What condition occurs when too much water moves into the cell and the cell membrane ruptures

B. Cervical Ripening

Further to membrane rupture, cervical ripening toward term and dilatation at delivery are essential processes. In the first part of gestation the cervix is hard and firmly holds the uterine contents. The biochemical process of “cervical maturation” commences at about the thirty-fourth week of pregnancy until the cervical os is fully dilated at delivery. The close cooperation between the myometrium and cervix is essential for normal uterine function, and defects in this relationship cause maternal and fetal morbidity.

There are three main structural components in the cervix of women: smooth muscle, collagen, and the connective tissue “ground-substance.” The last contains the cervical glucosaminoglycans: dermatan sulfate, chondroitin sulfates, and hyaluronic acid. In humans, smooth muscle has not been shown to have a role in cervical dilatation (Uldjerg and Malmstrom, 1991). The enzymatic breakdown of collagen is a key factor in cervical softening. The collagen fragments become soluble and leave the ripened cervical tissue. The degradation of collagen occurs as an action of the enzymes collagenase and leukocyte elastase. The latter is located in the azurophil granules of polymorphonuclear leukocytes. Leukocyte infiltration and degranulation occurs in the term cervix in a similar manner to that seen in inflammatory reactions (Jeffery, 1991). Indeed, it was Liggins who first proposed that cervical ripening was similar to an inflammatory reaction. Cervical dermatan sulfate concentrations diminish along with those of collagen and the cervix becomes swollen and soft due to increased hyaluronic acid and water content. The increased hyaluronic acid and water content accounts for the soft, fragile texture of the ripened cervix, whereas the breakdown and loss of collagen and dermatan/chondroitin sulfates facilitate flexibility and distensibility.

The biochemical events underlying cervical maturation indicate it is an active cellular process and is thus subject to regulatory control. The activity of collagenase and other proteolytic enzymes rises with the increasing intrauterine estrogen dominance in late gestation. Conversely, in non-pregnant human cervix explants, collagen breakdown is diminished by progesterone administration. PGs, especially PGE2 are clearly involved in cervical ripening at term in women. PGs have been used clinically for years to induce first and second trimester abortions and cervical ripening. Further, in humans ripening of the cervix is associated with increased PGI2 and HETE production. The latter are arachidonic acid metabolites produced by lipoxygenase enzymes. HETEs and their metabolites are potent chemoattractants; PGI2 is involved in increasing vascular permeability during inflammatory reactions. Based on these observations it is possible production of these mediators summons the polymorphonuclear leukocytes known to infiltrate the cervix at term and leads to enzyme secretion and collagen degradation.

In addition to evidence of their local production by the cervix, PGs have been shown to have effects on cervical ripening in vivo. In late pregnant sheep treated with epostane, a 3βHSD inhibitor which decreases progesterone synthesis, there was an increase in utero-ovarian plasma PGE2 and PGF2α. This was accompanied by increases in uterine activity and cervical softening. Addition of the PG synthesis inhibitor, mefenamic acid, caused PG levels to fall and uterine activity and cervical softening to cease.

The hormone relaxin is also postulated to be involved in cervical ripening. In non-pregnant, estrogen-primed rhesus monkeys, relaxin administration induced histologic, biochemical, and biomechanical changes that were similar to normal cervical ripening. Relaxin receptors are present in the human cervix and local administration of relaxin to women is beneficial in cervical dilatation.

Last, a relationship between cervical maturation and the initiation of labor is well demonstrated. In one study women received labor preinduction treatment of oxytocin infusion alone or oxytocin infusion and intracervical PGE2 gel. The contractile activity was no different in the two groups. However, in the PGE2 treated group, the women proceeded to spontaneous labor and delivered fast; the length of the active phase and the second stage of labor was shorter, and the incidence of cesarean sections was lower. Thus, pretreatment of the cervix with PG suppositories causing maturation facilitates a more efficient labor process without an increase in myometrial activity (for a review see Huszar and Walsh, 1991).

