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Early Path Medical Consultation Services
Pathology Services Working for Safer Pregnancies

Placental Pathology - Medical Student Lecture 2001
Carolyn M. Salafia, MD
Professor of Pathology and Pediatrics

CONTENT

1. OVERVIEW

2. INTRODUCTION

3. PREECLAMPSIA

4. FETAL GROWTH

5. INTRAUTERINE INFECTION

6. MULTIFETAL PREGNANCY

INTRAUTERINE INFECTION

Demonstrate the pathways of intrauterine infection: (ascending or bacterial infection, versus transplacental or hematogenous viral infection)

The pathways of intrauterine infection include ascending, hematogenous, transabdominal or transfallopian. The most common is infection ascending from the perineum, cervix and vagina. Ascending infections classically derive from cervicovaginal flora with "wanderlust", or in the context of abnormal host defenses (from cervical mucus plug, to immune response, to cervical competence). The causative organisms are often of low virulence and commonly colonize this area but may be pathogens (e.g. e.coli). The infectious agent passes directly through intact or ruptured membranes into the amniotic fluid space. Both the mother and the fetus can respond to the presence of intraamniotic infection. The mother's response is seen in the extraplacental membranes, and the chorionic plate. The maternal response to a bacterium or its toxins in the amniotic cavity results in neutrophil margination in extraplacental membranes. In the membranes, neutrophils are recruited from decidual capillaries, and neutrophils move through the decidua, into the chorion, and, eventually, will invade the amnion (Figure 10). In the subchorionic area of the intervillous space, maternal circulating neutrophils will first attach to subchorionic fibrin, and next invade the chorionic plate proper. (Figure 11) Amniotic fluid neutrophils can be obtained by amniocentesis to diagnose subclinical intra-amniotic infection. Even when neutrophils have entered the amniotic fluid (and the inflammatory process therefore so well established), the mother may be clinically asymptomatic.

On the fetal side, fetal neutrophils can be recruited from either umbilical or chorionic arteries or veins. (Figures 12, 13) Activated endothelium must precede neutrophils attachment and diapedesis, implicating some fetal cytokine load. When infection is longstanding, lysis and calficiation of fetal neutrophils in Wharton's jelly can lead to "sclerosing or necrotizing funisitis" (Figure 14). Timing of onset of infection is problematic, in general but can be estimated on a case-by-case basis by careful clinical-pathologic correlation. Variables include the bacterial load, bacterial virulence, maternal and fetal immunocompetence and antibiotic therapy.

Maternal white cells eventually reach the amniotic fluid where they may be swallowed and aspirated by the fetus. Intraamniotic bacteria may cause congenital pneumonia (Figure 15) gastroenteritis, sepsis, otitis media and meningitis. The inflammatory pattern of acute inflammation of membranes, chorionic plate, and umbilical cord is specific for ascending infection. Inflammation of the tissues abutting or contained within the amniotic fluid space is not a secondary effect of intrauterine fetal demise or meconium staining. Sometimes, when the baby is retained within the mother's body for several days asymptomatically before delivery, some mild maternal inflammation in membranes and plate can be seen, but there will be no fetal inflammatory response. This is most commonly a post-mortem event, ascending organisms arriving in the amniotic fluid space after fetal death upon the slow dilatation of the cervix. Organisms are frequently not recovered by routine culture methods; the addition of anaerobic, Mycoplasma and Ureaplasma cultures will result in recovery of organisms in over 75% of cases; many are mixed infections. Mild acute ascending infection may be missed on gross inspection of the membranes, but severe infection will result in opacification, discoloration (Figure 16), and depending upon the organisms, a foul odor of the placenta. Most ascending infections will result in an acute histologic inflammatory picture, if the pregnancy remains in utero long enough for cytokines to accumulate in the amniotic fluid and elicit neutrophil recruitment.

Infected membranes, filled with neutrophils containing digestive enzymes and releasing prostanoids (that can stimulate uterine contractions), are weaker, and may rupture before the third trimester when the lower uterine segment starts to dilate and the baby's head begins to descend (creating additional tensile strain on the membranes), or before the onset of labor (when the force of uterine contractions can also strain the membranes). When membranes rupture in the absence of any clinically identifiable stressors, membrane rupture is "spontaneous". Premature spontaneous rupture of membranes for greater than 18 hours may be associated with acute ascending infection, but membranes most often rupture because they are already infected, in this reviewer's clinical experience. The prostanoids released either by the mother's neutrophils, or by the invading organisms themselves may initiate uterine contractions before all the third trimester physiologic modifications that allow normal labor at term are complete. Acute intraamniotic infection may "cause" as many as 50% of premature deliveries, and only 25% (or fewer) of mothers are symptomatic. Rare infants are septic at the time of delivery. Poorer fetal well-being (as assessed by biophysical profile score), abnormal fetal heart rate, and at least in some populations, increased umbilical systolic/diastolic ratio are associated with acute ascending infections. Acute inflammation is more common and often more severe in more premature placentas. Some bacterial contamination of the amniotic fluid space appears to be common even in healthy term deliveries. This may be because it takes time for the cervix to efface and dilate, and the chance that some small number of bacteria could 'ascend' is large. However, in babies born preterm because of acute infections, those infections seem to be present long enough to have put in place the tissue injury and chemical processes described above so firmly that antibiotic intervention and/or tocolysis (medical attempts to stop uterine contractions) ends up clinically failing, possibly "too little, too late".

Acute inflammation is most common in bacterial infections. Chronic inflammation occurs in cases of viral and (very uncommon) chronic bacterial infections. Viral (hematogenous) infections are more often associated with chronic villitis. (Figure 17) The inflammatory cell type may occasionally help determine the etiologic agent. Plasma cells can be seen with CMV, herpes and syphilis, but this is hardly specific. CMV and syphilis also result in damage to the endothelium and may have variable amounts of hemosiderin in the villi. Congenital viral infections are important to identify for several reasons:

(1) There is long-term risk to the newborn, especially for neurodevelopmental sequelae.
(2) There should be minimal recurrence risk for pregnancy compromise in subsequent pregnancies if chronic villitis is of viral etiology.
(3) If congenital viral infection is not confirmed, an evaluation for phospholipid antibodies or other well-characterized autoimmune conditions may lead to treatment and improved subsequent pregnancy outcome.

Recurrent chronic placental inflammation in the absence of diagnosed maternal phospholipid antibody syndrome is a rare correlate of recurrent pregnancy loss, one that is particularly difficult to diagnose, and to treat.

Chronic villitis of undetermined etiology has been associated with maternal immunopathologic states, and we consider this possibility whenever a poor pregnancy outcome shows chronic villitis in the absence of confirmatory viral cultures. Clinical information regarding parity, intercurrent diseases, and past pregnancy outcome are crucial to appropriate interpretation of the histologic lesion. Chronic villitis means, as a diagnosis, "chronic inflammation in the villi". Especially in preterm cases, chronic inflammation may be predominantly, or only, around the villi. This is called chronic intervillositis. (Figure 18) Sometimes, a nixture of the two can be seen. Dr Redline in Cleveland was the first to demonstrate that the majority of the "extra" cells in villi with villitis are maternal in origin (by performing Y-chromosome probes in cases of chronic villitis of male fetuses). (Figure 19) Even the decidua can be involved. (Figure 20) Unfortunately, it is not clear that any pattern of histology differentiates among the potential causes of chronic placental inflammation, nor recurrence risk.