 1.7 per 1000 births in the 1998 to 2000 group. Comparing these same epochs, the rate of Escherichia coli sepsis increased from 3.2 to 6.8 per 1000 births. Almost 85 percent of coliform isolates from the more recent cohort were ampicillin resistant. Neonates with early-onset sepsis were more likely to die, especially if they were infected with coliforms. Kenyon and coworkers (2008a) found that antimicrobials given for women with PPROM had no effect on the health of children at age 7 years.

image Corticosteroids to Accelerate Fetal Lung Maturity

The National Institutes of Health (NIH) (2000) in their Consensus Development Conference recommended a single course of antenatal corticosteroids for women with preterm membrane rupture before 32 weeks and in whom there was no evidence of chorioamnionitis. Since then, several metaanalyses have addressed this issue, and according to the American College of Obstetricians and Gynecologists (2013d), single-dose therapy is recommended from 24 to 32 weeks. There is no consensus regarding treatment between 32 and 34 weeks. Corticosteroid therapy is not recommended before 24 weeks.

image Membrane Repair

Tissue sealants have been used for various purposes in medicine and have become important in maintaining surgical hemostasis and stimulating wound healing. Devlieger and colleagues (2006) have reviewed the efficacy of sealants in the repair of fetal membrane defects such as in preterm ruptured membranes.

image Management Recommendations

The management scheme recommended by the American College of Obstetricians and Gynecologists (2013d) is summarized in Table 42-9. This management is similar to that practiced at Parkland Hospital.

TABLE 42-9. Recommended Management of Preterm Ruptured Membranes

image

MANAGEMENT OF PRETERM LABOR WITH INTACT MEMBRANES

Women with signs and symptoms of preterm labor with intact membranes are managed much the same as described above for those with preterm ruptured membranes. If possible, delivery before 34 weeks is delayed. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed.

image Amniocentesis to Detect Infection

Several tests have been used to diagnose intraamnionic infection. Romero and coworkers (1993) evaluated the diagnostic value of amnionic fluid containing an elevated leukocyte count, a low glucose level, a high IL-6 concentration, or a positive Gram stain result in 120 women with preterm labor and intact membranes. Women with positive amnionic fluid culture results were considered infected. These investigators found that a negative Gram stain result was 99-percent specific to exclude amnionic fluid bacteria. A high IL-6 level was 82-percent sensitive for detection of amnionic fluid containing bacteria. Other investigators have also found good correlation between amnionic fluid IL-6 or leukocyte levels and chorioamnionic infection (Andrews, 1995; Yoon, 1996). Despite these correlations, amniocentesis to diagnose infection does not improve pregnancy outcomes in women with or without membrane rupture (Feinstein, 1986). The American College of Obstetricians and Gynecologists (2012a) has concluded that there is no evidence to support routine amniocentesis to identify infection.

image Corticosteroids for Fetal Lung Maturation

Because glucocorticosteroids were found to accelerate lung maturation in preterm sheep fetuses, Liggins and Howie (1972) evaluated them to treat women. Corticosteroid therapy was effective in lowering the incidence of respiratory distress syndrome 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 to age 31 years with no ill effects detected. In 1995, an NIH Consensus Development Conference panel recommended corticosteroids for fetal lung maturation in threatened preterm birth.

In a subsequent meeting, the NIH Consensus Development Conference (2000) concluded that data were insufficient to assess corticosteroid effectiveness in pregnancies complicated by hypertension, diabetes, multifetal gestation, fetal-growth restriction, and fetal hydrops. It concluded, however, that it was reasonable to administer corticosteroids in women with these complications.

The issue of the fetal and neonatal safety with single versus repeat courses of intramuscular corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneficial in reducing neonatal respiratory morbidity rates, the long-term consequences were much different. Specifically, Crowther and associates (2007) studied outcomes in 982 women who were given a single weekly dose of 11.4 mg of betamethasone. These investigators found no adverse effects in the infants followed to age 2 years. Wapner and colleagues (2007) studied infants born to 495 women who were randomly assigned to receive a single corticosteroid course or repeated courses that were given weekly. With each round, a 12-mg betamethasone dose was injected, followed by a second given 24 hours later. A nonsignificant rise in cerebral palsy rates was identified in infants exposed to repeated courses. The twice-as-large betamethasone dose in this study was worrisome because some experimental evidence supports the view that adverse corticosteroid effects are dose dependent. Bruschettini and coworkers (2006) studied the equivalent of 12-mg versus 6-mg betamethasone given to pregnant cats. They reported that the lower dose had less severe effects on somatic growth without affecting fetal brain cell proliferation. Stiles (2007) summarized these two human studies as “early gain, long-term questions.” We agree, and at Parkland Hospital, we follow the recommendation by the American College of Obstetricians and Gynecologists (2013c) for single-course therapy.

“Rescue Therapy”

This refers to administration of a repeated corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. The 2000 NIH Consensus Development Conference recommended that rescue therapy should not be routinely used and that it should be reserved for clinical trials. The first randomized trial, reported by Peltoniemi and coworkers (2007), allocated 326 women to placebo or 12-mg betamethasone single-dose rescue regimens. Paradoxically, these researchers found that the rescue dose of betamethasone increased the risk of respiratory distress syndrome! In a multicenter study of 437 women < 33 weeks who were randomly assigned to rescue therapy or placebo, Kurtzman and associates (2009) reported significantly decreased rates of respiratory complications and neonatal composite morbidity with rescue corticosteroids. There were, however, no differences in perinatal mortality rates and other morbidities. In another trial, McEvoy and colleagues (2010) showed that treated infants had improved respiratory compliance.

Garite and coworkers (2009) randomly assigned 437 women with singletons or twins < 33 weeks’ gestation and with intact membranes to one “rescue” course of either betamethasone or dexamethasone or placebo. These women had all previously completed a single course of corticosteroids before 30 weeks’ gestation and at least 14 days before the “rescue” course. Respiratory distress syndrome developed in 41 percent of the infants given corticosteroids compared with 62 percent of those randomized to placebo. There were no differences in other morbidities attributable to prematurity. In a metaanalysis, Crowther and colleagues (2011) concluded that a single course of corticosteroids should be considered in women whose prior course was administered at least 7 days previously and were < 34 weeks’ gestation. The American College of Obstetricians and Gynecologists (2012a) has taken the position that a single rescue course of antenatal corticosteroids should be considered in women before 34 weeks whose prior course was administered at least 7 days previously.

Choice of Corticosteroid

As summarized by Murphy (2007), there is a 10-year question as to whether betamethasone is superior to dexamethasone for fetal lung maturation. Elimian and associates (2007) randomly assigned 299 women between 24 and 33 weeks to betamethasone or dexamethasone. These two drugs were comparable in reducing rates of major neonatal morbidities in preterm infants.

image Antimicrobials

As with preterm ruptured membranes, antimicrobials have been given in an attempt to arrest preterm labor. Results have been disappointing. A Cochrane metaanalysis by King and colleagues (2000) found no difference in the rates of newborn respiratory distress syndrome or sepsis between placebo- and antimicrobial-treated groups. They did find, however, increased perinatal morbidity in the antimicrobial-treated group. Kenyon (2001) reported 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. The primary outcomes of neonatal death, chronic lung disease, and major cerebral abnormality were similar in both groups. In his review, Goldenberg (2002) also concluded that antimicrobial treatment of women with preterm labor for the sole purpose of preventing delivery is generally not recommended. In a follow-up of the ORACLE II trial, Kenyon and associates (2008b) reported that fetal exposure to antimicrobials in this clinical setting was associated with an increased cerebral palsy rate at age 7 years compared with that of children without fetal exposure.

image Bed Rest

This is one of the most often prescribed interventions during pregnancy, yet one of the least studied. Goldenberg (1994) reviewed the available literature on bed rest in pregnancy and found no evidence supporting or refuting the benefit of either bed rest or hospitalization for women with threatened preterm labor. Moreover, Sosa and colleagues (2004) searched the Cochrane Database and concluded that evidence neither supported nor refuted bed rest to prevent preterm birth.

Goulet and coworkers (2001) randomly assigned 250 Canadian women to either home care or hospitalization after treatment of an acute episode of preterm labor and also found no benefits. Yost and associates (2005) attempted a randomized study at Parkland Hospital but terminated the study after 6 years due to low recruitment. In this study, bed rest in the hospital compared with bed rest at home had no effect on pregnancy duration in women with threatened preterm labor before 34 weeks. Kovacevich and coworkers (2000) reported that bed rest for 3 days or more increased thromboembolic complications to 16 per 1000 women compared with only 1 per 1000 with normal ambulation. Promislow and colleagues (2004) observed significant bone loss in pregnant women prescribed outpatient bed rest.

