**3. The fetal side of fetoplacental interface**

Syncytial sprouts arise from the syncytiotrophoblast that covers the cytotrophoblast around the fetal stem villi. In early pregnancy large aggregates of trophoblastic cells proliferate and extend into the intervillous space forming drumstick-like syncytial structures. Syncytial sprouts are multinucleated and have large ovoid nuclei with very little heterochromatin. There are a large number of ribosomes with abundant rough endoplasmic reticulum. Larger nuclei are present in the sprouts as compared to other parts of syncytiotrophoblast. True sprouts are produced from the mesenchyme villi and immature intermediate villi (**Figure 5**). There are continuous differentiation and proliferation of cytotrophoblast into syncytiotrophoblast into sprouts. This can be (a) sprout-like apoptotic shedding, (b) knots or Tenny-Parker changes, (c) wavelike apoptotic shedding, (d) arrested apoptotic shedding, (e) aponecrotic shedding, and (e) necrotic shedding.

#### **3.1 Sprout-like apoptotic shedding**

This is a normal phenomenon in which villous trophoblast proliferates and differentiates into cytotrophoblast. The cytotrophoblast fuses with the overlying syncytiotrophoblast, and finally the old and aging material is packaged into apoptotic syncytial sprouts and released into the maternal circulation. If apoptotic shedding is blocked, the number of nuclei in the syncytium increases. Since it is a membrane-sealed apoptotic material, it does not induce an inflammatory response. In the maternal lung, the syncytial sprouts get trapped and are phagocytosized by lung macrophages without inflammatory reaction. Approximately 3 g of apoptotically shed trophoblast is destroyed in the lungs daily. This is the balance of 3.6 g of cytotrophoblast that is converted to syncytiotrophoblast each day and 0.6 g that is retained in the syncytium [17, 18].

#### **3.2 Tenny-Parker changes or syncytial knots**

The terms syncytial sprouts and syncytial knots are different. True syncytial sprouts happen in first half of pregnancy when they represent early stages of large euchromatic nucleus. Tenny-Parker changes also called as syncytial knots are

bridges between the neighboring villi that look like drumstick or mushroomlike projections containing normally structured nuclei. These are artifacts caused by tangential sectioning of highly branched fetal villi.

### **3.3 Wavelike apoptotic shedding**

In cases of placentas of fetal growth restricted with absent diastolic flow, there is a large decrease in the number of cytotrophoblastic cells, and the thickness of syncytiotrophoblast is also less [19]. The nuclei in syncytiotrophoblast accumulate like a ring around the vertical axis of villi. The underlying pathology is yet to be identified [17, 18].

#### **3.4 Arrested apoptotic shedding**

Apoptotic syncytial nuclei accumulate in knot-like structures but do not get extruded into the intervillous space. This is also seen in the cases of fetal growth restriction with absent diastolic flow. At some places the sites with nuclei are even larger than the cross section of villi from which they arise. It is seen that a large number of these giant knots form all over the placenta. In these cases the apoptotic cleavage of syncytial cytoskeleton may be defective [17, 18].

#### **3.5 Aponecrotic shedding**

Aponecrosis is a term used when signs of apoptotic trophoblast turnover and shedding are associated with signs of syncytial necrosis. Apoptosis continues with damaged plasma membranes, water influx and secondary hydropic changes of cellular structures, and release of cytoplasmic contents. This process is also called as secondary necrosis. Since apoptosis is a programmed cell death depending on cell energy, lack of cell energy reserves could be the cause of aponecrosis. These villous explants contain cell-free DNA, cell-free actin, and membrane-wrapped nuclei. In some studies in preeclampsia, the villous explants that had the packaged nuclei showed early signs of chromatin condensation, but the cytoplasm was edematous and plasma membrane had local defects.

#### **3.6 Necrotic shedding**

In pure necrotic shedding, the villous explants contain edematous nuclei in a hydropic cytoplasm with membrane defects. Placentas from severe preeclampsia and severe Rh incompatibility have shown features of necrotic shedding. The complete absence of chromatin condensation showed that the apoptotic pathway was blocked by inhibitory proteins and never restarted. In an experiment on pregnant guinea pigs, complete blockage of energy metabolism of trophoblast was done by monoiodine acetate or sodium fluoride (inhibitors of glycolysis). Continuous release of necrotic villous explants leads to the features of preeclampsia [17, 18].

If cytotrophoblast keeps growing and accumulating as syncytiotrophoblast and does not shed, it will lead to intrasyncytial accumulation of old and aged trophoblastic components which finally necrose. Cytoplasmic blebbing of syncytium with nuclear and cytoplasmic edema is a hallmark feature of necrotic shedding. Though there are phenotypic similarities among different types of villous explants, there are differences in modes of nuclear chromatin aggregation, nuclear or cytosolic edema. Cracks in the plasma membrane help to differentiate between physiological apoptotic shedding and pathological necrotic shedding.

**13**

**Figure 6.**

*Pathogenesis of preeclampsia in LACHD deficient fetus.*

*Introductory Chapter: The Multiple Etiologies of Preeclampsia*

**4. Placenta as a casualty and not the cause**

**4.1 Liver pathology as a cause of preeclampsia**

Preeclampsia is associated with three unique liver lesions described as liver lesions of preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy. HELLP syndrome has classical periportal or focal parenchymal liver necrosis. There is thrombotic microangiopathy with resulting hemolysis and liver damage. Few cases of HELLP are associated with defects in beta-oxidation of fatty acids. There is microangiopathic hemolytic anemia with schistocytes, thrombocytopenia, and elevated levels of ALT/AST/LDH/bilirubin. HELLP may even develop postpartum,

Acute fatty liver of pregnancy is due to defective oxidation of beta fatty acids. There is mitochondrial deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase in fetus. This leads to accumulation of 3-hydroxyacyl metabolites that are toxic to the liver. Half of the pregnancies with acute fatty liver of pregnancy develop

The renin-angiotensin system (RAS) recognizes pregnancy very early. In the luteal phase of menstrual cycle, the RAS is activated under the influence of progesterone, and if pregnancy occurs, this RAS activation is maintained. This activation of RAS may be caused by progesterone that is natriuretic or it could be the "perceived under filling" of circulation by macula densa in early pregnancy. Juxtaglomerular apparatus synthesizes and releases renin, an aspartyl protease. Estrogen simultaneously binds to the promoter region of alpha-2 globulin angiotensinogen (AOGEN) and leads to the synthesis of angiotensinogen. Plasma

so the placenta is an unlikely cause of HELLP syndrome (**Figure 6**).

**4.2 Renin-angiotensin system as a cause of preeclampsia**

*DOI: http://dx.doi.org/10.5772/intechopen.86177*

preeclampsia (**Figure 7**).
