Gestational Diseases and the Placenta

Historical/Clinical Background

Acute chorioamnionitis is the most common histologic diagnosis made in placentas sent for pathologic evaluation. Preterm births account for the majority of cases, with a decrease in prevalence with advancing gestational age. Almost all spontaneous preterm births at 21 to 24 weeks' gestation demonstrate histologic chorioamnionitis, whereas it is present in only 5% to 10% of cases at 35 to 36 weeks' gestation. Overall, acute chorioamnionitis has been reported in 21% to 24% of term placentas and as many as 67% of preterm placentas. Many associated complications exist, the frequencies of which are also gestational age dependent, including maternal or fetal sepsis, premature membrane rupture, preterm labor, and adverse long-term neurodevelopmental outcome.

Intrauterine infection can occur via four main routes, the first of which is by far the most common: (1) ascending from the cervix, vagina, and perineum (also called amniotic fluid infection syndrome ), (2) hematogenous maternal-to-fetal spread, (3) iatrogenic introduction via invasive techniques, and (4) retrograde spread through the fallopian tubes.

Pathophysiology

In each of these situations, in response to maternal innate immune system detection of microorganisms, inflammatory chemokines and cytokines (e.g., interleukin 8, interleukin 1β, tumor necrosis factor) are released. Microbial endotoxin and additional maternal inflammatory mediators, including matrix-degrading enzymes, contribute to progressive cervical dilation and eventual membrane rupture. Leukocytic prostaglandins stimulate uterine contractions, and labor is initiated.

Until only recently, it was believed that the fetus developed in an essentially sterile environment, and when intrauterine infection occurred, it was most often a consequence of ascending infection from the cervix, vagina, and/or perineum. Recent studies using comparative 16S ribosomal DNA-based and whole-genome shotgun metagenomics methods have demonstrated a unique low-biomass microbiome in human placentas. Furthermore, taxonomic analyses have revealed association of the placental microbiome with preterm birth. These studies at least call into question the long-standing belief that the majority of intrauterine infections are caused by ascending infection; however, the role of the placental microbiome in preterm birth, as well as other inflammatory conditions, requires future study because many questions remain to be addressed.

Microorganisms can be demonstrated with conventional culture technique in fewer than half of preterm births. However, recent molecular microbiologic techniques, such as polymerase chain reaction (PCR), have improved the detection rate, especially in the cases with negative amniotic fluid culture. Among numerous bacterial species that have been isolated, the most common organisms found in the amniotic cavity are genital Mycoplasma species, in particular Ureaplasma urealyticum , followed by Mycoplasma hominis, Streptococcus agalactiae, Escherichia coli, Fusobacterium species, and Gardnerella vaginalis . Candida albicans and other fungi also may occasionally cause acute amniotic fluid infection.

Clinical Evaluation

The clinical diagnosis of “acute chorioamnionitis” in women in preterm labor may be challenging owing to variable presentation and variable or inconsistent use of terminology and clinical diagnostic criteria. The results of a recent workshop focusing, in part, on the evaluation of women diagnosed with clinical chorioamnionitis, acknowledges that this term is clinically applied to a heterogeneous group of infectious and inflammatory conditions and also that this term conveys a definitive infectious etiology when one many not be present. Therefore, the term “intrauterine inflammation, infection, or both” is recommended. Furthermore, in the situation of maternal fever (>39° C or 102.2° F on one occasion or >38° C or 100.4° F on two occasions at least 30 minutes apart) absent other symptoms, the term isolated maternal fever is recommended. The diagnosis of intrauterine inflammation, infection, or both is recommended when maternal fever is present, as well as one or more of the following: fetal tachycardia (>160 beats/minute for >10 minutes), elevated maternal white blood cell (WBC) count (>15,000), purulent fluid from the cervical os, or biochemical or microbiologic amniotic fluid results consistent with microbial invasion of the amniotic cavity.

Clinical Correlates/Outcome

The clinical outcome of acute chorioamnionitis, including maternal and fetal inflammatory response, has been previously discussed in Chapters 31 and 32 .

Gross Evaluation

Features of ascending amniotic infection that can be appreciated on gross examination have been discussed previously in Chapter 31, Chapter 32 (see “ Ascending Infection in Amniotic Fluid Infection ”). From the clinical perspective, it is important to remember that gross pathologic features are variable and correlation with microscopic pathology is imperfect, but that histologic identification of maternal with or without fetal inflammation trumps gross features of inflammation.

Diagnostic Criteria

Microscopic features of acute chorioamnionitis have been discussed previously in Chapter 32 (see “Ascending Infection” ) and in multiple sections by location of inflammation (e.g., umbilical cord, membrane roll) in Chapter 31 . Schema for staging and grading maternal and fetal inflammatory responses are presented in Table 32.1 .