Most recently there were three articles on bed rest in the journal Obstetrics & Gynecology. Grobman and associates (2013) found that nearly 40 percent of women enrolled in a trial to study the efficacy of 17-OHPC in those with a sonographically short cervix had some form of activity restriction. 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 in that women with restricted activity may have received bed rest because they were viewed to be at more imminent risk of preterm delivery. In the same journal issue, McCall and coworkers (2013) summarized the literature on bed rest. They found insufficient evidence to support the use of bed rest and found several studies showing harm with its use. They opined that it is unethical to continue to prescribe bed rest. In an accompanying editorial, Biggio (2013) called for appropriate trials to settle these issues.

image Cervical Pessaries

There is increasing interest in the use of cervical pessaries to prevent preterm birth. Silicone rings, also know as the Arabin pessary, are being used to support the cervix in women with a sonographically short cervix. For 385 Spanish women with cervical lengths ≤ 25 mm, Goya and colleagues (2012) provided a silicone pessary or expectant management. There was spontaneous delivery before 34 weeks’ gestation in 6 percent of women in the pessary group compared with 27 percent in the expectant management group. Hui and associates (2013) randomly assigned approximately 100 women with cervices < 25 mm at 20 to 24 weeks to silicone pessaries or expectant management. The prophylactic use of silicone pessary did not reduce the rate of delivery before 34 weeks. These two studies with conflicting results are the only randomized trials to date. Currently, the MFMU Network is designing a trial to study pessary use to prevent preterm labor in twin pregnancies.

image Emergency or Rescue Cerclage

There is support for the concept that cervical incompetence and preterm labor lie on a spectrum leading to preterm delivery. Consequently, investigators have evaluated cerclage performed after preterm labor begins to manifest clinically. More than 30 years ago, Harger (1983) concluded that if cervical incompetence is recognized with threatened preterm labor, then emergency cerclage can be attempted, albeit with an appreciable risk of infection and pregnancy loss. Althuisius and colleagues (2003) randomly assigned 23 women with cervical incompetence before 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with that assigned to bed rest alone—54 versus 24 days. Terkildsen and coworkers (2003) studied 116 women who underwent second-trimester emergency cerclage. Nulliparity, membranes extending beyond the external cervical os, and cerclage before 22 weeks were associated with a significantly decreased chance of pregnancy continuation to 28 weeks or beyond.

image Tocolysis to Treat Preterm Labor

Although several drugs and other interventions have been used to prevent or inhibit preterm labor, none has been shown to be completely effective. The American College of Obstetricians and Gynecologists (2012a) 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 a regional obstetrical center and permit time for corticosteroid therapy. Beta-adrenergic agonists, calcium-channel blockers, or indomethacin are the recommended tocolytic agents for such short-term use—up to 48 hours. In contrast, the College has concluded that “Maintenance therapy with tocolytics is ineffective for preventing preterm birth and improving neonatal outcome and is not recommended for this purpose.” Moreover, the College recommends that women with preterm contractions without cervical change, especially those with cervical dilation of less than 2 cm, generally should not be treated with tocolytics.

β-Adrenergic Receptor Agonists

Several compounds react with β-adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (Chap. 21p. 421). In the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine had been approved for preterm labor by the FDA.

Ritodrine. According to the Federal Register, ritodrine was voluntarily withdrawn from the United States market in 2003. A discussion is included here because knowledge concerning β-mimetic drugs accrued with its use. In an early multicenter trial, neonates whose mothers were treated with ritodrine for threatened preterm labor had lower rates of preterm birth, death, and respiratory distress (Merkatz, 1980). In a randomized trial at Parkland Hospital, Leveno and associates (1986) found that intravenous drug treatment delayed delivery for 24 hours but without other benefits. Additional studies of parenteral β-agonists confirmed a delivery delay up to 48 hours (Canadian Preterm Labor Investigators Group, 1992).

Unfortunately, this delay in preterm delivery provided no fetal benefits. Macones and colleagues (1995) used metaanalysis to assess the efficacy of oral β-agonist therapy and found no benefits. Keirse (1995b) suggested that this brief delay may aid maternal transport to tertiary care or permit fetal lung maturation with corticosteroids. Although this intuitive reasoning is logical, there are no data to support this.

β-Agonist infusion has resulted in frequent and, at times, serious and even fatal maternal side effects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 47 (p. 942). 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). The cause of pulmonary edema is multifactorial. Risk factors include tocolytic therapy with β-agonists, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and large intravenous crystalloid volume infusion. Because β-agonists cause retention of sodium and water, 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.

Terbutaline. This β-agonist is commonly used to forestall preterm labor. Like ritodrine, it can cause pulmonary edema (Angel, 1988). Low-dose terbutaline can be administered long-term by subcutaneous pump (Lam, 1988). Marketed between 1987 and 1993, these pumps were used in nearly 25,000 women with suspected preterm labor (Perry, 1995). Adverse reports describe a sudden maternal death and a newborn with myocardial necrosis after the mother used the pump for 12 weeks (Fletcher, 1991; Hudgens, 1993). Elliott and associates (2004) used continuous terbutaline subcutaneous infusion in 9359 patients and reported that only 12 women experienced severe adverse events—primarily pulmonary edema.

However, randomized trials have reported no benefit for terbutaline pump therapy. Wenstrom and coworkers (1997) randomly assigned 42 women with preterm labor to a terbutaline pump, to a saline pump, or to oral terbutaline. In another trial, Guinn and colleagues (1998) randomly treated 52 women with terbutaline or with saline pump therapy. Terbutaline did not significantly prolong pregnancy, prevent preterm delivery, or improve neonatal outcomes in either of these studies.

Oral terbutaline therapy to prevent preterm delivery has also not been effective (How, 1995; Parilla, 1993). In a double-blind trial, Lewis and coworkers (1996) studied 203 women with arrested preterm labor at 24 to 34 weeks. Women were randomly assigned to receive 5-mg terbutaline tablets or placebo every 4 hours. Delivery rates at 1 week were similar in both groups, as was median latency, mean gestational age at delivery, and the incidence of recurrent preterm labor. In 2011, the FDA issued a warning regarding use of terbutaline to treat preterm labor because of reports of serious maternal side effects.

Magnesium Sulfate

Ionic magnesium in a sufficiently high concentration can alter myometrial contractility. Its role is presumably that of a calcium antagonist, and when given in pharmacological doses, it may inhibit labor. Steer and Petrie (1977) concluded that intravenous magnesium sulfate—a 4-g loading dose followed by a continuous infusion of 2 g/hr—usually arrests labor. The pharmacology and toxicology of magnesium are considered in more detail in Chapter 40 (p. 759). Samol and associates (2005) reported 67 cases—8.5 percent—of pulmonary edema among 789 women given tocolysis with magnesium sulfate at their hospital.

There have been only two randomized placebo-controlled studies of tocolysis with magnesium sulfate. Cotton and colleagues (1984) compared magnesium sulfate, ritodrine, and placebo in 54 women in preterm labor. They identified few differences in outcomes. Cox and coworkers (1990) randomly assigned 156 women to receive magnesium sulfate or normal saline infusions. Magnesium-treated women and their fetuses had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital. Grimes (2006) reviewed this tocolytic agent and concluded it was ineffective and potentially harmful.

Recently, the FDA (2013) warned against prolonged use of magnesium sulfate given to arrest preterm labor due to bone thinning and fractures in fetuses exposed for more than 5 to 7 days. This was attributed to low calcium levels in the fetus.

Prostaglandin Inhibitors

Prostaglandins are intimately involved in contractions of normal labor (Chap. 21p. 426). Antagonists act by inhibiting prostaglandin synthesis or by blocking their action on target organs. A group of enzymes collectively termed prostaglandin synthase is responsible for the conversion of free arachidonic acid to prostaglandins (Fig. 21-16p. 422). Several drugs block this system, including acetylsalicylate and indomethacin.

Indomethacin was first used as a tocolytic for 50 women by Zuckerman and associates (1974). Studies that followed reported the efficacy 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 efficacy to forestall preterm delivery. Berghella and associates (2006) reviewed four trials of indomethacin given to women with sonographically short cervices and found such therapy ineffective.

Indomethacin is administered orally or rectally. A dose of 50 to 100 mg is followed at 8-hour intervals not to exceed a total 24-hour dose of 200 mg. Serum concentrations usually peak 1 to 2 hours after oral administration, whereas levels after rectal administration peak slightly earlier. Most studies have limited indomethacin use to 24 to 48 hours because of concerns for oligohydramnios, which can develop with these doses. If amnionic fluid is monitored, oligohydramnios can be detected early, and it is reversible with drug discontinuation.

Case-control studies have assessed neonatal effects of exposure to indomethacin given for preterm labor. In a study of neonates born before 30 weeks, Norton and coworkers (1993) identified necrotizing enterocolitis in 30 percent of 37 indomethacin-exposed newborns compared with 8 percent of 37 control newborns. Higher incidences of intraventricular hemorrhage and patent ductus arteriosus were also documented in the indomethacin group. The impact of treatment duration and its timing in relation to delivery were not reported. In contrast, several investigators have challenged the association between indomethacin exposure and necrotizing enterocolitis (Muench, 2001; Parilla, 2000). Finally, Gardner (1996) and Abbasi (2003) and their colleagues found no link between indomethacin use and intraventricular hemorrhage, patent ductus arteriosus, sepsis, necrotizing enterocolitis, or neonatal death.

Schmidt and associates (2001) followed 574 newborns who were randomly assigned to receive either indomethacin or placebo to prevent pulmonary hypertension from patent ductus arteriosus. The infants, who weighed 500 to 1000 g, were followed to a corrected age of 18 months. Those given indomethacin had a significantly reduced incidence of both patent ductus arteriosus and severe intraventricular hemorrhage. Survival without impairment, however, was similar in both groups. Peck and coworkers (2003) reported that indomethacin therapy for 7 or more days before 33 weeks does not increase the risk of neonatal or childhood medical problems. Two metaanalyses of the effects of antenatal indomethacin on neonatal outcomes had conflicting findings (Amin, 2007; Loe, 2005).

Calcium-Channel Blockers

Myometrial activity is directly related to cytoplasmic free calcium, and a reduction in its concentration inhibits contractions (Chap. 21p. 417). Calcium-channel blockers act to inhibit, by various mechanisms, calcium entry through cell membrane channels. Although they were developed to treat hypertension, their ability to arrest preterm labor has been evaluated.

Using the Cochrane Database, Keirse (1995a) compared nifedipine and β-agonists. They concluded that although nifedipine treatment reduced births of neonates weighing < 2500 g, significantly more of these were admitted for intensive care. Other investigators have also concluded that calcium-channel blockers, especially nifedipine, are safer and more effective tocolytic agents than are β-agonists (King, 2003; Papatsonis, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks to either magnesium sulfate or nifedipine and found no substantial differences in efficacy or adverse effects. Salim and associates (2012) randomly assigned 145 women in preterm labor between 24 and 33 weeks to nifedipine or atosiban. No clear superiority of either to delay delivery was identified, and otherwise, neonatal morbidity was equivalent. Importantly, no randomized trial has compared nifedipine to placebo for acute tocolysis.

The combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami (1994) and Kurtzman (1993) and their coworkers reported that nifedipine enhances the neuromuscular blocking effects of magnesium that can interfere with pulmonary and cardiac function. How and associates (2006) randomly provided 54 women between 320/7 and 346/7 weeks with magnesium sulfate plus nifedipine or no tocolytic and found neither benefit nor harm.

Atosiban

This nonapeptide oxytocin analogue is a competitive antagonist of oxytocin-induced contractions. Goodwin and colleagues (1995) described its pharmacokinetics in pregnant women. In randomized clinical trials, atosiban failed to improve relevant neonatal outcomes and was linked with significant neonatal morbidity (Moutquin, 2000; Romero, 2000). The FDA has denied approval of atosiban because of concerns regarding efficacy and fetal–newborn safety. Goodwin (2004) has reviewed the history of atosiban both in the United States and in Europe, where this drug is approved and widely used as a tocolytic.

Nitric Oxide Donors

These potent smooth-muscle relaxants affect the vasculature, gut, and uterus. In randomized clinical trials, nitroglycerin administered orally, transdermally, or intravenously was not effective or showed no superiority to other tocolytics. In addition, maternal hypotension was a common side effect (Bisits, 2004; Clavin, 1996; El-Sayed, 1999; Lees, 1999).

Summary of Tocolysis for Preterm Labor

In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. In a metaanalysis of tocolytic therapy, Gyetvai and associates (1999) concluded that although delivery may be delayed long enough for administration of corticosteroids, treatment does not result in improved perinatal outcome. Berkman and colleagues (2003) reviewed 60 reports and concluded that tocolytic therapy can prolong gestation, but that β-agonists are no better than other drugs and pose potential maternal danger. They also concluded that there are no benefits of maintenance tocolytic therapy.

In general, if tocolytics are given, they should be administered concomitantly with corticosteroids. The gestational age range for their use is debatable. However, because corticosteroids are not generally used after 33 weeks and because the perinatal outcomes in preterm neonates are generally good after this time, most practitioners do not recommend use of tocolytics at or after 33 weeks (Goldenberg, 2002).

image Labor

Whether labor is induced or spontaneous, abnormalities of fetal heart rate and uterine contractions should be sought. We prefer continuous electronic monitoring. Fetal tachycardia, especially with ruptured membranes, is suggestive of sepsis. There is some evidence that intrapartum acidemia may intensify some of the neonatal complications usually attributed to preterm delivery. For example, Low and colleagues (1995) observed that intrapartum acidosis—umbilical artery blood pH less than 7.0—had an important role in neonatal complications (Chap. 32p. 629). Similarly, Kimberlin and coworkers (1996) found that increasing umbilical artery blood acidemia was related to more severe respiratory disease in preterm neonates. Despite this, no effects were found in short-term neurological outcomes that included intracranial hemorrhages.

Group B streptococcal infections are common and dangerous in the preterm neonate. Accordingly, as discussed in Chapter 64 (p. 1249), prophylaxis should be provided.

image Delivery

In the absence of a relaxed vaginal outlet, an episiotomy for delivery may be necessary once the fetal head reaches the perineum. Perinatal outcome data do not support routine 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. Principles of resuscitation described in Chapter 32 are applicable. 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.

image Prevention of Neonatal Intracranial Hemorrhage

Preterm newborns frequently have intracranial germinal matrix bleeding that can extend to more serious intraventricular hemorrhage (Chap. 34p. 656). It was hypothesized that cesarean delivery to obviate trauma from labor and vaginal delivery might prevent these complications. This has not been validated by most subsequent studies. Malloy (1991) analyzed 1765 newborns with birthweights less than 1500 g and found that cesarean delivery did not lower the risk of mortality or intracranial hemorrhage. Anderson (1988), however, made an interesting observation regarding the role of cesarean delivery in intracranial hemorrhage prevention. These hemorrhages correlated with exposure to active-phase labor. However, they emphasized that avoidance of active-phase labor is impossible in most preterm births because decisions for delivery route are not required until active labor is firmly established.

Magnesium Sulfate for Fetal Neuroprotection

In intriguing reports, very-low-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether, 2000; Nelson, 1995). Because epidemiological evidence suggested that maternal magnesium sulfate therapy had a fetal neuroprotective effect, randomized trials were designed to investigate this hypothesis. An Australian randomized trial by Crowther and coworkers (2003) included 1063 women at imminent risk of delivery before 30 weeks and who were given magnesium sulfate or placebo. These investigators showed that magnesium exposure improved some perinatal outcomes. Rates of both neonatal death and cerebral palsy were lower in the magnesium-treated group—but this study was not sufficiently powered. The multicenter French trial reported by Marret and associates (2008) had similar problems.

More convincing evidence for magnesium neuroprotection came from the NICHD MFMU Network study reported by Rouse and colleagues (2008). The Beneficial Effects of Antenatal Magnesium SulfateBEAM—Study was a placebo-controlled trial in 2241 women at imminent risk for preterm birth between 24 and 31 weeks. Almost 87 percent had preterm ruptured membranes, and almost a fifth had previously received magnesium sulfate for tocolysis. Women randomized to magnesium sulfate were given a 6-g bolus over 20 to 30 minutes followed by a maintenance infusion of 2 g per hour. Magnesium sulfate was actually infusing at the time of delivery in approximately half of the treated women. A 2-year follow-up was available for 96 percent of the children. Selected results are shown in Table 42-10. This trial can be interpreted differently depending on statistical philosophy. Some opt to interpret these findings to mean that magnesium sulfate infusion prevents cerebral palsy regardless of the gestational age at which the therapy is given. Those with a differing view conclude that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks. What is certain, however, is that maternally administered magnesium sulfate infusions cannot be implicated in increased perinatal deaths as reported by Mittendorf (1997).

TABLE 42-10. Magnesium Sulfate for the Prevention of Cerebral Palsya

image

Subsequent to these studies, Doyle and associates (2009) performed a Cochrane review of the five available randomized trials to assess neuroprotective effects of magnesium sulfate. A total of 6145 infants were studied, and as expected, most came from the three larger Australian, French, and MFMU Network multicenter studies. These reviewers reported that magnesium exposure compared with no exposure significantly decreased risks for cerebral palsy, with a relative risk of 0.68. There were no significant effects on rates of pediatric mortality or other neurological impairments or disabilities. It was calculated that treatment given to 63 women would prevent one case of cerebral palsy.

There was debate regarding magnesium efficacy for neuroprotection 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 vis-à-vis neuroprotection were false positive due to random statistical error in the Doyle (2009) metaanalysis. The American College of Obstetricians and Gynecologists (2013a) recognized that “none of the individual studies found a benefit with regard to their primary outcome.” It was concluded that “Physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimen. …” Subsequently, the American College of Obstetricians and Gynecologists (2012a) issued a Patient Safety Checklist that could be used if magnesium sulfate is given for neuroprotection.

Because of these findings, at Parkland Hospital our policy is to provide magnesium sulfate for threatened preterm delivery from 240/7 to 276/7 weeks. A 6-g loading dose is followed by an infusion of 2 g per hour for at least 12 hours.

REFERENCES

Aagaard K, Riehle K, Ma J, et al: A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One 7(6):e36466, 2012

Abbasi S, Gerdes JS, Sehdev HM, et al: Neonatal outcomes after exposure to indomethacin in utero: a retrospective case cohort study. Am J Obstet Gynecol 189:782, 2003

Alexander JM, Gilstrap LC, Cox SM, et al: Clinical chorioamnionitis and the prognosis for very low birthweight infants. Obstet Gynecol 91:725, 1998

Alexander JM, Mercer BM, Miodovnik M, et al: The impact of digital cervical examination on expectantly managed preterm ruptured membranes. Am J Obstet Gynecol 183:1003, 2000

Althuisius SM, Dekker G, Hummel P, et al: Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 189:907, 2003

American Academy of Pediatrics and the American College of Obstetricians and Gynecologists: Guidelines for Perinatal Care, 7th ed. Washington, 2012, p 158

American College of Obstetricians and Gynecologists: Preterm labor. Technical Bulletin No. 206, June 1995

American College of Obstetricians and Gynecologists: Management of preterm labor. Practice Bulletin No. 127, June 2012a

American College of Obstetricians and Gynecologists: Prediction and prevention of preterm birth. Practice Bulletin No. 130, October 2012b

American College of Obstetricians and Gynecologists: Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455, March 2010, Reaffirmed 2013a

American College of Obstetricians and Gynecologists: Medically indicated late-preterm and early-term deliveries. Committee Opinion No. 560, April 2013b

American College of Obstetricians and Gynecologists: Nonmedically indicated early-term deliveries. Committee Opinion No. 561, April 2013c

American College of Obstetricians and Gynecologists: Premature rupture of membranes. Practice Bulletin No. 139, October 2013d

Amin SB, Sinkin RA, Glantz C: Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 197:486, 2007

Ananth CV, Joseph KS, Oyelese Y, et al: Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet Gynecol 105:1084, 2005

Ananth CV, Liu S, Joseph KS, et al: A comparison of foetal and infant mortality in the United States and Canada. Int J Epidemiol 38(2):480, 2009

Anderson GD, Bada HS, Sibai BM, et al: The relationship between labor and route of delivery in the preterm infant. Am J Obstet Gynecol 158:1382, 1988

Andrews WW, Goldenberg RL, Hauth JC, et al: Interconceptional antibiotics to prevent spontaneous preterm birth: a randomized clinical trial. Am J Obstet Gynecol 194:617, 2006

Andrews WW, Hauth JC, Goldenberg RL, et al: Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol 173:606, 1995

Andrews WW, Sibai BM, Thom EA, et al: Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 101:847, 2003

Angel JL, O’Brien WF, Knuppel RA, et al: Carbohydrate intolerance in patients receiving oral tocolytics. Am J Obstet Gynecol 159:762, 1988

Annas GJ: Extremely preterm birth and parental authority to refuse treatment—the case of Sidney Miller. N Engl J Med 35:2118, 2004

