Spontaneous Preterm Labor and Delivery
Offer Erez
Talia Lanxberg
Tal Rafaeli Yehudai
Limor Besser
Elad Laron
Nandor Gabor Than
Arnon Wiznitzer
Introduction
Preterm birth (PTB) is a major global health problem and one of the most challenging obstetrical syndromes that affected 14.84 million (10.6%) of all live births in 2014, an increase of 0.8% in the prevalence of preterm deliveries since the year 2000.1 The highest rates of PTBs occur in Africa and North America; in the United States, the PTB rate increased from 9.8% in the year 2000 to 10.6% in 2014 (2.4% overall).1 The annual societal economic burden associated with PTB in the United States exceeded $26.2 billion in 2005,2 and it was estimated that employer-sponsored health plans spend an extra $6 billion on preterm neonates in 2013.3
Preterm parturition is a syndrome resulting from multiple underlining mechanisms, including intra-amniotic infection, inflammation, placental vascular disease, maternal antifetal rejection, cervical insufficiency, and progesterone deficiency,4,5,6 leading to the premature activation of the common pathway of parturition, and this poses a challenge in the identification of patient at risk, as well as the development of preventive strategies and treatments.7
PTB is the leading cause of perinatal morbidity and mortality worldwide,1,8 accounting for approximately 70% of neonatal and 36% of infant deaths in the United States.9,10,11 Neonates born preterm are at increased risk of short-term complications, such as respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), and sepsis, as well as long-term neonatal morbidity such as neurodevelopmental disorders and cerebral palsy.12,13,14,15,16,17,18
Preterm delivery can be either spontaneous or medically indicated due to maternal (ie, preeclampsia) or fetal (ie, fetal growth restriction) complications19,20,21,22,23 regardless of the gestational age at delivery. Spontaneous PTB accounts for 75% of all preterm deliveries20,24,25 and can be the end result of preterm labor (PTL) with intact membranes or preterm prelabor rupture of membranes (PPROM)26 (Figure 49.1). This chapter will discuss the epidemiology, underlying mechanisms of disease, clinical presentation, and management of the syndrome of spontaneous PTL with intact membranes.
Definitions
PTB is defined as a delivery occurring before 37 weeks of gestation.19,27 Although the upper cutoff of 37 weeks according to menstrual age is well accep ted,9,27,28 there is a debate regarding the lower cutoff. The World Health Organization (WHO) includes in its definition of preterm delivery all live births before 37 weeks of gestation regardless of gestational age at delivery. Other cutoffs at 22 or 24 weeks of gestation have been proposed in which the risk for neonatal death does not exceed 50% regardless of ethnicity or race27 (Figure 49.2). In the United States, the American College of Obstetricians and Gynecologists (ACOG) defines the lower cutoff for PTB at 20 0/7 weeks of gestation.9
The gestational age at which preterm delivery occurs has a direct effect on neonatal morbidity and mortality. Several cutoffs have been proposed to differentiate early from late PTB.9,27 The most used cutoffs are 32 or 34 weeks of gestation.29 Because the survival rate of neonates in developed countries born after 32 weeks of gestation is nearly 100%, and neonatal morbidity substantially declines at this gestational age,30 the use of 32 weeks of gestation as the cutoff for early PTB has been proposed.31 A WHO report defined moderate PTB as 32 to 36 6/7 weeks of gestation9 (Figure 49.2). However,
not all countries have well-developed neonatal intensive care units (NICUs); therefore, survival rates at 32 weeks of gestation are lower than in countries with advanced NICU capabilities. Given this variability, using the threshold set by the U.S. Centers for Disease Control and Prevention (CDC), 34 weeks of gestation, to distinguish between early- and late-preterm delivery32 may serve as a better cutoff for worldwide clinical and comparative epidemiological studies.
not all countries have well-developed neonatal intensive care units (NICUs); therefore, survival rates at 32 weeks of gestation are lower than in countries with advanced NICU capabilities. Given this variability, using the threshold set by the U.S. Centers for Disease Control and Prevention (CDC), 34 weeks of gestation, to distinguish between early- and late-preterm delivery32 may serve as a better cutoff for worldwide clinical and comparative epidemiological studies.
 Figure 49.1 Precursors of preterm birth. PROM, prelabor rupture of membranes. (Reprinted with permission from Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.) |
The incidence of preterm delivery can also be further stratified as (1) extreme prematurity, delivery before 28 weeks of gestation, accounting for 5% of preterm deliveries; (2) severe prematurity, delivery from 28 to 31 6/7 weeks, accounting for 15% of all preterm deliveries; (3) moderate prematurity, delivery between 32 and 33 6/7 weeks of gestation, accounting for about 20% of PTBs; and (4) near term, birth that occurs from 34 to 36 6/7 weeks of gestation and comprises the largest group, accounting for 60% to 70% of all preterm deliveries.8
Of interest, the definition of PTB as a delivery before 37 weeks of gestation lacks medical or biological meaning. Indeed, accumulating observations suggest that infants born between 37 and 39 weeks of gestation have a higher rate of respiratory complications than those delivered after 39 weeks and, therefore, should be considered “premature.” At the time of this publication, infants born between 37 and 39 weeks’ gestation are considered early term, and, as such, many professional societies recommend postponing elective induction of labor to 39 weeks of gestation.33,34
Neonates can also be defined according to their birthweights, which historically served to identify preterm newborns before the use of ultrasound dating of gestational age. The most common definitions are low birthweight (LBW), an infant who weighs less than 2500 g; very low birthweight (VLBW), an infant who weighs less than 1500 g; and extremely low birthweight (ELBW), an infant who weighs less than 1000 g.35
Epidemiology
In 2010, approximately 15 million infants were born prematurely.29 The overall prevalence of PTB for all live births worldwide was 11.1%, ranging from 5% to 18% depending on the geographic and demographic characteristics of the population tested.28,31 More than 60% of preterm babies were born in South Asia, Africa, and North America29 (Figure 49.3).
The rate of preterm deliveries in the United States increased from 11.2% in 1989 to 12.8% in 2004, then declined to 9.57% in 2014 (Figure 49.4), and increased again to 10.2% in 2018.36,37,38,39 While the rate of early (<34 weeks) PTB remained relatively constant over the past years (2.9% among singletons), the rate of late PTB (34-37 weeks) increased from 6.1% in 1990 to 7.1% in 2017.37 The CDC has proposed that this shift in prevalence may be the result of improved gestational dating by ultrasound, increased use of assisted reproductive technologies (ARTs), and indicated preterm deliveries due to obstetric complications.40
CLINICAL PRESENTATION
Risk Factors for PTB
The identification of patients at risk for preterm delivery has a significant role in its primary and secondary prevention. Because PTB is a syndrome that results from several underlying mechanisms, there is no single diagnostic test for it. Thus, the current
risk assessments for spontaneous PTB include a combination of maternal factors, prior obstetrical history, and current pregnancy risks.
risk assessments for spontaneous PTB include a combination of maternal factors, prior obstetrical history, and current pregnancy risks.