Pathogenesis

Before labor and membrane rupture, amniotic fluid is nearly always sterile. The physical and chemical barriers formed by intact amniotic membranes and cervical mucus are usually effective in preventing entry of bacteria. With the onset of labor or with membrane rupture, bacteria from the lower genital tract typically enter the amniotic cavity. With increasing interval after rupture of membranes, the numbers of bacteria can increase. This ascending route is the most common pathway for development of IAI [1]. In 1988, Romero and coworkers [1a] described four stages of ascending IAI (Fig. 3–1). Shifts in vaginal or cervical flora and the presence of pathologic bacteria in the cervix represent stage I. Bacterial vaginosis may also be classified as stage I. In stage II, bacteria ascend from the vagina or cervix into the decidua, the specialized endometrium of pregnancy. The inflammatory response here allows organisms to invade the amnion and chorion leading to chorioamnionitis. In state III, bacteria invade chorionic vessels (choriovasculitis) and migrate through the amnion into the amniotic cavity to cause IAI. When in the amniotic cavity, bacteria may gain access to the fetus through several potential mechanisms, culminating in stage IV; fetal bacteremia, sepsis, and pneumonia may result [8].

Occasional instances of documented IAI in the absence of rupture of membranes or labor support a presumed hematogenous or transplacental route of infection. IAI without labor and without rupture of membranes may be caused by Listeria monocytogenes [9–13]. Maternal sepsis caused by this aerobic gram-positive rod often manifests as a flulike illness and may result in fetal demise. In an outbreak caused by “Mexican-style” cheese contaminated with Listeria, several maternal deaths occurred [14]. Other virulent organisms, such as group A streptococci, may lead to a similar blood-borne infection [15].

IAI may develop as a consequence of obstetric procedures such as cervical cerclage, diagnostic amniocentesis, cordocentesis (percutaneous umbilical cord blood sampling), or intrauterine transfusion. The absolute risk is small with all these procedures. With cervical cerclage, data regarding infectious complications are sparse; reported rates range from 1% to 18%, with increasing rate with advanced dilation [16–18]. After diagnostic amniocentesis, rates of IAI range from 0% to 1% [19,20]. With intrauterine transfusion, infection is reported to develop in approximately 10%. Chorioamnionitis is a rare complication of chorionic villus sampling. Although IAI is very rare after percutaneous umbilical blood sampling, and the fetal loss rate accompanying this procedure is only 1% to 2%, infection is responsible for a high percentage of losses and may lead to life-threatening maternal complications [21].

Two large studies of risk factors for IAI identified characteristics of labor as the major risk factors by logistic regression analysis. These features included low parity, increased number of vaginal examinations in labor, increased duration of labor, increased duration of membrane rupture, and internal fetal monitoring [1,4]. Other data from a randomized trial of active management of labor showed that chorioamnionitis occurs less frequently when labor management features early diagnosis of abnormalities and early intervention [5]. Although internal fetal monitoring is associated with IAI, it should be employed if it enables practitioners to diagnose and treat abnormalities more efficiently.

Risk factors for IAI have been stratified for term versus preterm pregnancies [22]. For patients at term with IAI, the study investigators observed, by logistic regression analysis, that the independent risk factors were membrane rupture for longer than 12 hours (odds ratio [OR] 5.81), internal fetal monitoring (OR 2.01), and more than four vaginal examinations in labor (OR 3.07). For preterm pregnancies, these three risk factors were identified again as being independently associated with IAI, but with differing ORs. Specifically, in the preterm pregnancies, membrane rupture for longer than 12 hours was associated with an OR of 2.49; internal fetal monitoring, OR of 1.42; and more than four examinations in labor, OR of 1.59. One interpretation of these data regarding risk factors among preterm pregnancies is that there was some other risk factor not detected in this survey. Additionally, meconium staining of the amniotic fluid has been associated with an increased risk of chorioamnionitis (4.3% versus 2.1%) [23]. Prior spontaneous and elective abortion (at <20 weeks) in the immediately preceding pregnancy also has been associated with development of IAI in the subsequent pregnancy (OR 4.3 and OR 4.0) [24].

In 1996, a multivariable analysis showed the importance of chorioamnionitis in neonatal sepsis [25]. The OR for neonatal sepsis accompanying clinical chorioamnionitis was 25, whereas for preterm delivery, membrane rupture for longer than 12 hours, endometritis, and colonization with group B streptococcus (GBS), an ORs all were less than 5.

Although Naeye had reported an association between recent coitus and development of chorioamnionitis defined by histologic study [26], further analysis of the same population refuted this association [27]. Other studies have not shown any relationship between coitus and PROM, premature birth, or perinatal death [28].