Anum EA, Springel EH, Shriver MD, et al: Genetic contributions to disparities in preterm birth. Pediatr Res 65(1):1, 2009

Arechavaleta-Velasco F, Mayon-Gonzalez J, Gonzalez-Jimenez M, et al: Association of type II apoptosis and 92-kDa type IV collagenase expression in human amniochorion in prematurely ruptured membranes with tumor necrosis factor receptor-1 expression. J Soc Gynecol Investig 9:60, 2002

Bailit JL, Iams J, Silber A, et al: Changes in the indications for scheduled births to reduce nonmedically indicated deliveries occurring before 39 weeks of gestation. Obstet Gynecol 120:241, 2012

Beigi RH, Austin MN, Meyn LA, et al: Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol 191:1124, 2004

Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. BJOG 101:262, 1994

Berghella V, Odibo AO, To MS, et al: Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 106(1):181, 2005

Berghella V, Rust OA, Althuisius SM: Short cervix on ultrasound: does indomethacin prevent preterm birth? Am J Obstet Gynecol 195:809, 2006

Berkman ND, Thorp JM, Lohr KN, et al: Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol 188:1648, 2003

Biggio JR: Bed rest in pregnancy: time to put the issue to rest. Obstet Gynecol 1212(6):1158, 2013

Bisits A, Madsen G, Knox M, et al: The randomized nitric oxide tocolysis trial (RNOTT) for the treatment of preterm labor. Am J Obstet Gynecol 191:683, 2004

Bloom SL, Yost NP, McIntire DD, et al: Recurrence of preterm birth in singleton and twin pregnancies. Obstet Gynecol 98:379, 2001

Bruschettini M, van den Hove DL, Gazzolo D, et al: Lowering the dose of antenatal steroids: the effects of a single course of betamethasone on somatic growth and brain cell proliferation in the rat. Am J Obstet Gynecol 194:1341, 2006

Buekens P, Alexander S, Boutsen M, et al: Randomised controlled trial of routine cervical examinations in pregnancy. Lancet 344:841, 1994

Bullard I, Vermillion S, Soper D: Clinical intraamniotic infection and the outcome for very low birth weight neonates [Abstract]. Am J Obstet Gynecol 187:S73, 2002

Buxton IL, Singer CA, Tichenor JN: Expression of stretch-activated two-pore potassium channels in human myometrium in pregnancy and labor. PLoS One 5(8):e12372, 2010

Canadian Preterm Labor Investigators Group: Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 327:308, 1992

Carey JC, Klebanoff MA: Is a change in the vaginal flora associated with an increased risk of preterm birth? Am J Obstet Gynecol 192(4):1341, 2005

Caritis SN, Rouse DJ, Peaceman AM, et al: Prevention of preterm birth in triplets using 17alpha-hydroxyprogesterone caproate. Obstet Gynecol 113:285, 2009

Carlan SJ, O’Brien WF, Parsons MT, et al: Preterm premature rupture of membranes: a randomized study of home versus hospital management. Obstet Gynecol 81:61, 1993

Carroll SG, Blott M, Nicolaides KH: Preterm prelabor amniorrhexis: outcome of live births. Obstet Gynecol 86:18, 1995

Carroll SG, Papaionnou S, Ntumazah IL, et al: Lower genital tract swabs in the prediction of intrauterine infection in preterm prelabour rupture of the membranes. BJOG 103:54, 1996

Casanueva E, Ripoll C, Meza-Camacho C, et al: Possible interplay between vitamin C deficiency and prolactin in pregnant women with premature rupture of membranes: facts and hypothesis. Med Hypotheses 64:241, 2005

Casey ML, Cox SM, Word RA, et al: Cytokines and infection-induced preterm labour. Reprod Fertil Devel 2:499, 1990

Casey ML, MacDonald PC: Biomolecular mechanisms in human parturition: Activation of uterine decidua. In d’Arcangues C, Fraser IS, Newton JR, Odlind V (eds): Contraception and Mechanisms of Endometrial Bleeding. Cambridge, England, Cambridge University Press, 1990, p 501

Casey ML, MacDonald PC: Transforming growth factor-beta inhibits progesterone-induced enkephalinase expression in human endometrial stromal cells. J Clin Endocrinol Metab 81:4022, 1996

Chaim W, Mazor M: Intraamniotic infection with fusobacteria. Arch Gynecol Obstet 251:1, 1992

Challis JR, Sloboda DM, Alfaidy N, et al: Prostaglandins and mechanisms of preterm birth. Reproduction 124:1, 2002

Chao TT, Bloom SL, Mitchell JS, et al: The diagnosis and natural history of false preterm labor. Obstet Gynecol 118(6):1301, 2011

Christian LM: Psychoneuroimmunology in pregnancy: immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development. Neurosci Biobehav Rev 36(1):350, 2012a

Christian LM, Iams JD, Porter K, et al: Epstein-Barr virus reactivation during pregnancy and postpartum: effects of race and racial discrimination. Brain Behav Immun 26(8), 1280, 2012b

Chuang TH, Ulevitch RJ: Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8, and hTLR9. Eur Cytokine Netw 11:372, 2000

Clavin DK, Bayhi DA, Nolan TE, et al: Comparison of intravenous magnesium sulfate and nitroglycerin for preterm labor: preliminary data. Am J Obstet Gynecol 174:307, 1996

Cnattingius S, Villamor E, Johansson S, et al: Maternal obesity and risk of preterm delivery. JAMA 309(22):2362, 2013

Collaborative Home Uterine Monitoring Study Group: A multicenter randomized controlled trial of home uterine monitoring: active versus sham device. Am J Obstet Gynecol 173:1170, 1995

Collins JW Jr, David RJ, Simon DM, et al: Preterm birth among African American and white women with a lifelong residence in high-income Chicago neighborhoods: an exploratory study. Ethn Dis 17(1):113, 2007

Conde-Agudelo A, Rosas-Bermúdez A, Kafury-Goeta AC: Birth spacing and risk of adverse perinatal outcomes: a meta-analysis. JAMA 295:1809, 2006

Consortium on Safe Labor: Respiratory morbidity in preterm births. JAMA 301(1):419, 2010

Cook CM, Ellwood DA: A longitudinal study of the cervix in pregnancy using transvaginal ultrasound. BJOG 103:16, 1996

Copper RL, Goldenberg RL, Dubard MB, et al: Cervical examination and tocodynamometry at 28 weeks’ gestation: prediction of spontaneous preterm birth. Am J Obstet Gynecol 172:666, 1995

Cotton DB, Strassner HT, Hill LM, et al: Comparison between magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor: a randomized study. J Reprod Med 29:92, 1984

Cox SM, Leveno KJ: Intentional delivery versus expectant management with preterm ruptured membranes at 30–34 weeks’ gestation. Obstet Gynecol 86:875, 1995

Cox SM, Sherman ML, Leveno KJ: Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 163:767, 1990

Cox SM, Williams ML, Leveno KJ: The natural history of preterm ruptured membranes: what to expect of expectant management. Obstet Gynecol 71:558, 1988

Crowther CA, Doyle LW, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 357:1179, 2007

Crowther CA, Hiller JE, Doyle LW, et al: Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 290:2669, 2003

Crowther CA, McKinlay CJ, Middleton P, et al: Repeat doses of prenatal corticosteroids for women at risk for preterm birth for improving neonatal health outcomes. Cochran Database Syst Rev 6:CD003935, 2011

Culhane JF, Rauh V, McCollum KF, et al: Exposure to chronic stress and ethnic differences in rates of bacterial vaginosis among pregnant women. Am J Obstet Gynecol 187(5):1272, 2002

Devlieger R, Millar LK, Bryant-Greenwood G, et al: Fetal membrane healing after spontaneous and iatrogenic membrane rupture: a review of current evidence. Am J Obstet Gynecol 195:1512, 2006

Dinarello CA: The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 20:S1, 2002

Dolan SM, Gross SJ, Merkatz IR, et al: The contribution of birth defects to preterm birth and low birth weight. Obstet Gynecol 110:318, 2007

Doyle LW, Crowther CA, Middleton S, et al: Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 1:CD004661, 2009

Eichenwald EC, Stark AR: Management and outcomes of very low birth weight. N Engl J Med 358(16):1700, 2008

El-Bastawissi AY, Williams MA, Riley DE, et al: Amniotic fluid interleukin-6 and preterm delivery: a review. Obstet Gynecol 95:1056, 2000

Elimian A, Garry D, Figueroa R, et al: Antenatal betamethasone compared with dexamethasone (Betacode Trial): a randomized controlled trial. Obstet Gynecol 110:26, 2007

Elliott JP, Istwan NB, Rhea D, et al: The occurrence of adverse events in women receiving continuous subcutaneous terbutaline therapy. Am J Obstet Gynecol 191:1277, 2004

El-Sayed Y, Riley ET, Holbrook RH, et al: Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor. Obstet Gynecol 93:79, 1999

Esplin MS, Romero R, Chaiworapongsa T, et al: Amniotic fluid levels of immunoreactive monocyte chemotactic protein-1 increase during term parturition. J Matern Fetal Neonatal Med 14:51, 2003

Esplin MS, Varner MW: Genetic factors in preterm birth—the future. BJOG 112 Suppl 1):97, 2005

Fanaroff AA, Stoll BJ, Wright LL, et al: Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196:e1.147, 2007

Farooqi A, Holmgren PA, Engberg S, et al: Survival and 2-year outcome with expectant management of second trimester rupture of membranes. Obstet Gynecol 92:895, 1998

Feinstein SJ, Vintzileos AM, Lodeiro JG, et al: Amniocentesis with premature rupture of membranes. Obstet Gynecol 68:147, 1986

Fletcher SE, Fyfe DA, Case CL, et al: Myocardial necrosis in a newborn after long-term maternal subcutaneous terbutaline infusion for suppression of preterm labor. Am J Obstet Gynecol 165:1401, 1991

Fonseca EB, Celik E, Para M, et al: Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 357:462, 2007