 Figure 49.2 Definitions and cutoffs applied for preterm births, stillbirths, and miscarriages. HIC, high-income countries; ICD, International Classification of Diseases; LMIC, low- and middle-income countries; WHO, World Health Organization. (Reprinted with permission from Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):2162-2172.) |
Maternal Risk Factors
Ethnicity
The risk for PTB is almost double among African Americans in comparison to other ethnic populations41 (Figure 49.4). The rate of PTB among African Americans in 2016 was 13.77%, while among Pacific Islanders it was 11.5%, and among non-Hispanic whites it was 9.04%.37 This disparity persists even after adjustment for social and medical risk factors.42,43,44,45 Indeed, African American women living in high-income neighborhoods in Chicago still have a twofold higher rate of PTB (at <37 weeks) than white women living in the same neighborhoods (relative risk [RR] 2.2; 95% confidence interval [CI] 1.7-2.9).46 Of note, Ananth et al reported that the preterm delivery rate was still almost double among African Americans (16%) than among whites (8.4%),42 suggesting that other factors aside from socioeconomic status contribute to the ethnic disparity in the preterm delivery rate.
The effect of African American origin on the risk for PTB is not limited to maternal ethnicity. African American paternal ethnicity also increases the risk for PTB. Indeed, in a cohort of 2,845,686 singleton deliveries, paternal African American origin was associated with an increased risk for PTB (odds ratio [OR] 1.2; 95% CI 1.1-1.3), regardless of maternal race.47 Similarly, a white mother
and African American father have a higher risk for preterm delivery (OR 1.17), as do an African American mother and white father (OR 1.37) and an African American mother and father (OR 1.78), when compared with white couples.48 Currently, there is no explanation for the observed ethnic disparity in the rate of PTB that exceeds the effect of socioeconomic status.
and African American father have a higher risk for preterm delivery (OR 1.17), as do an African American mother and white father (OR 1.37) and an African American mother and father (OR 1.78), when compared with white couples.48 Currently, there is no explanation for the observed ethnic disparity in the rate of PTB that exceeds the effect of socioeconomic status.
 Figure 49.3 Global prevalence of preterm birth. (Reprinted with permission from Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):2162-2172.) |
 Figure 49.4 Preterm birth rates in the United States (1990-2013) by race and Hispanic origin of mother. (Reprinted from Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: final data for 2017. Natl Vital Stat Rep. 2018;67(8):1-50.) |
Familial Risk
Studies suggest that there is a genetic predisposition for PTB as it is more prevalent in women who were born preterm themselves or in women who are monozygotic twins, and there is a negative correlation between the gestational age of mother at the time of her birth and her risk of delivering preterm.49,50,51,52
Socioeconomic Factors
Maternal Age
The rate of PTB is elevated at the extremes of maternal age. Advanced maternal age (40 years and over) is independently associated with an increased risk of PTB.59 Adolescent pregnancies have a high risk for PTB (RR 1.9; 95% CI 1.7-2.1)59,60 (Figure 49.5).
Smoking Status
Cigarette smoking is associated with increased risk for PTB. This effect persists even after adjustment for confounders, such as intrauterine growth restriction (IUGR), placental abruption, and PROM, suggesting that smoking is an independent risk factor for preterm delivery.61
Müllerian Anomalies
The presence of a Müllerian anomaly has been reported to be an independent risk factor for indicated preterm delivery.24 However, the incidence of PTB is dependent on the specific type of Müllerian anomaly, with the highest rate of preterm deliveries in women with uterus didelphys, bicornis, or septated uterus.55,62,63,64,65,66
 Figure 49.5 Risk for preterm birth (spontaneous) and indicated according to maternal age. aOR, adjusted odds ratio; CI, confidence interval. (Reprinted from Fuchs F, Monet B, Ducruet T, et al. Effect of maternal age on the risk of preterm birth: a large cohort study. PLoS One. 2018;13(1):e0191002.) |
Cervical Surgery
Cervical procedures carry an increased risk factor for PTB that is proportional to the extent of the surgery. The frequency and severity of adverse perinatal outcomes are higher for excision than for ablation and are increased with increasing cone depth.67,68,69 The RRs found for preterm delivery were 2.70 (2.14-3.40) for cold knife conization, 2.11 (1.26-3.54) for laser conization, 1.56 (1.36-1.79) for large loop excision of the transformation zone, and 1.46 (1.27-1.66) for ablation not otherwise specified.68 A meta-analysis, including 19 studies with a total of 6589 patients with a history of Loop Electrosurgical Excision Procedure (LEEP) and 1,415,015 patients without, showed that women with a history of LEEP have an overall higher rate of preterm term delivery at the subsequent pregnancy (pooled RR 1.61; 95% CI 1.35-1.92),70 but a similar risk of PTB when compared
with women with prior dysplasia but no cervical excision.70 The authors concluded that their findings “indicate that the increased risk for preterm birth before 37 weeks of gestation in women with a history of LEEP may be related to shared risk factors rather than the cervical excision procedure itself.”70 However, this meta-analysis was based on retrospective cohorts and case-control studies; thus further studies with stronger evidence are required before the association between the LEEP procedure and risk for subsequent PTB can be established.
with women with prior dysplasia but no cervical excision.70 The authors concluded that their findings “indicate that the increased risk for preterm birth before 37 weeks of gestation in women with a history of LEEP may be related to shared risk factors rather than the cervical excision procedure itself.”70 However, this meta-analysis was based on retrospective cohorts and case-control studies; thus further studies with stronger evidence are required before the association between the LEEP procedure and risk for subsequent PTB can be established.