Immunohistochemistry and Special Studies

As also discussed in Chapter 32 , placental cultures and special stains have a limited role in identifying causative organisms. Using conventional culture techniques, microorganisms can be demonstrated in fewer than half of preterm births. Gram and silver stains (e.g., Gomori methenamine silver [GMS], methenamine silver stain [MSS]) can be used to confirm the presence of microorganisms but are usually insufficient to determine species. The specificity of viral immunohistochemical stains (e.g., CMV, HSV I/II) often allow identification of the causative organism. Recently, PCR-based techniques using bacterial 16S or fungal 18S ribosomal RNA have improved the detection rate, especially in the cases with negative amniotic fluid culture. Among numerous bacterial species that have been isolated, the most common organisms found in the amniotic cavity are genital Mycoplasma species, in particular U. urealyticum , followed by M. hominis, S. agalactiae, E. coli, Fusobacterium species, and G. vaginalis . Candida albicans and other fungi also may occasionally cause acute amniotic fluid infection.

Differential Diagnosis and Potential Pitfalls

The main histologic differential diagnosis when considering acute chorioamnionitis is chronic chorioamnionitis, a process that may, at least in some cases, represent maternal anti-fetal rejection. In chronic chorioamnionitis the inflammatory infiltrate also involves the chorionic plate but is instead composed of maternal CD8 ⁺ T cells. The extent of the infiltrate is often less severe and less diffuse than the infiltrate seen in acute chorioamnionitis. It is also important to remember that maternal and/or fetal neutrophilic inflammation is not de facto equivalent to infection; correlation with additional clinical and pathologic findings is needed.

Key Clinicopathologic Questions Faced by the Pathologist

• Q: If there is no clinical query of chorioamnionitis but I see subchorionic neutrophils, should I make the diagnosis?

• A: Maternal inflammation limited to the subchorionic zone is best termed acute subchorionitis (early/evolving chorioamnionitis).

Historical/Clinical Background

Cervical incompetence is a clinical diagnostic term that is synonymous with cervical insufficiency and is classically defined as recurrent second-trimester pregnancy loss following painless cervical dilatation, attributed to the inability of the cervix to retain the gestation. Cervical incompetence can result from prior traumatic injury to the cervix associated with a prior delivery or previous surgery (e.g., conization, amputation), congenital uterine anomalies, such as those resulting from diethylstilbestrol (DES) exposure, or intrinsic deficiencies in cervical collagen and elastin. The incidence of cervical insufficiency is estimated to be 1% of all pregnancies and as many as 20% of midsecond trimester spontaneous pregnancy losses. In general, cervical incompetence is classified on a continuum, in that gradations of cervical length may influence risk. Recent studies have examined cervical length as a screening tool utilizing transvaginal ultrasound, demonstrating progressive increase in risk as a function of reduced cervical length, with a cut-off point assigned according to gestational age, being demonstrated. The ideal gestational age for screening transvaginal ultrasound is 16 to 24 weeks, with reported cervical length ranges from 1.5 to 5 cm. Cervical length less than 2.5 cm falls below the 10th percentile for 16 to 24 weeks, and at 21 to 25 weeks, 1.5 cm is the second percentile. This screening test is not considered useful after 28 weeks' gestation, when physiologic cervical shortening occurs.

Pathophysiology

The cervix plays a critical role in protecting the intrauterine environment. Before parturition, the cervix is firm, composed predominantly of collagen. Any con­dition that degrades collagen enhances cervical softening and pliability, which sets the stage for dilatation. As previously mentioned, this process involves several mediators, including prostaglandins and cytokines; thus, it is not surprising that inflammation is frequently seen in the setting of preterm labor. The cervical canal normally contains mucus with antibacterial properties. With cervical dilatation, these antibacterial properties are impaired, increasing the risk of ascending infection, which subsequently stimulates progressive cervical dilatation. As a result, the cervix becomes incompetent to retain intrauterine contents, and preterm delivery ensues.

Clinical Evaluation

The typical clinical presentation of preterm delivery associated with cervical incompetence is painless cervical dilatation with protruding or ruptured membranes and abrupt delivery. Efforts at prevention have focused on the cervical cerclage. However, only a proportion of women with prior early gestational losses experience repeat miscarriage, irrespective of management; thus, the value of cerclage placement in a given case has been controversial. Furthermore, cerclage does not entirely prevent preterm birth in all women with short cervical length assessed by transvaginal ultrasonography. There is no proven benefit of prophylactic cerclage in women at low or medium risk of second-trimester loss, regardless of cervical length by ultrasound.