Fortunato SJ, Menon R: IL-1 beta is a better inducer of apoptosis in human fetal membranes than IL-6. Placenta 24:922, 2003

Fortunato SJ, Menon R, Lombardi SJ: MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. J Perinat Med 27:362, 1999a

Fortunato SJ, Menon R, Lombardi SJ: Role of tumor necrosis factor-alpha in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol 187:1159, 2002

Fortunato SJ, Menon R, Lombardi SJ: Stromelysins in placental membranes and amniotic fluid with premature rupture of membranes. Obstet Gynecol 94:435, 1999b

Fuchs K, Albright C, Scott K, et al: Obstetric factors affecting respiratory morbidity among late preterm infants. Am J Obstet Gynecol 199(6SA):S63, 2008

Gajer P, Brotman RM, Bai G, et al: Temporal dynamics of the human vaginal microbiota. Sci Transl Med 4(132):132ra52, 2012

Gardner MO, Owen J, Skelly S, et al: Preterm delivery after indomethacin: a risk factor for neonatal complications? J Reprod Med 41:903, 1996

Garite TJ, Freeman RK, Linzey EM, et al: Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation. Am J Obstet Gynecol 141:508, 1981

Garite TJ, Keegan KA, Freeman RK, et al: A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation. Am J Obstet Gynecol 157:388, 1987

Garite TJ, Kurtzmann J, Maurel K, et al: Impact of a “rescue course” of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 200:248.e.1, 2009

Goya M, Pratcorona L, Merced C, et al: Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 379(9828):1790, 2012

Gerber S, Vial Y, Hohlfeld P, et al: Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis 187:518, 2003

Gibson CS, MacLennan AH, Dekker GA, et al: Genetic polymorphisms and spontaneous preterm birth. Obstet Gynecol 109:384, 2007

Gielchinsky Y, Mankuta D, Samueloff A, et al: First pregnancy in women over 45 years of age carries increased obstetrical risk [Abstract]. Am J Obstet Gynecol 187:S87, 2002

Gluck L: Fetal lung maturity. Paper presented at the 78th Ross Conference on Pediatric Research, San Diego, May 1979

Goepfert AR, Jeffcoat MK, Andrews W, et al: Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet Gynecol 104:777, 2004

Goldenberg RL: The management of preterm labor. Obstet Gynecol 100:1020, 2002

Goldenberg RL, Cliver SP, Bronstein J, et al: Bed rest in pregnancy. Obstet Gynecol 84:131, 1994

Goldenberg RL, Culhane JF, Iams JD, et al: Preterm birth 1: epidemiology and causes of preterm birth. Lancet 371:75, 2008

Goldenberg RL, Hauth JC, Andrews WW: Intrauterine infection and preterm delivery. N Engl J Med 342:1500, 2000

Goldenberg RL, Iams JD, Miodovnik M, et al: The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 175:1047, 1996

Goldenberg RL, Mwatha A, Read JS, et al: The HPTN 024 Study: the efficacy of antibiotics to prevent chorioamnionitis and preterm birth. Am J Obstet Gynecol 194:650, 2006

Gomez R, Romero R, Edwin SS, et al: Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am 11:135, 1997

Gomez R, Romero R, Glasasso M, et al: The value of amniotic fluid interleukin-6, white blood cell count, and gram stain in the diagnosis of microbial invasion of the amniotic cavity in patients at term. Am J Reprod Immunol 32:200, 1994

Goncalves LF, Chaiworapongsa T, Romero R: Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 8:3, 2002

Gonzalez JM, Xu H, Ofori E, et al: Toll-like receptors in the uterus, cervix, and placenta: is pregnancy an immunosuppressed state? Am J Obstet Gynecol 197(3):296, 2007

Goodwin TM: The Gordian knot of developing tocolytics. J Soc Gynecol Investig 11(6)339, 2004

Goodwin TM, Millar L, North L, et al: The pharmacokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions. Am J Obstet Gynecol 173:913, 1995

Gotsch F, Romero R, Kusanovic JP, et al: The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: a role for interleukin-10. J Matern Fetal Neonatal Med 21(8):529, 2008

Goulet C, Gevry H, Lemay M, et al: A randomized clinical trial of care for women with preterm labour: home management versus hospital management. CMAJ 164:985, 2001

Goya M, Pratcorona L, Merced C, et al: Cervical pessary in pregnancy women with a short cervix (PECEP): an open-label randomized controlled trial. Lancet 379(9828):1800, 2012

Gravett MG, Adams KM, Sadowsky DW, et al: Immunomodulators plus antibiotics delay preterm delivery after experimental intraamniotic infection in a nonhuman primate model. Am J Obstet Gynecol 197(5):518.e1, 2007

Gravett MG, Hitti J, Hess DL, et al: Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. Am J Obstet Gynecol 182:1404, 2000

Grether JK, Hoogstrate J, Walsh-Greene E, et al: Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia. Am J Obstet Gynecol 183:717, 2000

Grimes DA, Nanda K: Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 108:986, 2006

Grobman WA, Gilbert SA, Iams JD, et al: Activity restriction among women with a short cervix. Obstet Gynecol 121:1181, 2013

Grobman WA, Thom EA, Spong CY, et al: 17alpha-Hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol 207(5):390e.1, 2012

Grobman WA, Welshman EE, Calhoun EA: Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Obstet Gynecol 191:235, 2004

Gross G, Imamura T, Vogt SK, et al: Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. Am J Physiol Regul Integr Comp Physiol 278(6):R1415, 2000

Guillen Ú, DeMauro S, Ma L, et al: Survival rates in extremely low birthweight infants depend on the denominator: avoiding potential for bias by specifying denominators. Am J Obstet Gynecol 205:328.e1, 2011

Guinn DA, Goepfert AR, Owen J, et al: Terbutaline pump maintenance therapy for prevention of preterm delivery: a double-blind trial. Am J Obstet Gynecol 179:874, 1998

Gyetvai K, Hannah ME, Hodnett ED, et al: Tocolytics for preterm labor: a systematic review. Obstet Gynecol 94:869, 1999

Hadi HA, Hodson CA, Strickland D: Premature rupture of the membranes between 20 and 25 weeks’ gestation: role of amniotic fluid volume in perinatal outcome. Am J Obstet Gynecol 170:1139, 1994

Hallak M, Bottoms SF: Accelerated pulmonary maturation from preterm premature rupture of membranes: a myth. Am J Obstet Gynecol 169:1045, 1993

Hamilton S, Oomomian Y, Stephen G, et al: Macrophages infiltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor. Biol Reprod 86(2):39, 2012

Hampton T: Genetic link found for premature birth risk. JAMA 296:1713, 2006

Hankins GD, Hauth JC, Cissik JH, et al: Effects of ritodrine hydrochloride on arteriovenous blood gas and shunt in healthy pregnant yellow baboons. Am J Obstet Gynecol 158:658, 1988

Harger JM: Cervical cerclage: patient selection, morbidity, and success rates. Clin Perinatol 10: 321, 1983

Hassan SS, Romero R, Vidyadhari D, et al: Vaginal progesterone reduces the rate of preterm birth in women with sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 38:18, 2011

Hedegaard M, Henriksen TB, Sabroe S, et al: Psychological stress in pregnancy and preterm delivery. BMJ 307(6898):234, 1993

Heine RP, McGregor JA, Goodwin TM, et al: Serial salivary estriol to detect an increased risk of preterm birth. Obstet Gynecol 96:490, 2000

Hillier SL, Martius J, Krohn M, et al: A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 319:972, 1988

Hillier SL, Nugent RP, Eschenbach DA, et al: Association between bacterial vaginosis and preterm delivery of a low-birthweight infant. N Engl J Med 333:1737, 1995

Himes KP, Simhan HN: Plasma corticotropin-releasing hormone and cortisol concentrations and perceived stress among pregnant women with preterm and term birth. Am J Perinatol 28(6):443, 2011

Hitti J, Tarczy-Hornoch P, Murphy J, et al: Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks’ gestation or less. Obstet Gynecol 98:1080, 2001

Ho M, Ramsey P, Brumfield C, et al: Changes in maternal and neonatal infectious morbidity as latency increases after preterm premature rupture of membranes [Abstract]. Obstet Gynecol 101:41S, 2003

Hobel C, Culhane J: Role of psychosocial and nutritional stress on poor pregnancy outcome. J Nutr 133:1709S, 2003

Holmlund U, Cabers G, Dahlfors AR, et al: Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 107:145, 2002

Holt R, Timmons BC, Akgul Y, et al: The molecular mechanisms of cervical ripening differ between term and preterm birth. Endocrinology 152:1036, 2011

Holzman C, Jetton J, Siler-Khodr T, et al: Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity. Obstet Gynecol 97:657, 2001

How HY, Hughes SA, Vogel RL, et al: Oral terbutaline in the outpatient management of preterm labor. Am J Obstet Gynecol 173:1518, 1995

How HY, Zafaranchi L, Stella CL, et al: Tocolysis in women with preterm labor between 320/7 and 346/7 weeks of gestation: a randomized controlled pilot study. Am J Obstet Gynecol 194:976, 2006

Hua R, Pease JE, Cheng W, et al: Human labour is associated with decline in myometrial chemokine receptor expression: the role of prostaglandins, oxytocin, and cytokines. Am J Reprod Immunol 69:21, 2013

Hudgens DR, Conradi SE: Sudden death associated with terbutaline sulfate administration. Am J Obstet Gynecol 169:120, 1993

Hui SYA, Chor CM, Lau TK, et al: Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial. Am J Perinatol 30:283, 2013

Iams JD, Clapp DH, Contox DA, et al: Does extraamniotic infection cause preterm labor? Gas-liquid chromatography studies of amniotic fluid in amnionitis, preterm labor, and normal controls. Obstet Gynecol 70:365, 1987

Iams JD, Goldenberg RL, Meis PJ, et al: The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 334:567, 1996