Nutritional Status
Maternal nutritional status affects her ability to support the growing and developing fetus. There is a relatively consistent relationship between maternal size, duration of pregnancy, and litter size.71 Nutritional status plays an important role in determining the rate of fetal growth. For example, maternal prepregnancy weight and weight gain during pregnancy appear to be major determinants of fetal growth.72 Indeed, women with low body mass index (BMI; <19 kg/m2) are at increased risk to have small for gestational age (SGA) neonates (OR 1.81; 95% CI 1.76-1.87),73,74,75,76 while obesity (BMI ≥ 30 kg/m2) is associated with a high frequency of large for gestational age (OR 2.08; 95% CI 1.95-2.23).77,78,79,80,81,82,83,84,85,86,87 Similarly, the risk for PTB is associated with maternal nutritional status and BMI. Low maternal prepregnancy weight and prepregnancy overweight and obesity are associated with PTB.88,89 A 2011 meta-analysis reported that underweight women have an increased overall risk of preterm delivery (RR 1.29; 95% CI 1.15-1.46) as well as spontaneous (RR 1.32; 95% CI 1.10-1.57) and indicated (RR 1.21; 95% CI 1.07-1.36) PTB.90 The same group conducted a different meta-analysis to examine prepregnancy overweight and obesity and found a similar association with PTB (RR 1.24; 95% CI 1.13-1.37).91
Bacterial Vaginosis
Bacterial vaginosis is a dysbiosis of vaginal bacterial flora, characterized by increasing numbers of anaerobic and facultative bacteria as well as a decrease in the number of lactobacilli.92,93,94,95,96,97,98,99 This condition is a risk factor for spontaneous PTB with intact or ruptured membranes.100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117 In addition, bacterial vaginosis is associated with a higher rate of pregnancy losses in the first and second trimesters, intra-amniotic infection, PPROM, histologic chorioamnionitis, post-cesarean delivery endometritis and wound infection.112,117,118,119,120,121
The rate of bacterial vaginosis during pregnancy is 15% to 20%98,103,104,122,123,124,125,126,127,128; however, 50% of these patients are asymptomatic. A meta-analysis of 20,232 women included in 18 studies129 concluded that bacterial vaginosis is associated with an increased risk for preterm delivery at <37 weeks of gestation (OR 2.19; 95% CI 1.54-3.12), and this effect was significant among women with low and high risk for preterm delivery, especially if the bacterial vaginosis was detected prior to 16 weeks of gestation (OR 7.55; 95% CI 1.8-31.65).129
Randomized clinical trials for the prevention of PTB by antibiotic treatment of patients with bacterial vaginosis have yielded contradictory results.94,130,131,132,133,134,135,136,137 The randomized trial of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) network130 included 1953 women with bacterial vaginosis who were assigned to treatment with oral metronidazole or placebo. Treatment with metronidazole was not associated with a significant reduction in the rate of PTB. Moreover, a subanalysis of high-risk patients for preterm delivery demonstrated a higher rate of preterm delivery and PPROM in the treatment group. A Cochrane review138 including 21 studies involving 7847 women concluded that, overall, antibiotic treatment of bacterial vaginosis did not reduce the risk for PTB prior to 37 weeks even if the treatment was started before 20 weeks of gestation; this was also the case in women with a prior PTB who had bacterial vaginosis in the current pregnancy. Based on these results professional societies do not recommend screening for the condition in women at low risk for PTB.95,96,128,139,140
Current Pregnancy Risks
Mode of Conception
Vaginal Bleeding
Vaginal bleeding during pregnancy is a risk factor for spontaneous and indicated PTB.104,146,147,148
Pregnancy complications, such as placenta previa and placental abruption, as well as idiopathic vaginal bleeding during the first and second trimester are associated with an increased risk for a subsequent preterm delivery.104,146,147,148 Women who experience unexplained vaginal bleeding during the first trimester have double the risk for PTB compared with women who do not experience vaginal bleeding (OR 2.11; 95% CI 1.43-3.10).149
Pregnancy complications, such as placenta previa and placental abruption, as well as idiopathic vaginal bleeding during the first and second trimester are associated with an increased risk for a subsequent preterm delivery.104,146,147,148 Women who experience unexplained vaginal bleeding during the first trimester have double the risk for PTB compared with women who do not experience vaginal bleeding (OR 2.11; 95% CI 1.43-3.10).149
Multifetal Gestations
Twin and higher-order multifetal gestations have a strong association with PTB. In 2016, approximately 61% of multifetal gestations in the United States delivered prematurely.40 In addition to spontaneous PTL, multifetal gestations have an increased rate of medical and obstetrical disorders, including discordant fetal growth, fetal anomalies, hypertension, placental abruption, and fetal compromise, which lead to indicated preterm delivery.150 A detailed discussion of multifetal pregnancies is the topic of Chapter 5.
Obstetrical History
Previous PTB
A previous PTB is an independent risk factor for a subsequent preterm delivery and recurrence often occurs at the same gestational age.50,151 The frequency of recurrent spontaneous PTB is 15% to 30% after one spontaneous PTB and increases after two prior spontaneous preterm deliveries.50,152,153,154 The risk for PTB in subsequent pregnancies is influenced by the number, sequence, and gestational age of prior PTBs.155 The risk increases as the gestational age at the time of a prior PTB declines, especially before 32 weeks of gestation156 (Figure 49.6). All types of PTBs are associated with an increased risk of spontaneous preterm delivery in subsequent pregnancies. In a large retrospective cohort study, the rate of recurrent PTB was 23% for women with a prior indicated PTB and 31.6% for prior spontaneous PTB.157 Patients with indicated preterm delivery have an increased risk for spontaneous (RR 9.1; 95% CI 4.6-17.7) an indicated preterm delivery (RR 2.7; 95% CI 2-3.65) in subsequent pregnancies157 (Table 49.1).
 Figure 49.6 Risk of recurrent preterm birth according to the order and gestational age of the previous delivery. Very preterm: 21 to 31 weeks; moderate preterm: 32 to 36 weeks of gestation. (Modified with permission McManemy J, Cooke E, Amon E, Leet T. Recurrence risk for preterm delivery. Am J Obstet Gynecol. 2007;196(6):576.e1-576.e6.) |
Underlying Mechanisms of Preterm Parturition Syndrome
PTL as a Syndrome
The current taxonomy of disease in obstetrics is based on the clinical presentation rather than on the underlying mechanism of disease responsible for the premature activation of the common pathway of parturition, which is defined as (1) the switch of the myometrium from the quiet phase 0 to active and contractile mode; (2) shortening and ripening of the uterine cervix; and (3) activation of the decidua and chorioamniotic membranes and their rupture. This is the consequence of anatomical, physiological, biochemical, endocrinological, immunological, and clinical events that occur in the mother and/or fetus in both term and PTL. In contrast to term labor (described in Chapter 44), in which the common pathway of parturition is physiologically activated, PTL results from a synchronous or nonsynchronous, premature pathological activation of the components of parturition
(Figure 49.7). PTL is the clinical presentation of premature activation of the uterine and cervical components of the common pathway of parturition. This could be the clinical presentation of different underlying mechanisms,5,28,158 including intrauterine infection,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176 uteroplacental ischemia,177,178,179,180,181,182,183,184,185,186,187 uterine overdistention,188,189,190 cervical disease,7,191,192,193 abnormal allograft rejection,194,195 allergic phenomena,196,197,198 and endocrine disorders.199,200 However, the term “preterm labor” (PTL) relates only to the clinical presentation of the disease and is not indicative to whether this condition is caused by any of the abovementioned pathological processes. Thus, PTL is a syndrome, and the possible underlying mechanisms leading to the premature activation of parturition are discussed herein.
(Figure 49.7). PTL is the clinical presentation of premature activation of the uterine and cervical components of the common pathway of parturition. This could be the clinical presentation of different underlying mechanisms,5,28,158 including intrauterine infection,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176 uteroplacental ischemia,177,178,179,180,181,182,183,184,185,186,187 uterine overdistention,188,189,190 cervical disease,7,191,192,193 abnormal allograft rejection,194,195 allergic phenomena,196,197,198 and endocrine disorders.199,200 However, the term “preterm labor” (PTL) relates only to the clinical presentation of the disease and is not indicative to whether this condition is caused by any of the abovementioned pathological processes. Thus, PTL is a syndrome, and the possible underlying mechanisms leading to the premature activation of parturition are discussed herein.