Gross Evaluation (Including Pitfalls)

The possibility of cervical incompetence can only be evaluated indirectly on placental examination. Often, cervical incompetence is associated with significant acute chorioamnionitis, therefore, the placenta, umbilical cord, and/or membranes may show gross features of acute chorioamnionitis (previously discussed). The placentas associated with cervical incompetence may also show marginal, retroplacental, or subchorionic hemorrhage. We have termed this constellation of findings inflammatory abruption, a pattern that raises concern for cervical incompetence (discussed later), or at the very least for an increased risk of recurrent preterm delivery.

Clinical Correlates/Outcome

Without intervention, cervical incompetence often results in preterm delivery. In women without signs of intrauterine infection or painful uterine contractions, emergency cerclage placement prior to 26 weeks' gestation has been shown to prolong pregnancy compared to conservative management. History of prior preterm birth is a risk factor for subsequent preterm birth; however, only a proportion of women with prior early gestation in the setting of cervical incompetence experience repeat miscarriage, regardless of management strategy. As such, the value of cerclage placement in a given case has been controversial. Furthermore, cerclage does not entirely prevent preterm birth in all women with short cervical length. There is no proven benefit of prophylactic cerclage in women at low or medium risk of second-trimester loss, regardless of cervical length by ultrasound.

Diagnostic Criteria

As with the gross examination, cervical incompetence cannot be determined based on microscopic examination. However, associated features such as acute chorioamnionitis, acute deciduitis, and “inflammatory abruption” may be seen.

Differential Diagnosis (and Potential Pitfalls)

After placental examination, and in the context of clinical correlation (e.g., spontaneous pre-viable delivery), the pathologist can raise concern for cervical incompetence/recurrent preterm delivery based on the constellation of findings; however, the diagnosis is ultimately a clinical one. It remains important for the pathologist to exclude mimics of acute chorioamnionitis (such as, chronic chorioamnionitis) and non-inflammatory abruption.

Key Clinicopathologic Questions Faced by the Pathologist

• Q: What is the most accurate way to word a comment raising concern of clinical cervical incompetence, based on pathologic findings in a placenta with chorioamnionitis and “inflammatory abruption” in the pre-viable period?

• A: After enumerating the findings in the diagnosis, a comment can be added that: “The constellation of findings noted above and occurring in the pre-viable period raises concern for an increased risk of recurrent preterm delivery. Clinical correlation is recommended.”

Historical/Clinical Background

Histologic abruption is more prevalent with advanced stage maternal inflammation (stages 2 and 3) in second-trimester compared with third-trimester deliveries. The term inflammatory abruption applies to cases of inflammation-induced maternal bleeding and is more prevalent with advanced stage maternal inflammation (stages 2 and 3) in second-trimester compared with third-trimester deliveries. Inflammatory abruption must be distinguished, at least conceptually, from classic placental abruption (see Chapter 32 ) resulting from maternal vascular disorders that typically occur later in gestation, and from chronic abruption (see later).

Pathophysiology

The pathogenesis of inflammatory abruption begins with cervical dilatation, which allows infectious organisms to ascend through the endocervical canal, infecting first the decidua adjacent to the internal os, leading to acute deciduitis and chorioamnionitis. Decidual inflammation is believed to then contribute to aberrant coagulation. In this model, a plausible pathogenesis is that proinflammatory cytokine release from acute deciduitis destroys extracellular matrix and maternal vessel walls, causing perivascular leakage of plasma proteins and coagulation factors, loss of vessel integrity, and ultimately leading to hemorrhage ( Fig. 33.1 ). Bleeding usually originates in the marginal area of the placenta ( Fig. 33.2A ), undermining the placental edge and extending into the subchorionic and retroplacental zones (see Fig. 33.2B ). Because the placenta is relatively fragile in mid-gestation, dissecting intervillous hemorrhage is also commonly seen (see Fig. 33.2C ).

Clinical Evaluation

The clinical presentation of inflammatory abruption is variable depending on the extent of infection and hemorrhage. Gestational bleeding is not a reliable indicator of abruption.

Clinical Correlates/Outcomes

Placental abruption of any type is associated with adverse perinatal outcomes including stillbirth, preterm delivery, and intrauterine fetal growth restriction; however, outcome studies tend not to distinguish among types of abruption, and conclusions and magnitude of risk are likely biased toward outcomes typical of classic placental abruption.

Gross Evaluation (Including Pitfalls)

The placenta may show similar features as seen in acute chorioamnionitis, such as discolored membranes, as well as evidence of bleeding. Bleeding usually originates in the marginal area of the placenta (see Fig. 33.2A ), undermining the placental edge and extending into the subchorionic and retroplacental zones (see Fig. 33.2B ). If not disrupted during delivery or en route to pathology, adherent blood clot may be found on the maternal surface.

Diagnostic Criteria

In inflammatory abruption, evidence of acute deciduitis, acute subchorionitis, and/or acute chorioamnionitis will be seen. Additionally, subchorionic and/or intervillous hemorrhage are often present; the placenta is relatively fragile in mid-gestation, therefore maternal blood more readily dissects into the disc parenchyma (see Fig. 33.2C ).