Iams JD, Johnson FF, Parker M: A prospective evaluation of the signs and symptoms of preterm labor. Obstet Gynecol 84:227, 1994

Iams JD, Newman RB, Thom EA, et al: Frequency of uterine contractions and the risk of spontaneous preterm birth. N Engl J Med 346:250, 2002

Iams JD, Stilson R, Johnson FF, et al: Symptoms that precede preterm labor and preterm premature rupture of the membranes. Am J Obstet Gynecol 162:486, 1990

Ingelfinger JR: Prematurity and the legacy of intrauterine stress. N Engl J Med 356:2093, 2007

Institute of Medicine: Preterm Birth: Causes, Consequences, and Prevention. Washington, National Academies Press, 2007

Jacobsson B, Holst RM, Wennerholm UR, et al: Monocyte chemotactic protein-1 in cervical and amniotic fluid: relationship to microbial invasion of the amniotic cavity, intraamniotic inflammation, and preterm delivery. Am J Obstet Gynecol 189:1161, 2003

Janssens S, Beyaert R: Role of Toll-like receptors in pathogen recognition. Clin Microbiol Rev 16:637, 2003

Joseph KS, Huang L, Liu S, et al: Reconciling the high rates of preterm and postterm birth in the United States. Obstet Gynecol 109(4):813, 2007

Keelan JA, Blumenstein M, Helliwell RJ, et al: Cytokines, prostaglandins and parturition—a review. Placenta 24:S33, 2003

Keirse MJNC: Calcium antagonists vs. betamimetics in preterm labour. In Neilson JP, Crowther C, Hodnett ED, et al (eds): Pregnancy and Childbirth Module. Cochrane Database System Review Issue 2. Oxford, Update Software, 1995a

Keirse MJNC: New perspectives for the effective treatment of preterm labor. Am J Obstet Gynecol 173:618, 1995b

Kent AS, Sullivan MH, Elder MG: Transfer of cytokines through human fetal membranes. J Reprod Fertil 100:81, 1994

Kenyon S, Boulvain M, Neilson J: Antibiotics for preterm rupture of the membranes: a systematic review. Obstet Gynecol 104:1051, 2004

Kenyon S, Pike K, Jones DR, et al: Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 372:1310, 2008a

Kenyon S, Pike K, Jones DR, et al: Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 372:1319, 2008b

Kenyon SL, Taylor DJ, Tarnow-Mordi, et al: Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomized trial. Lancet 357:989, 2001

Kimberlin DF, Hauth JC, Goldenberg RL, et al: Relationship of acid–base status and neonatal morbidity in 1000 g infants. Am J Obstet Gynecol 174:382, 1996

King J, Flenady V: Antibiotics for preterm labour with intact membranes. Cochrane Database Syst Rev 2:CD000246, 2000

King JF, Flenady V, Papatsonis D, et al: Calcium channel blockers for inhibiting preterm labour: a systematic review of the evidence and a protocol for administration of nifedipine. Aust N Z J Obstet Gynaecol 43:192, 2003

Koopmans CM, Bijilenga D, Groen H, et al: Induction of labour versus expectant monitoring for gestation hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet 374:979, 2009

Korita D, Sagawa N, Itoh H, et al: Cyclic mechanical stretch augments prostacyclin production in cultured human uterine myometrial cells from pregnant women: possible involvement of up-regulation of prostacyclin synthase expression. J Clin Endocrinol Metab 87:5209, 2002

Kovacevich GJ, Gaich SA, Lavin JP, et al: The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes. Am J Obstet Gynecol 182:1089, 2000

Kragt H, Keirse MJ: How accurate is a woman’s diagnosis of threatened preterm delivery? BJOG 97:317, 1990

Kramer MS, Coates AL, Michoud MC, et al: Maternal anthropometry and idiopathic preterm labor. Obstet Gynecol 86:744, 1995

Kurki T, Sivonen A, Renkonen OV, et al: Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 80:173, 1992

Kurtzman J, Garite T, Clark R, et al: Impact of a “rescue course” of antenatal corticosteroids (ACS): a multi-center randomized placebo controlled trial. Am J Obstet Gynecol 200(3):248.e1, 2009

Kurtzman JL, Thorp JM Jr, Spielman FJ, et al: Do nifedipine and verapamil potentiate the cardiac toxicity of magnesium sulfate? Am J Perinatol 10:450, 1993

Lam F, Gill P, Smith M, et al: Use of the subcutaneous terbutaline pump for long-term tocolysis. Obstet Gynecol 72:810, 1988

Lee HC, Gould JB: Survival advantage associated with cesarean delivery in very low birth weight vertex neonates. Obstet Gynecol 107:97, 2006

Lee SE, Romero R, Jung H: The intensity of the fetal inflammatory response in intraamniotic inflammation with and without microbial invasion of the amniotic cavity. Am J Obstet Gynecol 197(3):294, 2007

Lee SE, Romero R, Park CW: The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol 198(6):633, 2008

Lees CC, Lojacono A, Thompson C, et al: Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. Obstet Gynecol 94:403, 1999

Leeson SC, Maresh MJA, Martindale EA, et al: Detection of fetal fibronectin as a predictor of preterm delivery in high risk symptomatic pregnancies. BJOG 103:48, 1996

Leitich H, Bodner-Adler B, Brunbauer M, et al: Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 189:139, 2003a

Leitich H, Brunbauer M, Bodner-Adler B, et al: Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 188:752, 2003b

Leung TN, Chung TK, Madsen G, et al: Rate of rise in maternal plasma corticotrophin-releasing hormone and its relation to gestational length. BJOG 108:527, 2001

Leveno KJ, Klein VR, Guzick DS, et al: Single-centre randomised trial of ritodrine hydrochloride for preterm labour. Lancet 1:1293, 1986

Leveno KJ, McIntire DD, Bloom SL, et al: Decreased preterm births in an inner-city public hospital. Obstet Gynecol 113(3):578, 2009

Lewis DF, Adair CD, Robichaux AG, et al: Antibiotic therapy in preterm premature rupture of membranes: are seven days necessary? A preliminary, randomized clinical trial. Am J Obstet Gynecol 188:1413, 2003

Lewis DF, Robichaux AG, Jaekle RK, et al: Expectant management of preterm premature rupture of membranes and nonvertex presentation: what are the risks? Am J Obstet Gynecol 196:566, 2007

Lewis R, Mercer BM, Salama M, et al: Oral terbutaline after parenteral tocolysis: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol 175:834, 1996

Li D, Liu L, Odouli R: Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study. Hum Reprod 24:146, 2008

Li D-K, Odouli R, Liu L, et al: Transmission of parentally shared human leukocyte antigen alleles and the risk of preterm delivery. Obstet Gynecol 104:594, 2004

Lieman JM, Brumfield CG, Carlo W, et al: Preterm premature rupture of membranes: is there an optimal gestational age for delivery? Obstet Gynecol 105:12, 2005

Liggins GC, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50:515, 1972

Likis FE, Velez Edwards DR, Andrews JC, et al: Progestogens for preterm birth prevention. Obstet Gynecol 120:897, 2012

Littleton HL, Breitkopf CR, Berenson AB: Correlates of anxiety symptoms during pregnancy and association with perinatal outcomes: a meta-analysis. Am J Obstet Gynecol 196:424, 2007

Lobel M: Conceptualizations, measurement, and effects of prenatal maternal stress on birth outcomes. J Behav Med 17:225, 1994

Locatelli A, Ghidini A, Paterlini G, et al: Gestational age at preterm premature rupture of membranes: a risk factor for neonatal white matter damage. Am J Obstet Gynecol 193:947, 2005

Lockwood CJ: Stress-associated preterm delivery: the role of corticotropin-releasing hormone. Am J Obstet Gynecol 180:S264, 1999

Lockwood CJ, Senyei AE, Dische MR, et al: Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 325:669, 1991

Loe SM, Sanchez-Ramos L, Kaunitz AM: Assessing the neonatal safety of indomethacin tocolysis: a systematic review with meta-analysis. Obstet Gynecol 106:173, 2005

Low JA, Panagiotopoulos C, Derrick EJ: Newborn complication after intrapartum asphyxia with metabolic acidosis in the preterm fetus. Am J Obstet Gynecol 172:805, 1995

Luke B, Mamelle N, Keith L, et al: The association between occupational factors and preterm birth: a United States nurses study. Am J Obstet Gynecol 173:849, 1995

Lyall F, Lye S, Teoh T, et al: Expression of Gsalpha, connexin-43, connexin-26, and EP1, 3, and 4 receptors in myometrium of prelabor singleton versus multiple gestations and the effects of mechanical stretch and steroids on Gsalpha. J Soc Gynecol Investi 9:299, 2002

Lyell DJ, Pullen K, Campbell L, et al: Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol 1108:61, 2007

Macones GA, Berlin M, Berlin JA: Efficacy of oral beta-agonist maintenance therapy in preterm labor: a meta-analysis. Obstet Gynecol 85:313, 1995

Macones GA, Parry S, Elkousy M, et al: A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 190:1504, 2004

Major CA, Towers CW, Lewis DF, et al: Expectant management of preterm premature rupture of membranes complicated by active recurrent genital herpes. Am J Obstet Gynecol 188:1551, 2003

Malloy MH, Onstad L, Wright E: The effect of cesarean delivery on birth outcome in very low birth weight infants. Obstet Gynecol 77:498, 1991

Marret S, Marpeau L, Bénichou J: Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 121(1):225, 2008

Martin JA, Hamilton BE, Sutton PD, et al: Births: final data for 2004. Natl Vital Stat Rep 55(1):1, 2006

Martin JA, Hamilton BE, Sutton PD, et al: Births: final data for 2006. Natl Vital Stat Rep 57(7):1, 2009a

Martin JA, Hamilton BE, Ventura SJ, et al: Births: final data for 2009. Natl Vital Stat Rep 60:1, 2011

Martin JA, Kirmeyer S, Osterman M, et al: Born a bit too early: recent trends in later preterm births. NCHS Data Brief 24:1, 2009b