Table 49.1 Recurrence of Preterm Birth at <37, <35, and <32 Weeks and Subtypes in Second Pregnancy Based on Preterm Birth at <37, <35, and <32 Weeks in the First Pregnancy, Respectively: Missouri, 1989 to 1997 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Figure 49.7 Activation of the common pathway of parturition, including myometrial contractility by an increase in the number of gap junctions between the myometrial cells, and increased activity of contraction-associated proteins and prostaglandin leading to reduction in the effect of progesterone. Additionally, the ripening of the cervix and disruption of its collagen structure, and disruption and thinning of the chorioamniotic membranes that will eventually lead to their rupture during the process of parturition. A, amnion; C, chorion; D, decidua; E, extracelluar matrix. (Reprinted with permission from Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-765.) |
Infection and Inflammation
Infection is the only proven mechanism of disease leading to premature delivery. Microbiological and histopathological studies suggest that infection-related inflammation may account for 25% to 40% of cases of preterm deliveries.201,202,203 The evidence supporting the role of infection in the onset of labor includes the following: (1) systemic maternal infection is associated with the onset of labor and these patients have a higher frequency of PTB; (2) intrauterine infection is associated with spontaneous preterm parturition; and (3) in animal models, intrauterine injection of bacteria or bacterial products leads to preterm delivery.201,202,203 Infectious processes leading to PTB can be clinically evident (ie, pyelonephritis or chorioamnionitis); subclinical, limited to the uterus,
and present as PTL or preterm PROM, resulting from bacteria that crossed through the placenta from the maternal blood and are detected in the amniotic fluid; and/or detected only after delivery in the placenta (ie, acute histologic chorioamnionitis) (Figure 49.8).
and present as PTL or preterm PROM, resulting from bacteria that crossed through the placenta from the maternal blood and are detected in the amniotic fluid; and/or detected only after delivery in the placenta (ie, acute histologic chorioamnionitis) (Figure 49.8).
Systemic Maternal Infection
Pyelonephritis, pneumonia, malaria, and other systemic maternal diseases are frequently associated with the onset of premature labor and delivery204,205,206,207,208,209,210,211,212 (discussed in Chapter 39). Evidence suggests that the maternal immune response to these infectious diseases induces inflammatory processes that affect the intrauterine environment, placenta, and membranes, leading to activation of the common pathway of parturition.
 Figure 49.8 Mechanisms of microbial induced preterm labor. A, Bacteria from the lower genital tract gain access to the amniotic cavity and stimulate the production of chemokines and cytokines, as well as prostaglandins and reactive oxygen radicals and proteases, initiating myometrial contractility with/without membrane rupture. B, (Top left) Amniotic fluid containing bacteria that was retrieved by amniocentesis from a patient with preterm labor. Bacteria and nuclei stained with DAPI (4′,6-diamidino-2-phenylindole) (blue). (Top middle) Bacteria identified with a probe against 16S ribosomal RNA (rRNA) using fluorescent in situ hybridization. (Bottom left and middle) Bacteria invading the amnion epithelium. Note the absence of bacteria in the subepithelial part of the amnion, suggesting that the pathway of microbial invasion is ascending into the amniotic cavity. C, Chorioamniotic membranes without evidence of inflammation. Amnion and chorion are identified. D, A similar membrane section as (C) from a patient with intra-amniotic infection. Inflammatory cells from the mother infiltrate the chorion and amnion. FISH, fluorescence in situ hybridization; rRNA, ribosomal RNA. (Reprinted with permission from Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-765.) |
Intra-amniotic Infection
The presence of bacteria or other microorganisms in the amniotic fluid, which should be sterile,213 is associated with adverse pregnancy outcomes.164,171,172,173,174,175,176,214,215,216,217,218,219,220,221,222,223,224,225 Intrauterine infection is a frequent and important mechanism of disease leading to premature contraction, PTL, and PTB.166,201,203,226,227,228,229,230,231,232,233 Intra-amniotic infection is a chronic process,234 and identification of microorganisms during mid-trimester amniocentesis in asymptomatic patients has been associated with subsequent late miscarriage,235 preterm delivery,236 and even fetal demise.171,172,173,174,175,176,237
Pathogenic microorganisms can invade the amniotic fluid through several routes. The most common is ascending infection from the vagina to the cervical canal through the membranes into the amniotic cavity and subsequently infecting the
membranes and the fetus.201,238 Other routes are maternal transmission of bacteria by hematogenous239,240,241 spread through the placenta or through the membranes, and finally iatrogenic introduction of bacteria into the amniotic cavity during amniocentesis of other medical intervention242,243 (Figure 49.9).
membranes and the fetus.201,238 Other routes are maternal transmission of bacteria by hematogenous239,240,241 spread through the placenta or through the membranes, and finally iatrogenic introduction of bacteria into the amniotic cavity during amniocentesis of other medical intervention242,243 (Figure 49.9).
 Figure 49.9 Potential route of microbial invasion of the amniotic cavity. The most common is ascending infection from the vagina to the cervical canal, through the membranes into the amniotic cavity and subsequently infecting the membranes and the fetus. Other routes are maternal transmission of bacteria by hematogenous spread through the placenta or through the membranes. (Reprinted with permission from Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.) |
Goncalves et al226 reported that the overall prevalence of intra-amniotic infection in patients with PTL was 12.8% and about 50% were polymicrobial. The rate of microbial invasion of amniotic cavity (MIAC) in patients with PTL and intact membrane is gestational age dependent, ranging from as high as 45% at 23 to 26 weeks to 11.5% by 31 to 34 weeks of gestation.244 Thus, the earlier the gestational age in which PTL develops, the more likely that MIAC is present.244
The diagnosis of MIAC using standardized cultivation techniques is limited by the number of bacteria detected and by the interval from sample collection to bacterial growth and identification in cultures. The introduction of 16s ribosomal DNA-polymerase chain reaction (PCR) techniques has improved the detection rate of MIAC.238,245,246,247,248,249 Indeed, in a study of amniotic fluid samples from 166 patients with PTL and intact membranes, the overall rate of positive cultures was 15.06% (25/166), of them 24% (6/25) had only positive amniotic fluid cultures, 36% (9/25) had only positive amniotic fluid 16s rDNA PCR, and in 40% (10/25) both tests were positive.246 A study by Combs et al reported that patients with PTL and intact membranes had a rate of MIAC of 10.1% (31/305), of them 65% (20/31) had both tests positive, 19% (6/31) had only 16s rDNA-PCR positive, and 16% (5/31) only cultures positive.245 These observations have clinical implications since in women presenting with PTL, a positive 16s rDNA-PCR test for microbial invasion had a positive predictive value of 100% for preterm delivery <37, <32, or <25 weeks of gestation and 68% for delivery within 1 day of amniocentesis.246 Recently, a novel molecular microbiologic technique that includes 16s PCR and electrospray ionization time-of-flight mass spectrometry (PCR/ESI-MS).250 This method can yield results within 8 hours of amniotic fluid collection and therefore in time for clinical decision. The authors reported that the introduction of this method increased the detection rate of microbial of amniotic fluid by 100% and increased the positive predictive value for spontaneous preterm delivery before 37 or 32 weeks, delivery within 7 or 2 days of amniocentesis.250 Collectively these studies suggest that there is a role for the introduction of novel molecular microbiologic techniques in the clinical workup of amniotic fluid for the detection of intra-amniotic infection in patients with PTL and intact membranes.
The most common microbial organisms isolated (either by culture or by 16s PCR) from the amniotic fluid of patients with PTL and intact membranes were genital mycoplasmas; followed by Fusobacterium species,201 Streptococcus agalactiae, Peptostreptococcus spp., Fusobacterium spp., Staphylococcus aureus, Gardnerella vaginalis, Streptococcus viridans, and Bacteroides spp.202,251,252,253,254,255,256,257,258,259 (Figure 49.10).