Differential Diagnosis and Potential Pitfalls

Based on the finding of blood clot adherent to the maternal surface of the placenta on gross examination, the differential diagnosis may include classic placental abruption and chronic abruption; however, these can usually be excluded microscopically based on the absence of associated acute inflammation in the chorionic plate, decidua, membranes, and/or umbilical cord and by correlation with the clinical history.

Key Clinicopathologic Questions Faced by the Pathologist

• Q: If the patient is hypertensive and has a pre-viable delivery with abruption, how can I be sure the abruption isn't a consequence of underlying hypertension?

• A: Hypertension-induced abruption in mid-gestation is rare; if present, one would expect to see additional features of maternal malperfusion, such as fetal and/or placental growth restriction, decidual arteriopathy, patterns of villous ischemia, and so on. One would also not expect to see chorioamnionitis. Correlation with the clinical history (features of infection, clinical severity of hypertension) should also be informative.

Historical/Clinical Background

The term chronic abruption applies to cases of maternal venous hemorrhage leading to marginal premature placental separation. Chronic abruption is associated with several conditions including oligohydramnios, in which case the clinical constellation is termed chronic abruption-oligohydramnios sequence . Chronic placental bleeding typically occurs days or weeks before delivery and is reflected in the placenta by a constellation of features termed diffuse chorioamnionic hemosiderosis (DCH) (see later).

Clinical Evaluation

Placental abruption is defined as premature detachment of the placenta. Classical placental abruption is associated with maternal vascular disorders caused by arterial bleeding, whereas venous hemorrhage leads to marginal and chronic abruption. The classic clinical presentation with abdominal pain, heavy vaginal bleeding, and fetal distress is seen with large acute arterial abruption (see Chapters 31 and 32 for discussion of abruptio placentae). By contrast, venous abruption often presents with low-level, persistent, or recurrent vaginal bleeding, often in the absence of other signs of maternal or fetal disease. Maternal history associated with DCH includes subchorionic hematoma diagnosed by ultrasound in the first trimester, recurrent vaginal bleeding, and brown discolored amniotic fluid.

Clinical Correlates/Outcomes

DCH is associated with many adverse neonatal outcomes, such as preterm delivery, intrauterine growth restriction (IUGR), persistent pulmonary hypertension of the newborn, “dry lung syndrome,” and neurologic impairment.

Gross Evaluation (Including Pitfalls)

Chronic/persistent vaginal bleeding induces placental changes that manifest as (1) circumvallation (a consequence of blood dissecting beneath the membrane attachment to the placental disc); (2) degenerating retromembranous, subchorionic, or marginal blood; and (3) muddy brown or green-brown discolored membranes and chorionic plate, which may appear similar to long-standing meconium staining ( Fig. 33.3A ).

Diagnostic Criteria

Microscopic examination reveals scattered to abundant hemosiderin deposition that appears as refractile dark brown pigment on hematoxylin and eosin (H&E) stained slides. The hemosiderin is usually phagocytosed by macrophages within the extraplacental membranes and chorionic plate (see Fig. 33.3B ). Other pathologic features of chronic maternal circulatory compromise (e.g., accelerated villous maturation, villous agglutination, increased intervillous fibrin, proliferation of intermediate trophoblast) may also be seen in placentas with chronic abruption. This malperfusion constellation likely reflects diminished placental efficiency due to circumvallation, because there is no association between DCH and maternal hypertensive-type disorders.

Immunohistochemistry and Special Studies

Confirmation of the pigment as hemosiderin can be demonstrated by Prussian blue iron stain (see Fig. 33.3C ), which stains hemosiderin blue. Of note, blood breakdown pigments, such as bilirubin, will appear yellow on H&E stained slides and will not be highlighted by Prussian blue stain.

Differential Diagnosis and Potential Pitfalls

Based on the finding of blood clot adherent to the maternal surface of the placenta on gross examination, the differential diagnosis may include classic placental abruption and inflammatory abruption. These can usually be excluded microscopically based on the absence of hemosiderin deposition in extraplacental membranes and/or the chorionic plate, the absence of circumvallation, and the absence of established chorioamnionitis.

Key Clinicopathologic Questions Faced by the Pathologist

• Q: How many features of DCH are required to make the categorical diagnosis?

• A: We recommend identification of degenerated maternal blood with associated hemosiderin-laden macrophages in the membranes and chorionic plate, and involving at least half of the area sampled. There should also be a third piece of corroboratory evidence (such as circumvallation) and/or associated clinical features (such as non-acute vaginal bleeding, oligohydramnios, preterm delivery, or fetal growth restriction).

Hypertensive Disorders of Pregnancy

Placental Abruption/Abruptio Placentae

Maternal Diabetes and Fetal Macrosomia