Martin JA, Menacker F: Expanded health data from the new birth certificate, 2004. Natl Vital Stat Rep 55(12):1, 2007

Mathews TJ, MacDorman MF: Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep 61(8):1, 2013

Maymon E, Romero R, Pacora P, et al: Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes. Am J Obstet Gynecol 183(4):914, 2000

McCall CA, Grimes DA, Drapkin Lyerly A: “Therapeutic” bed rest in pregnancy unethical and unsupported by data. Obstet Gynecol 121:1305, 2013

McElrath TF, Allred E, Leviton A: Prolonged latency after preterm premature rupture of membranes: an evaluation of histologic condition and intracranial ultrasonic abnormality in the neonate born at < 28 weeks of gestation. Am J Obstet Gynecol 189:794, 2003

McElrath TF, Norwitz ER, Lieberman ES, et al: Perinatal outcome after preterm premature rupture of membranes with in situ cervical cerclage. Am J Obstet Gynecol 187:1147, 2002

McEvoy C, Schilling D, Segel S, et al: Improved respiratory compliance in preterm infants after a single rescue course of antenatal steroids: a randomized trial. Am J Obstet Gynecol 202(6):544.e1, 2010

McGrath S, McLean M, Smith D, et al: Maternal plasma corticotropin-releasing hormone trajectories vary depending on the cause of preterm delivery. Am J Obstet Gynecol 186:257, 2002

McGrath S, Smith R: Prediction of preterm delivery using plasma corticotrophin-releasing hormone and other biochemical variables. Ann Med 34:28, 2002

McGregor JA, Jackson GM, Lachelin GC, et al: Salivary estriol as risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol 173:1337, 1995

McIntire DD, Leveno KJ: Neonatal mortality and morbidity rates in later preterm births compared with births at term. Obstet Gynecol 111:35, 2008

McLean M, Bisits A, Davies J, et al: A placental clock controlling the length of human pregnancy. Nat Med 1(5):460, 1995

Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm delivery by 17alpha-hydroxyprogesterone caproate. N Engl J Med 348:2379, 2003

Meis PJ, Michielutte R, Peters TJ, et al: Factors associated with preterm birth in Cardiff, Wales, I. Univariable and multivariable analysis. Am J Obstet Gynecol 173:590, 1995

Mercer BM: Preterm premature rupture of the membranes. Obstet Gynecol 101:178, 2003

Mercer BM, Arheart KL: Antimicrobial therapy in expectant management of preterm premature rupture of the membranes. Lancet 346:1271, 1995

Mercer BM, Carr TL, Beazley DD, et al: Antibiotic use in pregnancy and drug-resistant infant sepsis. Am J Obstet Gynecol 181:816, 1999

Mercer BM, Crocker LG, Boe NM, et al: Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol 169:775, 1993

Mercer BM, Miodovnik M, Thurnau GR, et al: Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. JAMA 278:989, 1997

Merkatz IR, Peter JB, Barden TP: Ritodrine hydrochloride: a betamimetic agent for use in preterm labor, II. Evidence of efficacy. Obstet Gynecol 56:7, 1980

Michalowicz BS, Hodges JS, DiAngelis AJ, et al: Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 355:1885, 2006

Mittendorf R, Covert R, Boman J, et al: Is tocolytic magnesium sulfate associated with increased total paediatric mortality? Lancet 350:1517, 1997

Miyazaki K, Furuhashi M, Yoshida K, et al: Aggressive intervention of previable preterm premature rupture of membranes. Acta Obstet Gynaecol Scand 91(8):923, 2012

Moawad AH, Goldenberg RL, Mercer B, et al: The Preterm Prediction Study: the value of serum alkaline phosphatase, alpha-fetoprotein, plasma corticotropin-releasing hormone, and other serum markers for the prediction of spontaneous preterm birth. Am J Obstet Gynecol 186:990, 2002

Mogami H, Kishore AH, Shi H, et al: Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Biol Chem 288(3):1953, 2013

Montalbano AP, Hawgood S, Mendelson CR: Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inflammatory and contractile genes. Endocrinology 154(1):483, 2013

Morales WJ, Madhav H: Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 169:97, 1993a

Morales WJ, Smith SG, Angel JL, et al: Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Obstet Gynecol 74:567, 1989

Morales WJ, Talley T: Premature rupture of membranes at < 25 weeks: a management dilemma. Am J Obstet Gynecol 168:503, 1993b

Morency AM, Bujold E: The effect of second-trimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can 29:35, 2007

Moutquin JM, Sherman D, Cohen H, et al: Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 183:1191, 2000

Muench MV, Baschat AA, Kopelman J, et al: Indomethacin therapy initiated before 24 weeks of gestation for the prevention of preterm birth [Abstract]. Obstet Gynecol 101:65S, 2003

Muench V, Harman CR, Baschat AA, et al: Early fetal exposure to long term indomethacin therapy to prevent preterm delivery: neonatal outcome. Am J Obstet Gynecol 185:S149, 2001

Murphy KE: Betamethasone compared with dexamethasone for preterm birth: a call for trials. Obstet Gynecol 110:7, 2007

National Institutes of Health: Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement 17(2):1, 2000

Neggers Y, Goldenberg R, Cliver S, et al: Effects of domestic violence on preterm birth and low birth weight. Acta Obstet Gynecol Scand 83:455, 2004

Nelson KB, Grether JK: Can magnesium sulfate reduce the risk of cerebral palsy in very-low-birthweight infants? Pediatrics 95:263, 1995

Nelson LH, Anderson RL, O’Shea M, et al: Expectant management of preterm premature rupture of the membranes. Am J Obstet Gynecol 171:350, 1994

Nelson LH, Meis PJ, Hatjis CG, et al: Premature rupture of membranes: a prospective, randomized evaluation of steroids, latent phase, and expectant management. Obstet Gynecol 66:55, 1985

Ness RB, Hillier SL, Richter HE: Douching in relation to bacterial vaginosis, lactobacilli, and facultative bacteria in the vagina. Obstet Gynecol 100:765, 2002

Niebyl JR, Blake DA, White RD, et al: The inhibition of premature labor with indomethacin. Am J Obstet Gynecol 136:1014, 1980

Norton ME, Merrill J, Cooper BA, et al: Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 329:1602, 1993

Nugent RP, Krohn MA, Hillier SL: Reliability of diagnosing bacterial vaginosis by a standardized method of gram stain interpretation. J Clin Microbiol 29:297, 1991

O’Brien JM, Adair CD, Lewis DF, et al: Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 30:687, 2007

Okun N, Gronau KA, Hannah ME: Antibiotics for bacterial vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol 105:857, 2005

Olson DM, Zaragoza DB, Shallow MC: Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor—a review. Placenta 24:S47, 2003

Osterman MJ, Martin JA, Mathews TJ, et al: Expanded data from the new birth certificate, 2008. Natl Vital Stat Rep 59(7):1, 2011

Owen J, Baker SL, Hauth JC, et al: Is indicated or spontaneous preterm delivery more advantageous for the fetus? Am J Obstet Gynecol 163:868, 1990

Owen J, Hankins G, Iams JD, et al: Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened mid-trimester cervical length. Am J Obstet Gynecol 201(4):375.e1, 2009

Park KH, Chaiworapongsa T, Kim YM, et al: Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity. J Perinat Med 31:12, 2003

Parker CR Jr, Stankovic AM, Goland RS: Corticotropin-releasing hormone stimulates steroidogenesis in cultured human adrenal cells. Mol Cell Endocrinol 155:19, 1999

Papatsonis DN, Van Geijn HP, Ader HJ, et al: Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 90:230, 1997

Parilla BV, Dooley SL, Minogue JP, et al: The efficacy of oral terbutaline after intravenous tocolysis. Am J Obstet Gynecol 169:965, 1993

Parilla BV, Grobman WA, Holtzman RB, et al: Indomethacin tocolysis and risk of necrotizing enterocolitis. Obstet Gynecol 96:120, 2000

Parry S, Simhan H, Elovitz M, et al: Universal maternal cervical length screening during the second trimester: pros and cons of a strategy to identify women at risk of spontaneous preterm delivery. Am J Obstet Gynecol 207(2):101, 2012

Peck T, Lutheran G: Long-term and short-term childhood health after long-term use of indomethacin in pregnancy. Am J Obstet Gynecol 189:S168, 2003

Peltoniemi OM, Kari MA, Tammela O, et al: Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics, 119:290, 2007

Pereira L, Cotter A, Gómez R, et al: Expectant management compared with physical examination-indicated cerclage (EM-PEC) in selected women with a dilated cervix at 140/7–256/7 weeks: results from the EM-PEC international cohort study. Am J Obstet Gynecol 197:483, 2007

Perry KG Jr, Martin RW, Blake PG, et al: Maternal mortality associated with adult respiratory distress syndrome. South Med J 91(5):441, 1998

Perry KG Jr, Morrison JC, Rust OA, et al: Incidence of adverse cardiopulmonary effects with low-dose continuous terbutaline infusion. Am J Obstet Gynecol 173:1273, 1995

Petraglia F, Imperatore A, Challis JRG: Neuroendocrine mechanisms in pregnancy and parturition. Endocrine Rev 31(6):783, 2010

Petrini JR, Dias T, McCormick MC, et al: Increased risk of adverse neurological development for late preterm infants. J Pediatr 154(2):169, 2009

Petrova A, Demissie K, Rhoads GG, et al: Association of maternal fever during labor with neonatal and infant morbidity and mortality. Obstet Gynecol 98:20, 2001

Phupong V, Kulmala L: Clinical course of preterm prelabor rupture of membranes in the era of prophylactic antibiotics. BMC Res Notes 5(1):515, 2012

Promislow JH, Hertz-Picciotto I, Schramm M, et al: Bed rest and other determinants of bone loss during pregnancy. Am J Obstet Gynecol 191:1077, 2004

Raju TN, Higgins RD, Stark AR, et al: Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics 118:1207, 2006