Bacteria in amniotic fluid can be either planktonic (free floating) or in the form of biofilm.260,261 The latter is more challenging since bacteria use biofilms to avoid the host inflammatory response and are more difficult to isolate in standard cultivation
techniques, and such infections are often underdiagnosed. Amniotic fluid sludge, which is a particulate matter identified by ultrasound near the internal os of the uterine cervix, is in fact in part of the cases a bacterial biofilm260,261 (Figure 49.11). The identification of sludge in asymptomatic patients and in those at risk for PTB, especially when accompanied by a short sonographic cervix, is associated with an increased risk for spontaneous PTL with intact membranes, PPROM of membranes, microbial invasion of amniotic fluid, PTB, and histologic chorioamnionitis.262,263
techniques, and such infections are often underdiagnosed. Amniotic fluid sludge, which is a particulate matter identified by ultrasound near the internal os of the uterine cervix, is in fact in part of the cases a bacterial biofilm260,261 (Figure 49.11). The identification of sludge in asymptomatic patients and in those at risk for PTB, especially when accompanied by a short sonographic cervix, is associated with an increased risk for spontaneous PTL with intact membranes, PPROM of membranes, microbial invasion of amniotic fluid, PTB, and histologic chorioamnionitis.262,263
 Figure 49.10 Most frequent microorganisms identified in amniotic cavity and placenta in term and preterm deliveries. PTB, preterm birth; sp., species. (Reprinted from Payne MS, Bayatibojakhi S. Exploring preterm birth as a polymicrobial disease: an overview of the uterine microbiome. Front Immunol. 2014;5:595.) |
Inflammation has a seminal role in the process of term and preterm parturition. However, while in labor at term, inflammation is a physiologic phenomenon. In the context of PTL, intra-amniotic inflammation that initiates preterm parturition is derived from pathological processes such as intra-amniotic infection or sterile inflammation.5,202,264,265,266,267,268
 Figure 49.11 Transvaginal detection of amniotic fluid sludge in a patient at 28 weeks of gestation, with bulging membranes preterm labor and chorioamnionitis. (Reprinted with permission from Costerton JW, Hassan SS, Schaudinn C, et al. What is amniotic fluid ‘sludge’? Ultrasound Obstet Gynecol. 2007;30(5):793-798.) |
Microbial invasion of amniotic fluid can be either isolated (colonization) or as microbial associated intra-amniotic inflammation. This distinction has clinical significance, in a nested case control study of asymptomatic women who underwent mid-trimester genetic amniocentesis at 16 to 18 weeks of gestation269: (1) Women who delivered preterm had higher amniotic fluid concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF) than those who delivered at term; (2) mid-trimester amniotic fluid IL-6 concentration ≥ 99.3 pg/mL had a sensitivity of 89.6%, specificity of 80.2%, and RR of 11.4 (95% CI 4.8-27.0) for preterm delivery <37 weeks of gestation; (3) mid-trimester amniotic fluid IL-6 concentration ≥ 99.3 pg/mL had a sensitivity of 91.9%, specificity of 73.8%, and RR of 15.0 (95% CI 4.8-45.5) for a positive amniotic fluid culture; (4) mid-trimester amniotic fluid TNF concentrations ≥ 6.6 pg/mL had a sensitivity of 81.3%, specificity of 79.2%, and RR of 6.2 (95% CI 3.3-11.9) for preterm delivery <37 weeks of gestation; and (5) mid-trimester amniotic fluid TNF concentrations ≥ 6.3 pg/mL had a sensitivity of 78.4%, specificity of 70.1%, and RR of 4.9 (95% CI 2.4-10.0) for positive amniotic fluid culture. Of interest, among those who delivered preterm, 47.9% had a positive mid-trimester amniotic fluid culture and elevated IL-6 and 45.8% had a positive mid-trimester amniotic fluid culture and elevated TNF, while among those who delivered preterm, the corresponding rates were 11.5% and 7.3%, respectively. Of interest, the rate of PTBs with those who had a positive amniotic fluid culture with elevated IL or TNF were 4.2% and 6.3%, respectively. Nevertheless, negative amniotic fluid cultures with elevated IL-6 or TNF were present in 41.7% and 35.4% of preterm deliveries.269 This report and others164,201,202,203,215,225,245,270,271,272,273 suggest that the inflammatory process elicited by the presence of microbacteria in the amniotic cavity is the driving force that leads to preterm parturition in cases of MIAC.
In cases of microbial associated intra-amniotic inflammation, the inflammatory reaction in the amniotic fluid is triggered by the activation of pattern recognition receptors including toll-like receptors or RAGE in response to the presence of danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (ie, lipopolysaccharides).274 The activation of pattern recognition receptors (PPRs) by microbes or their products illicits an inflammatory response, which in turn leads to the production of cytokines (IL-6 and TNFα) and matrix degrading enzymes (matrix metalloproteinase [MMP]-8), leading to the production of prostaglandins and activation of the common pathway of parturition6 (Figure 49.8).
Sterile Intra-amniotic Inflammation
Inflammatory processes in the amniotic fluid in which microorganisms cannot be detected are defined as sterile intra-amniotic inflammation. This process is activated by the presence of DAMPs in the amniotic fluid. These are endogenous intracellular molecules that are exposed during unprogrammed cellular death and can serve as a preliminary sign of tissue injury. DAMPs are also referred to as alarmins, and prominent members of this family are high-mobility group box 1 (HMGB1), uric acid, IL-1α, S100 calcium binding protein B, uric acid, and cell-free DNA.6,222,224,264,265,267,275,276,277,278,279,280 The generation of DAMPs activates the PPR that illicits an inflammatory response, which in turn leads to the production of cytokines (IL-6 and TNFα) and matrix degrading enzymes (MMP-8), leading to the production of prostaglandins and activation of the common pathway of parturition (Figure 49.12).
Yoon et al281 and others245 reported that for any given gestational age, the rate of intra-amniotic inflammation is higher than that of MIAC (Figure 49.13). The clinical characteristics of patients with PTL who had sterile intra-amniotic inflammation are similar in terms of gestational age at delivery, amniocentesis to delivery interval, and adverse neonatal outcomes, to those reported in women with PTL and microbial associated intra-amniotic inflammation.221,245,281,282 Indeed, among patients with PTL, the amniotic fluid concentration of HMGB1 proteins is increased in both patients with sterile or microbial mediated intra-amniotic inflammation.283 Moreover, the amniocentesis to delivery interval of patients with PTL and sterile amniotic fluid inflammation who had amniotic fluid HMGB1 concentration ≥8.55 pg/mL was similar to that of those with microbial associated intra-amniotic inflammation, and shorter than those with sterile intra-amniotic inflammation but HMGB1 concentration <8.55 pg/mL (P = .02).282 In a mice model, intra-amniotic administration of HMGB-1 leads to PTB.283 In vitro evidence suggests a role for HMGB1 in activation of the chorioamniotic
membranes, leading to increased production of IL-6 and IL-8, and its extranuclear fraction is detected in the uterine cervix during term and PTL, suggesting a role in cervical ripening.280 Moreover, intra-amniotic infection is associated with higher amniotic fluid concentrations of HMGB-1. Other alarmins, such as IL-1α and IL-1β, are implicated in spontaneous PTB as well.
membranes, leading to increased production of IL-6 and IL-8, and its extranuclear fraction is detected in the uterine cervix during term and PTL, suggesting a role in cervical ripening.280 Moreover, intra-amniotic infection is associated with higher amniotic fluid concentrations of HMGB-1. Other alarmins, such as IL-1α and IL-1β, are implicated in spontaneous PTB as well.