Historical/Clinical Background

Vasa previa, although uncommon, is highly likely to result in fetal mortality if undetected before membrane rupture. It occurs in approximately 1 of 2500 pregnancies and is associated with velamentous or marginal cord insertions, in vitro fertilization, placenta previa, multifetal gestations, and bilobed or succenturiate placentas.12,26 The incidence is highest with velamentous cord insertions, estimated to be 1 in every 50 cases.18 Velamentous vessels in vasa previa course through the membranes below the presenting part and are thus vulnerable to traumatic injury by the presenting fetal part, or transection at membrane rupture (Fig. 32.3A). Vasa previa can be detected in asymptomatic women as early as the second trimester by ultrasonography and color flow Doppler study.27

Because of the unpredictability of vasa previa and the high fetal mortality rate, screening transvaginal ultrasonography and Doppler study have been recommended in all cases at risk for vasa previa (e.g., low-lying placentas).12,26 However, management later in gestation remains controversial; the primary issue involves when in gestation to intervene, weighing potential complications of prematurity against the likelihood of spontaneous membrane rupture leading to mortality.

4 PMR role in other pathogen infections

It is known that in order to gain entry into its host cells, nonenveloped viruses induce membrane rupture or piercing (Browning, Shneider, Bowman, Schwarzer, & Leiman, 2012; Suomalainen & Greber, 2013). In the case of Adenoviruses, rupture is coupled to dynamin-dependent virus endocytosis and uncoating leading to exposure of the membrane lytic protein-VI (Burckhardt et al., 2011; Meier et al., 2002; Wiethoff, Wodrich, Gerace, & Nemerow, 2005). Based on these data, Luisoni and coworkers showed that human Adenovirus (hAV) use lysosomal mediated PMR to infect HeLa cells (Luisoni et al., 2015). In their work they showed that hAV infection induced the increase of ceramide in cell membranes and that inhibition of ASM activity leads to decreased invasion by the virus. On the other hand, incubation of cells with ASM led to an enhancement of virus endocytosis by the cell. Additionally, they showed that ceramide facilitates insertion of the virus lytic protein-VI, which is responsible to make pores on the host cell membrane (Luisoni et al., 2015). They further showed that insertion of hAV lytic protein-VI leads to lysosome secretion. These data altogether strongly indicates a role for lysosome-triggered PMR in hAV infection. First, exposure and insertion of virus lytic protein-VI in host cell membranes occurs through virus binding to host cell receptors and is further potentiated by ASM generation of ceramide. This would then enhance viral endocytosis and later help virus escape to host cell cytosol (Luisoni et al., 2015). Additional reports show the importance of ASM/membrane ceramide enrichment and most likely PMR in other nonenveloped viruses, such as rhinoviruses, Japanese encephalitis virus, Misles virus, Ebola virus and Porcine Alphaherpesvirus pseudorabies virus (Avota, Gulbins, & Schneider-Schaulies, 2011; Grassme, Riehle, Wilker, & Gulbins, 2005; Pastenkos, Miller, Pritchard, & Nicola, 2019; Tani et al., 2010). In many of them, ASM activity is involved not only in viral entry into host cells, but also its later escape from endosomal vacuole. The latter, as mentioned, is probably related to the fact that these viruses secrete lytic proteins, which insertion into host cell membranes may be facilitated by ceramide enrichment in vacuolar membranes, as has been described for hAV (Luisoni et al., 2015). For caliciviruses, ASM activity and ceramide has been implicated in virus endosome escape, but not invasion (Shivanna, Kim, & Chang, 2015). However it has been shown that calicivirus invasion occurs in a dynamin and cholesterol-dependent pathway, which does not involve clathrin (Gerondopoulos, Jackson, Monaghan, Doyle, & Roberts, 2010; Perry & Wobus, 2010). Cholesterol have been implicated with PMR so it is possible that also for this virus, ASM and PMR may be involved with its host cell entry process.

Other than viruses it has been shown that ASM is implicated with Neisseria gonorrhoeae infection in epithelial cells (Grassme et al., 1997), which may suggest a role for PMR also in host cell invasion by this bacteria. PMR-related mechanisms have also been shown to interfere with other bacterial infection. For Salmonella enterica serovar Typhimurium, PMR-related mechanisms were shown to be involved with restriction of bacteria growth inside the host cell, working as a host resistance factor (Roy et al., 2004). Salmonella, like other bacteria, use a very sophisticated secretion system, which is able to inject a series of bacterial components that hijacks intracellular pathways facilitating bacteria invasion and replication inside host cells (Costa et al., 2015). These secretion systems assemble a structure that is able to insert into the host cell membranes, forming a pore that allows for the delivery of bacterial components into the host cells (Costa et al., 2015). In the case of Salmonella, they use the type III secretion system (T3SS) not only for invasion, but also for its intracellular trafficking and vacuole maturation (Deng et al., 2017). Salmonella invades host intestinal epithelia, by inducing host cell cytoskeleton remodeling, which leads to its phagocytosis by these cells (Patel & Galan, 2005). Later, this system is also responsible for controlling bacteria containing vacuole (BCV) maturation, avoiding intracellular fusion with lysosomes (van der Heijden & Finlay, 2012). However, it was also shown that shortly after invasion, some BCVs may fuse with lysosomes and that this is responsible for bacterial killing, suggesting that it might be a way that host cells restrict intracellular growth. This fusion with lysosomes was shown to be dependent on Synaptotagmin VII (SytVII), a calcium sensor localized to lysosomes and responsible for inducing lysosomal exocytosis upon calcium signaling (Martinez et al., 2000). Absence of SytVII or its inhibition abolished lysosomal fusion and bacterial growth restriction in epithelial cells or macrophages (Roy et al., 2004). It was then postulated that T3SS pores formed during bacterial invasion would induce calcium signaling events that would trigger lysosomal exocytosis and fusion with nascent vacuoles, helping host cells control Salmonella infection, at least partially (Roy et al., 2004).