Reddy UM, Ko CW, Raju TN: Delivery indications at late-preterm gestations and infant mortality rates in the United States. Pediatrics 124(1):234, 2009

Reddy UM, Zhang J, Sun L, et al: Neonatal mortality by attempted route of delivery in early preterm birth. Am J Obstet Gynecol 207:117.e1, 2012

Romero R, Chaiworapongsa T, Espinoza J, et al: Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. Am J Obstet Gynecol 187:1125, 2002

Romero R, Espinoza J, Kusanovic JP, et al: The preterm parturition syndrome. BJOG 3:17, 2006

Romero R, Nores J, Mazor M, et al: Microbial invasion of the amniotic cavity during term labor. Prevalence and clinical significance. J Reprod Med 38:543, 1993

Romero R, Sibai BM, Sanchez-Ramos L, et al: An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 182:1173, 2000

Romero R, Stanczyk FZ: Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice. Am J Obstet Gynecol 208(6): 421, 2013

Rouse DJ: Magnesium sulfate for fetal neuroprotection. Am J Obstet Gynecol 205(4):296, 2011

Rouse DJ, Caritis SN, Peaceman AM, et al: A trial of 17alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 357:454, 2007

Rouse DJ, Hirtz DG, Thom E, et al: A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 359:895, 2008

Ruiz RJ, Fullerton J, Dudley DJ: The interrelationship of maternal stress, endocrine factors and inflammation on gestational length. Obstet Gynecol Surv 58:415, 2003

Salim R, Garmi G, Zohar N, et al: Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial. Obstet Gynecol 120(6):1323, 2012

Samol JM, Lambers DS: Magnesium sulfate tocolysis and pulmonary edema: the drug or the vehicle? Am J Obstet Gynecol 192:1430, 2005

Satin AJ, Leveno KJ, Sherman ML, et al: Maternal youth and pregnancy outcomes: middle school versus high school age groups compared to women beyond the teen years. Am J Obstet Gynecol 171:184, 1994

Schmidt B, Davis P, Moddemann D, et al: Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 344:1966, 2001

Segel SY, Miles AM, Clothier B, et al: Duration of antibiotic therapy after preterm premature rupture of fetal membranes. Am J Obstet Gynecol 189:799, 2003

Serenius F, Källén K, Blennow M, et al: Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden. JAMA 309(17):1810, 2013

Shynlova O, Nedd-Roderique T, Li Y, et al: Infiltration of myeloid cells into decidua is a critical early event in the labour cascade and post-partum uterine remodeling. J Cell Mol Med 17(2):311, 2013a

Shynlova O, Nedd-Roderique T, Li Y, et al: Myometrial immune cells contribute to term parturition, preterm labour and post-partum involution in mice. J Cell Mol Med 17(1):90, 2013b

Sibai BM: Magnesium sulfate for neuroprotection in patients at risk for early preterm delivery: not yet. Am J Obstet Gynecol 205(4):296, 2011

Silver RM, Cunningham FG: Deus ex Makena? Obstet Gynecol 117:1263, 2011

Smith R, Mesiano S, Chan EC, et al: Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. J Clin Endocrinol Metab 83:2916, 1998

Sooranna SR, Lee Y, Kim LU, et al: Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells. Mol Hum Reprod 10:109, 2004

Sosa C, Althabe F, Belizan J, et al: Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 1:CD003581, 2004

Spong CY: Defining “term” pregnancy. Recommendations from the Defining “Term” Pregnancy Workgroup. JAMA 309(23):2445, 2013

Spong CY: Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol 110:405, 2007

Stamilio DM, Chang JJ, Macones GA: Periodontal disease and preterm birth: do the data have enough teeth to recommend screening and preventive treatment? Am J Obstet Gynecol 196:93, 2007

Steer CM, Petrie RH: A comparison of magnesium sulfate and alcohol for the prevention of premature labor. Am J Obstet Gynecol 129:1, 1977

Steer P: The epidemiology of preterm labour. BJOG 112(1):1, 2005

Stiles AD: Prenatal corticosteroids—early gain, long-term questions. N Engl J Med 357:1248, 2007

St Louis Business Journal: KV Pharmaceutical files for Chapter 11 bankruptcy. August 6, 2012. Available at: http://www.bizjournals.com/stlouis/morning_call/2012/08/kv-pharmaceutical-files-for-chapter-11.html. Accessed September 4, 2013

Stoll BJ, Hansen NI, Bell EF, et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126:443, 2010

Stoll BJ, Hansen N, Fanaroff AA, et al: Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 347:240, 2002

Tattershell M, Cordeaux Y, Charnock-Jones DS, et al: Expression of gastrin-releasing peptide is increased by prolonged stretch of human myometrium, and antagonists of its receptor inhibit contractility. J Physiol 590(Pt 9):2018, 2012

Terkildsen MFC, Parilla BV, Kumar P, et al: Factors associated with success of emergent second-trimester cerclage. Obstet Gynecol 101:565, 2003

Timmons BC, Fairhurst AM, Mahendroo MS: Temporal changes in myeloid cells in the cervix during pregnancy and parturition. J Immunol 182(5):2700, 2009

Tita A, Owen J, Cliver S, et al: Decreasing temporal trends in adjusted preterm birth among women receiving prenatal care at a university-based health system. Am J Obstet Gynecol 204:S183, 2011

Tita AT, Cliver SP, Goepfert AR, et al: Clinical trial of interconceptional antibiotics to prevent preterm birth: subgroup analyses and possible adverse antibiotic-microbial interaction. Am J Obstet Gynecol 196:367, 2007

To MS, Alfirevic Z, Heath VCF, et al: Cervical cerclage for prevention of preterm delivery in women with short cervix: randomized controlled trial. Lancet 363(9424):1849, 2004

Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, et al: Differences in mortality between late-preterm and term singleton infants in the United States, 1995–2002. J Pediatr 151:450, 2007

U.S. Food and Drug Administration: FDA drug safety communication: new warnings against use of terbutaline to treat preterm labor. February 17, 2011. Available at: http://www.fda.gov/drugs/drugsafety/ucm243539.htm. Accessed September 4, 2013

U.S. Food and Drug Administration: FDA drug safety communication: FDA recommends against prolonged use of magnesium sulfate to stop pre-term labor due to bone changes in exposed babies. May 30, 2013. Available at: http://www.fda.gov/drugs/drugsafety/ucm35333.htm. Accessed September 4, 2013

Üstün C, Kocak I, Baris S, et al: Subclinical chorioamnionitis as an etiologic factor in preterm deliveries. Int J Obstet Gynecol 72:109, 2001

Varner MW, Esplin MS: Genetic factors in preterm birth—the future. BJOG 112(Suppl 1):28, 2005

Velez DR, Fortunato SJ, Williams SM, et al: Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth. Hum Mol Genet 17:1619, 2008

Vergnes J-N, Sixou M: Preterm low birthweight and maternal periodontal status: a meta-analysis. Am J Obstet Gynecol 196:135.e1, 2007

Wadhwa PD, Culhane JF, Rauh V, et al: Stress and preterm birth: neuroendocrine, immune/inflammatory, and vascular mechanisms. Matern Child Health J 5:119, 2001

Wang H, Parry S, Macones G, et al: A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. PNAS 103:13463, 2006

Wapner RJ, Sorokin Y, Mele L, et al: Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 357:1190, 2007

Ward K: Genetic factors in common obstetric disorders. Clin Obstet Gynecol 51:74, 2008

Warren JE, Silver RM, Dalton J, et al: Collagen 1A1 and transforming growth factor-β polymorphisms in women with cervical insufficiency. Obstet Gynecol 110:619, 2007

Warren WB, Goland RS, Wardlaw SL, et al: Elevated maternal plasma corticotropin releasing hormone levels in twin gestation. J Perinat Med 18:39, 1990

Watts DH, Krohn MA, Hillier SL, et al: The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 79:351, 1992

Weiss JL, Malone FD, Vidaver J, et al: Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am J Obstet Gynecol 190:745, 2004

Wenstrom K, Weiner CP, Merrill D, et al: A placebo controlled randomized trial of the terbutaline pump for prevention of preterm delivery. Am J Perinatol 14:87, 1997

Werner EF, Han CS, Savitz DA, et al: Health outcomes for vaginal compared with cesarean delivery of appropriately grown preterm neonates. Obstet Gynecol 121:1195, 2013

White BA, Creedon DJ, Nelson KE, et al: The vaginal microbiome in health and disease. Trends Endocrinol Metab 22(10):389, 2011

Winn HN, Chen M, Amon E, et al: Neonatal pulmonary hypoplasia and perinatal mortality in patients with mid-trimester rupture of amniotic membranes—a critical analysis. Am J Obstet Gynecol 182:1638, 2000

Wolfe CD, Patel SP, Linton EA, et al: Plasma corticotrophin-releasing factor (CRF) in abnormal pregnancy. BJOG 95:1003, 1988

Wu YY, Singer CA, Buxton ILO: Variants of stretch-activated two-pore potassium channel TREK-1 associated with preterm labor in humans. Biol Reprod 87(4):96, 2012

Yoon BH, Romero R, Park JS, et al: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 182:675, 2000

Yoon BH, Romero R, Park JS, et al: Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 179:1254, 1998

Yoon BH, Yang SH, Jun JK, et al: Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count. Obstet Gynecol 87:231, 1996

Yost NP, Bloom SL, McIntire DD, et al: Hospitalization for women with arrested preterm labor: a randomized trial. Obstet Gynecol 106:14, 2005

Yost NP, Bloom SL, Twickler DM, et al: Pitfalls in ultrasonic cervical length measurement for predicting preterm birth. Obstet Gynecol 93:510, 1999

Young A, Thomson AJ, Ledingham M, et al: Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod 66:445, 2002

Ziyan J, Huaibin R, Xiaotian M, et al: Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi. Acta Obstet Gynecol Scand 89(5):705, 2010

Zuckerman H, Reiss U, Rubinstein I: Inhibition of human premature labor by indomethacin. Obstet Gynecol 44:787, 1974