 Figure 49.12 A, Cellular stress will affect cell viability and lead to the release of damage-associated molecular patterns (DAMPs) (alarmins) by the fetal membranes and the placenta. These DAMPs will then act on the placenta, uterus, cervix, and fetal membranes, inducing inflammation. B, Inflammatory mechanism of action of alarmins at the maternal-fetal interface. Following stimulation, alarmins are released from cells at the maternal-fetal interface and act on placental cells (primarily trophoblasts) and maternal myeloid cells to induce an inflammatory response and secretion of inflammatory mediators (cytokines/chemokines), which will recruit maternal immune cells. CCL2, chemokine (C-C motif) ligand 2; cffDNA, cell free fetal DNA; HMGB-1, high mobility group box 1; IL, interleukin; MSU, monosodium urate; mtDNA, mitochondrial DNA; NALP3, NLR family pyrin domain containing 3; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; RAGE, receptor for advanced glycation endproducts; TLR, toll-like receptor. (A and B, Reprinted with permission from Nadeau-Vallee M, Obari D, Palacios J, et al. Sterile inflammation and pregnancy complications: a review. Reproduction. 2016;152(6):R277-R292.) |
 Figure 49.13 The frequency of intra-amniotic inflammation and intra-amniotic infection in patients with preterm labor according to gestational age at amniocentesis. AF, amniotic fluid. (Reprinted with permission from Yoon BH, Romero R, Moon JB, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001;185(5):1130-1136.) |
In addition to IL-1 and TNFα, many other cytokines and chemokines (ie, IL-6, IL-8, IL-16, IL-18, colony-stimulating factor, macrophage migration inhibitory factor, monocyte chemotactic protein-1) are involved in the inflammatory process of microbial associated or sterile intra-amniotic inflammation.274 These observations suggest that the process of intra-amniotic inflammation involves a network of cytokines and chemokines. Indeed, Romero et al demonstrated that in patients with PTL and intact membranes, microbial associated or sterile intra-amniotic inflammation are characterized by unique network of perturbed inflammatory-related protein concentration and correlations284 (Figure 49.14).
Maternal Antifetal Rejection
A novel inflammatory process leading to PTB is maternal antifetal rejection, a graft-versus-host response of the fetus and the mother. This process is associated with chronic placental inflammation, characterized by villitis of unknown etiology, chronic chorioamnionitis, and chronic deciduitis and is similar to the type of graft rejection observed in patients with failed heart, lung, and kidney transplant.285 A high amniotic fluid concentration of C-X-C motif ligand (CXCL)-10 observed in patients with spontaneous preterm labor was associated with the presence of lesion consistent with chronic placental inflammation (villitis of unknown etiology, chronic chorioamnionitis, and chronic deciduitis).285 This type of placental lesion is characterized by infiltration of lymphocytes, plasma cells, and histiocytes. The maternal antifetal rejection is characterized by (1) infiltration of maternal CD8+ T cells into fetal tissues; (2) the presence of antifetal human leukocyte antigen antibodies in maternal circulation; and (3) depositions of C4d in umbilical vein and syncytiotrophoblast194 (Figure 49.15). Chronic placental inflammatory lesions are the most common placental findings in late PTB but can be observed in the mid-trimester of patients who eventually have late-preterm delivery.194 Maternal antifetal rejection is associated with fetal morbidity and mortality. Among preterm neonates born between 24 and 34 weeks of gestation, those who had periventricular leukomalacia (PVL) had a higher rate of placental chronic inflammatory lesions than those without it,286 suggesting that processes associated with maternal antifetal rejection leading to PTL and PTB may be associated with long-term sequelae in the preterm infant.
Fetal Inflammatory Response Syndrome
Fetal inflammatory response syndrome (FIRS) can be considered the fetal equivalent of systemic inflammatory response syndrome, described in adults with sepsis.287,288 FIRS is characterized by systemic activation of the fetal immune system involving all major fetal systems (ie, hematopoietic, heart, brain, lungs, kidneys, adrenals, and skin).287,288,289 Additionally, preterm neonates affected in utero by FIRS have a shorter interval from cordocentesis to delivery and a higher rate of short- and long-term complication of prematurity including RDS, neonatal sepsis, pneumonia, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), PVL, NEC, and cerebral palsy than those without this syndrome.287,290,291,292 The rate of FIRS in pregnancies complicated by preterm parturition is about 39% and increases to 49.3% in fetuses delivered within 1 week from cordocentesis.287,293
Currently, there are two types of FIRS: type I and type II. Type I is considered the highest degree of intra-amniotic infection/inflammation. It describes fetuses who mounted a systemic inflammatory immune response to microorganisms that invaded the amniotic cavity. Type I FIRS is characterized by high cord blood concentrations of proinflammatory
cytokines, especially IL-6 and TNF-α. A concentration of 11 pg/mL of IL-6 detected in fetal cord blood is the cutoff for prenatal diagnosis of FIRS type I281 as it was associated with adverse neonatal outcome and complications of prematurity. The characteristic placental lesions of FIRS type I syndrome include histologic chorioamnionitis, evidence of umbilical cord inflammation (funisitis), and chorionic vasculitis. The presence of funisitis allows a postnatal diagnosis of neonates with FIRS type I and is associated with an increased risk for the subsequent development of cerebral palsy (OR 5.5; 95% CI 1.2-24.5)287,294,295 (Figure 49.16).
cytokines, especially IL-6 and TNF-α. A concentration of 11 pg/mL of IL-6 detected in fetal cord blood is the cutoff for prenatal diagnosis of FIRS type I281 as it was associated with adverse neonatal outcome and complications of prematurity. The characteristic placental lesions of FIRS type I syndrome include histologic chorioamnionitis, evidence of umbilical cord inflammation (funisitis), and chorionic vasculitis. The presence of funisitis allows a postnatal diagnosis of neonates with FIRS type I and is associated with an increased risk for the subsequent development of cerebral palsy (OR 5.5; 95% CI 1.2-24.5)287,294,295 (Figure 49.16).