IRREVERSIBLE CELL INJURY

Elective cesarean delivery

Prolonged duration of membrane rupture is associated with MTCT; elective cesarean delivery (performed prior to labor and membrane rupture) has been shown to reduce MTCT in an individual patient data meta-analysis including 8,533 non-breastfeeding mother–child pairs from 15 prospective US and international cohort studies, and a randomized clinical trial [8, 9]. Non-elective cesarean delivery performed after onset of labor or rupture of membranes did not reduce MTCT compared with vaginal delivery.

It is unclear if benefit would be observed in women on receiving potent combination drugs who have undetectable virus [78, 79]; in this situation, the risk of MTCT is very low and the risk of operative delivery to the mother may outweigh the potential benefit in reducing MTCT.

Abstract

Necrosis is a form of cell death morphologically characterized by a gain in cell volume, swelling of organelles, plasma membrane rupture, and subsequent loss of intracellular contents. In sharp contrast to widely held beliefs of the past, necrosis can be triggered by unregulated as well as regulated events. Unregulated cell necrosis (UCN) is an accidental type of cell death that lacks an underlying coordinated program of signaling events, and it is caused by overwhelming levels of cell injury or stress. Conversely, regulated cell necrosis (RCN) is a tightly regulated and genetically controlled process that occurs as a consequence of an extensive crosstalk between several and distinct biochemical and molecular events at different cellular levels. RCN plays a major role in numerous pathophysiological disorders. Recently, various forms of RCN have been described including necroptosis, which is the most studied at the cellular and molecular levels. Modulation of key mediators and cellular processes involved in RCN signaling may provide benefits to the treatment of multiple human diseases. In this article, we present a comprehensive overview on recent advances in our understanding of cell death and regulated cell death modalities, with emphasis on necroptosis, and discuss its emerging role in biology, toxicology, and medicine as a new potential cytoprotective approach for therapeutic interventions.

Smoking

Smoking during pregnancy increases health risk for both the mother and infant in the form of complications such as miscarriage, membrane ruptures, ectopic pregnancy, pneumonia, and stillbirth. Women who smoke during pregnancy have lower birth weight babies on average and are at a greater risk for having an infant classified as low birth weight. The seminal study of the impact of smoking on infant health is the randomized-controlled trial of Sexton and Hebel (1984), in which pregnant smokers were randomized into a treatment group receiving assistance quitting smoking and a control group receiving no intervention. Babies whose mothers were in the treatment group were on average 92 g heavier than control group babies.

The 1964 Surgeon General Report on Smoking and Health alerted the nation to the health hazards of smoking resulting in a reduction in smoking among pregnant women that was concentrated among higher-educated mothers. A study comparing birth outcomes of children before and after the release of the Surgeon General Report reveals that higher smoking rates are associated with lower birth weight. However, no effect of smoking was found on gestation, prematurity, or the likelihood of having a low birth weight baby. These results are similar to studies that use increases in cigarette excise taxes to estimate the impact of smoking on birth weight.

Elective Cesarean Delivery

Prolonged duration of membrane rupture is associated with the risk of MTCT; elective cesarean delivery (performed prior to labor and membrane rupture) has been shown to reduce the risk of MTCT in an individual patient data meta-analysis including 8533 non-breast-feeding mother-child pairs from 15 prospective US and international cohort studies, and a randomized clinical trial.4,5 However, non-elective cesarean delivery (performed after onset of labor or rupture of membranes) did not reduce MTCT compared with vaginal delivery.