 Figure 49.14 Perturbation of the cytokine network in women with preterm labor. Each node (sphere) represents 1 of the 33 analytes; its color represents the direction of concentration change between the groups (red, increased; blue, decreased; white, no change). The link (line) between two nodes represents a significantly perturbed correlation, and its color gives the direction of correlation change (red, increased; blue, decreased). The type of line denotes the nature of the link (solid line, within module link; dashed line, cross-module link). Thick radial lines separate the modules and the set of unconnected nodes. The numbers inside/outside the dotted black circles represent the node degree/average absolute difference in correlations. A, Network of perturbed inflammatory-related protein concentration correlations between sterile intra-amniotic inflammation and no intra-amniotic inflammation. B, Network of perturbed inflammatory-related protein concentration correlations between microbial associated intra-amniotic inflammation and no intra-amniotic inflammation. C, Network of perturbed inflammatory-related protein concentration correlations between microbial associated intra-amniotic inflammation and sterile intra-amniotic inflammation. CXCL, C-X-C motif chemokine ligand; GMCSF, granulocyte macrophage-colony stimulating factor; Groa, melanoma growth-stimulatory activity; HMGB-1, high mobility group box 1; IFN, interferon; IL, interleukin; IP, interferon gamma-induced protein; MCP1, monocyte chemoattractant protein 1; MI, macrophage inflammatory proteins; RANTES, regulated on activation, normal T cell expressed and secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; xMCSF, macrophage colony-stimulating factor. (Reprinted with permission from Romero R, Grivel JC, Tarca AL, et al. Evidence of perturbations of the cytokine network in preterm labor. Am J Obstet Gynecol. 2015;213(6):836.e1-836.e18.) |
 Figure 49.15 Maternal antifetal rejection is characterized by (A) infiltration of maternal CD8+ T cells into fetal tissues, and (B) the presence of antifetal human leukocyte antigen (HLA) antibodies in maternal circulation that transfer to the fetus. (Reprinted with permission from Kim CJ, Romero R, Chaemsaithong P, Kim JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol. 2015;213(4 suppl):S53-S69.) |
Type II FIRS results from maternal antifetal rejection and manifests as a unique cord blood transcriptome in the affected fetuses. The clinical manifestations of FIRS type II await further research.296 The summary of the characteristics of the two types of FIRS is depicted in Figure 49.16.
Allergic Phenomena
Preliminary evidence suggest an allergic-like immune response (type I hypersensitivity) can be associated with PTL and delivery.5,297 Indeed, case reports of women who had severe latex allergy298 and developed uterine contraction as well as that of women who developed PTL and acute hypersensitivity reaction after ingestion of lobster meat that resolved with treatment by steroids antihistaminic medications297 support this assumption. Type I hypersensitivity is defined as immunoglobulin (Ig)E-mediated hypersensitivity, in which the exposure of these antibodies to the allergens leads to mast cell activation, degranulation, and initiation of an inflammatory response and the section of histamine and prostaglandins and other products of mast cell degranulation can induce myometrial contractility.299,300,301 The mast cell-mediated inflammatory response is characterized by the secretion
of IL-8, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which attract and activate eosinophils that enhance the inflammatory response by secreting leukotrienes, platelet activating factors, IL-4, and IL-10 as well as activation of proteases leading to tissue damage.297 Indeed, among women who presented with PTL and had diagnostic amniocentesis without evidence of MIAC, those who had >20% eosinophils in their amniotic fluid blood cell count had a lower gestational age at delivery and a higher rate of PTB <35 and <37 weeks of gestation than those who had ≤20% eosinophils in their amniotic fluid blood cell count. This suggests that a subset of patients with PTL and a high number of eosinophils in their amniotic fluid has type I hypersensitivity-mediated PTB.
of IL-8, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which attract and activate eosinophils that enhance the inflammatory response by secreting leukotrienes, platelet activating factors, IL-4, and IL-10 as well as activation of proteases leading to tissue damage.297 Indeed, among women who presented with PTL and had diagnostic amniocentesis without evidence of MIAC, those who had >20% eosinophils in their amniotic fluid blood cell count had a lower gestational age at delivery and a higher rate of PTB <35 and <37 weeks of gestation than those who had ≤20% eosinophils in their amniotic fluid blood cell count. This suggests that a subset of patients with PTL and a high number of eosinophils in their amniotic fluid has type I hypersensitivity-mediated PTB.
 Figure 49.16 The characteristics of the fetal inflammatory response syndrome (FIRS) type I and type II. Type I results from ascending inflammation, and the feature cytokine found in fetal cord blood is IL-6. FIRS type II is maternal antifetal rejection, and the characteristic chemokine found in cord blood is CXCL-10 (C-X-C motif chemokine ligand 10). ACA, acute chorioamnionitis; CCA, chronic chorioamnionitis; CDP, chronic deciduitis; VUE, villitis of unknown etiology. (Reprinted with permission from Kim CJ, Romero R, Chaemsaithong P, Kim JS. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am J Obstet Gynecol. 2015;213(4 suppl):S53-S69.) |
Uteroplacental Ischemia
Placental Vascular Disease
This is one of the mechanisms leading to spontaneous PTB (Figure 49.17). Placental lesions consistent with maternal vascular malperfusion are present in 20% to 30% of patients who had spontaneous PTB,177,186,302,303 and they are more prevalent after 28 weeks of gestation.186,303 Moreover “failure of physiologic transformation of the spiral arteries,” atherosis, fibrinoid necrosis of the decidual vessels, and decidual vessel thrombosis consistent with decidual vasculopathy were more frequent among patients with PTL than those who delivered at term delivery.304 Of interest, failure of transformation of spiral arteries is a vascular lesion that is usually associated with preeclampsia, suggesting that in a subset of patients, the same mechanisms of disease that lead to preeclampsia may be manifested as spontaneous PTL. Additionally, 36% of patients with PTL and intact membranes who delivered preterm have evidence for decidual bleeding including hemosiderin depositions and retrochorionic hematoma formation.305,306
Placental lesions consistent of maternal vascular malperfusion are also associated with abnormal ratio between angiogenic (placental growth factor) and antiangiogenic (vascular endothelial growth factor receptor 1) factors called angiogenic index 1. Indeed, a low angiogenic index 1 at the mid-trimester was associated with a high burden of placental lesions consistent with maternal vascular malperfusion and PTB <34 weeks.307
Role of Thrombin
The effect of decidual bleeding on the activation of premature uterine contractions and/or rupture of membranes is thought to be mediated by thrombin,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328 an enzyme generated by the coagulation cascade that cleaves fibrinogen into fibrin and has a role in the activation of inflammatory and angiogenic processes.329,330,331
The decidua is rich in tissue factor, and even minor bleeding can lead to activation of the coagulation cascade and the generation of thrombin. The effect of thrombin on the activation of the myometrium and generation of contraction was reported
in an in vitro study in which the administration of blood to the uterus generated uterine contractions that resolved by adding heparin, and this effect was related to the action of thrombin because hirudin, a thrombin inhibitor, abolished the contractile activity of the uterine muscle exposed to thrombin in a dose-dependent manner.332 Thrombin can activate preterm parturition through several mechanisms: (1) uterotonic activities, as evidenced by experiments in which the administration of a whole blood, but not saline or heparinized blood, into a nonpregnant uterus generated uterine contractions311,312,332; (2) production of proinflammatory cytokines333,334,335,336,337,338,339,340,341 associated with prostaglandins generation, premature myometrial activation, and contractions; and (3) activation of matrix degrading enzymes, such as MMP-1, MMP-3, and MMP-9, which can degrade the chorioamniotic membranes leading to rupture of membranes342,343,344,345 (Figure 49.18).
in an in vitro study in which the administration of blood to the uterus generated uterine contractions that resolved by adding heparin, and this effect was related to the action of thrombin because hirudin, a thrombin inhibitor, abolished the contractile activity of the uterine muscle exposed to thrombin in a dose-dependent manner.332 Thrombin can activate preterm parturition through several mechanisms: (1) uterotonic activities, as evidenced by experiments in which the administration of a whole blood, but not saline or heparinized blood, into a nonpregnant uterus generated uterine contractions311,312,332; (2) production of proinflammatory cytokines333,334,335,336,337,338,339,340,341 associated with prostaglandins generation, premature myometrial activation, and contractions; and (3) activation of matrix degrading enzymes, such as MMP-1, MMP-3, and MMP-9, which can degrade the chorioamniotic membranes leading to rupture of membranes342,343,344,345 (Figure 49.18).
 Figure 49.17 The mechanisms of placental vascular disorder in preterm labor and delivery. One of the most prominent features of placental vascular lesions is failure of physiologic transformation of the uterine spiral arteries. A, Schematic drawing of the maternal-fetal interface in normal pregnancy. A physiologically transformed uterine spiral artery with a wide lumen delivers blood to the chorionic villi of the placenta. B, A spiral artery with an expanded ostium that normally enables adequate perfusion of the chorionic villi. C, Ostium of a narrow spiral artery with failure of physiologic transformation in a patient with spontaneous preterm labor. D, Periodic acid-Schiff staining of a histological section of the maternal-fetal interface in normal pregnancy shows a spiral artery transformed by cytokeratin 7-positive cytotrophoblasts (brown) that line the lumen. E, Failure of physiologic transformation of a spiral artery in a patient with preterm labor. The lumen is narrow, and cytotrophoblasts have not invaded the muscular wall. (Reprinted from Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760.) |
PTL is associated with an increased activation of the coagulation cascade and thrombin generation (see Chapter 2). Patients with PTL have a higher median concentration of maternal plasma thrombin-antithrombin III complexes than women with normal pregnancy.310 This is particularly evident among those without intra-amniotic infection/inflammation in which elevated concentrations of the antithrombin III complex concentrations in the amniotic fluid are associated with a shorter amniocentesis-to-delivery interval and a lower gestational age at delivery than those with normal or low concentrations of this complex.313 Additionally, among asymptomatic women who have a mid-trimester amniocentesis, those with elevated amniotic fluid thrombin-antithrombin concentration have a higher risk for subsequent spontaneous preterm delivery.346 Regardless of the presence of intra-amniotic infection/inflammation, women with PTL and intact membranes have higher median tissue factor activity and lower median tissue factor pathway inhibitor activity than those with a normal pregnancy.314 Women with spontaneous PTL without intra-amniotic infection or inflammation, and women with vaginal bleeding who deliver preterm, have a lower median maternal plasma protein Z (a cofactor of protein Z-dependent protease inhibitor that inhibits the activity of factor X) than women with normal pregnancy.317 Collectively, these reports indicate that PTL is associated with increased thrombin generation. Yet, it is not clear whether this is due to increased activation of the coagulation cascade or inadequate activity of anticoagulation proteins.
 Figure 49.18 The role of thrombin in preterm parturition. A schematic description of the effect of decidual bleeding on increased thrombin generation that, in turn, directly activates the myometrium or works through its action on neutrophil activation. Moreover, thrombin affects the membranes through its activation that eventually lead to membranes rupture. FVIIa, factor VII activated; IL, interleukin; MMPs, matrix metalloproteinases; PARs, protease activated receptors; PPROM, preterm prelabor rupture of membranes; PTD, preterm delivery; TF, tissue factor. (Reprinted with permission Lockwood CJ, Krikun G, Aigner S, Schatz F. Effects of thrombin on steroid-modulated cultured endometrial stromal cell fibrinolytic potential. J Clin Endocrinol Metab. 1996;81(1):107-112.) |
Cellular Senescence
Cellular senescence is a process of arrested cell growth and proliferation without progression to apoptosis (programmed cell death)347,348 in response to physiological stresses and molecular damage. Cellular senescence has a negative impact not only on the affected cells but also on the surrounding tissue as the changes in the affected cells affect the metabolic capacity of the adjacent cells and extracellular environment, limiting the renewal potential of the affected tissue.349 Cellular senescence is associated with specific molecular markers350 (Table 49.2). It has been proposed the parturition at
term involves senescence of the fetal membranes350,351 (Figure 49.19). The chorioamniotic membranes in women with PTL without acute histologic chorioamnionitis exhibit evidence of cellular senescence, including downregulation of expression of genes for cyclin-dependent kinase 2, cyclins (CCNA2, CCNB1, and CCNE), tumor suppressor p53 (TP53), and increased activity of the senescence-associated beta-galactosidase enzyme.277 These signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous PTL compared to those who delivered preterm in the absence of labor.277
term involves senescence of the fetal membranes350,351 (Figure 49.19). The chorioamniotic membranes in women with PTL without acute histologic chorioamnionitis exhibit evidence of cellular senescence, including downregulation of expression of genes for cyclin-dependent kinase 2, cyclins (CCNA2, CCNB1, and CCNE), tumor suppressor p53 (TP53), and increased activity of the senescence-associated beta-galactosidase enzyme.277 These signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous PTL compared to those who delivered preterm in the absence of labor.277
Table 49.2 Biomarkers of Senescence | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||
 Figure 49.19 Cellular senescence is associated with specific molecular markers. It has been proposed the parturition at term involves senescence of the fetal membranes. DAMPs, damage-associated molecular patterns; ROS, reactive oxygen species; SASPs, senescence-associated secretory phenotypes. (Reprinted from Menon R, Mesiano S, Taylor RN. Programmed fetal membrane senescence and exosome-mediated signaling: a mechanism associated with timing of human parturition. Front Endocrinol (Lausanne). 2017;8:196.) |
Additionally, it has been proposed that stimuli like reactive oxygen species (ROS), which cause oxidative DNA damage, lead to a senescence-associated secretory phenotype (the secretion of proinflammatory cytokines, chemokines, growth factors, and proteases by senescence cells) in intrauterine tissue or fetal membranes that may contribute to the development of preterm parturition.350,352,353,354
Uterine Overdistention
Polyhydramnios and multifetal gestations are risk factors for PTL and delivery. These conditions are associated with uterine overdistension that has been proposed as one of the mechanisms leading to PTB through myometrial activation. During normal pregnancy, the uterus expands about 250-fold in size,355 and the chorioamniotic membranes are distended by 40% at 25 to 29 weeks of gestation, 60% at 30 to 34 weeks of gestation, and 70% at
term.356 Despite this increase in size and volume, the intra-amniotic pressure remains relatively constant throughout gestation despite the growth of the fetus and placenta. This is attributed to the effect of progesterone on the myometrium to ensure the uterine muscles remain quiescent.357 At late stages of pregnancy, uterine growth does not catch up with the rapid growth of the fetus; however, the inhibitory effect of progesterone on the myometrium decreases,357,358,359 leading to an increased effect of stretch that reaches its peak during labor.
term.356 Despite this increase in size and volume, the intra-amniotic pressure remains relatively constant throughout gestation despite the growth of the fetus and placenta. This is attributed to the effect of progesterone on the myometrium to ensure the uterine muscles remain quiescent.357 At late stages of pregnancy, uterine growth does not catch up with the rapid growth of the fetus; however, the inhibitory effect of progesterone on the myometrium decreases,357,358,359 leading to an increased effect of stretch that reaches its peak during labor.
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