In these studies, elective cesarean delivery reduced transmission among women receiving antiretroviral drugs (primarily AZT alone). However, it is unclear if benefit would be observed in women on HAART with undetectable virus. The European Collaborative Study recently reported data from 4525 women that suggested MTCT was reduced with elective cesarean delivery among all women delivering in the HAART era; however, among the subset of 560 women with undetectable HIV-1 RNA levels, while on univariate analysis elective cesarean delivery was associated with a significant reduction in MTCT, this effect was no longer significant after adjusting for antiretroviral therapy.48 In women with low risk of transmission, such as those on HAART with low viral load, the risk of operative delivery to the mother may outweigh the potential benefit in reducing MTCT. Additionally, postoperative complications are slightly more common after elective cesarean delivery among HIV-infected than uninfected women, with the difference greatest among women with immunologic suppression.32

Ascending Infection

Ascending infection is an extremely common process and minimal degrees are frequent in term placentas. It is seen with intact membranes although membrane rupture facilitates the process. Acute inflammation in the membranes is not associated with any process other than ascending infection (e.g. meconium, hypertension), and its presence indicates that some organism has contaminated the amniotic cavity. Although typical hospital cultures may be negative, organisms are recovered in the majority of cases when sensitive specific culture techniques are used. Mycoplasma, Ureaplasma, and anaerobes are frequent agents and are relatively nonpathogenic for the fetus. Organisms enter the lungs from fetal aspiration of amniotic fluid. Infants with early sepsis usually have ascending infections in their placentas, but most (95%) infants with placental inflammation are not septic. Some but not complete correlation of the severity of fetal and placental disease exists.

The inflammatory process itself creates problems. It may directly weaken the membranes and release substances promoting premature labor. The incidence of chorioamnionitis increases with decreasing gestational age, and ascending infection contributes to more than 30% of preterm deliveries, depending on the population. Treatment of intrauterine infections with antibiotics has not been successful in significantly delaying delivery. Inflammation in large fetal blood vessels may cause abnormal intrauterine heart patterns through changes in umbilical vascular reactivity with potential hypoxia.38 There is much interest in the systemic effects of cytokines released by the inflammatory process. Neurologic problems and cerebral palsy are more common in infants with chorioamnionitis.

In severe amniotic sac infections, the fetal surface is green and opaque with an indistinct vascular pattern (Fig. 40-19A). Mild processes are difficult to identify by gross examination. Some placentas smell foul. On microscopic examination, inflammation of the fetal surface is often seen first. This inflammation progresses from aggregation of maternal neutrophils in the intervillous space under the chorion to invasion of the chorion and amnion (see Fig. 40-19B). This maternal response is often accompanied by fetal response with neutrophils migrating toward the amnion from surface vessels (Fig. 40-20A). Different observers use different criteria for the minimal level of inflammation, as low as the aggregation of five neutrophils under the subchorionic fibrin. The membranes first show maternal neutrophils in a diffuse decidual perivascular reaction, then a bandlike infiltrate at the decidual-chorion interface, and finally infiltration of the chorion and amnion. The rupture point usually has the most severe reaction, frequently with necrosis. Fetal reaction also occurs in the umbilical cord, usually the vein first. Cells move from all three vessels into Wharton's jelly (funisitis).

The degree of inflammation can differ widely at different locations. The severity of the inflammation should be evident from the diagnosis rendered in the report. Some pathologists have used grading corresponding to the terms subchorionic intervillositis, chorionitis, and chorioamnionitis. Bacteria and necrosis should be noted. Cell breakdown suggests a longer duration. The exact time course for ascending infection is unknown because it is difficult to identify the true time of amniotic sac contamination given that chorioamnionitis often precedes rupture of membranes or labor. Clinical signs often do not correlate with placental findings. Many asymptomatic mothers have well-developed pathologic changes. The time course and exact pattern of inflammation likely vary by organism. Fusobacteria lead to severe necrotizing inflammation with visible organisms on routine and bacterial stains. Candida produces distinct nodular, yellow fungal microabscesses on the cord surface. Group B streptococcal infections may show evidence of chorioamnionitis, although some fulminant infections show no inflammation with abundant organisms. Herpes causes chronic chorioamnionitis with plasma cells but is very uncommon in current obstetric practices.

Necrotizing funisitis is a mixed or chronic inflammatory process surrounding the vessels of the umbilical cord. Necrosis and calcification are common (see Fig. 40-20B).39 Grossly these cords are stiff and have a “barber pole” configuration. This nonspecific finding apparently results from a long-standing ascending antenatal infection by an organism of low virulence. The infants are usually premature but do not have sepsis.