1. GESTATIONAL AND
PLACENTAL DISORDERS

2. 1-Early pregnancy
-Spontaneous abortion
-Ectopic pregnancy
2-Complications of late pregnancy
-Placenta accreata
-Twin placenta
-Placental inflammation
-Toxemia of pregnancy (preeclampsia-eclampsia)

3. 3-Gestastational Trophoblastic Disease
Trophoblastic neoplasms:
-Choriocarcinoma
-Placental site trophoblastic tumour
-Epitheloid trophoblastic tumour
Molar pregnancies
Hydatiform mole (complete-partial-invasive)
Non trophoblastic-non molar trophoblastic lesions
-Placental site nodule
-Exaggerated placental site

4. Disorders of Early Pregnancy
1-SPONTANEOUS ABORTION
Ten per cent to 15% of recognized pregnancies terminate in spontaneous abortion
The mechanisms leading to early loss of pregnancy are still mysterious.
The causes-fetal and maternal
Fetal: Defective implantation
-Some genetic or acquired abnormalities constitute the major origins of spontaneous abortion.
Numerous studies have indicated chromosome abnormalities in more than half of spontaneous abortuses.

5. Maternal:
-Inflammatory diseases: Toxoplasma, Mycoplasma, Listeria, and viral infections, both localized to the placenta and systemic;
- Uterine abnormalities;
- Trauma.

6. Morphologic changes:
Focal areas of decidual necrosis with intense neutrophilic infiltration, thrombi within decidual blood vessels, hemorrhage, and necrotic decidua.
Spontaneous abortions, no fetal products can be identified,
They are present, they should be carefully examined for anomalies that would suggest specific genetic or karyotypic defects. Chromosomal studies are recommended
(1) in habitual or recurrent abortion and
(2) when there is a malformed fetus

7. 2-ECTOPIC PREGNANCY
Implantation of the fetus in any site other than a normal uterine location.
The most common site is within the tubes (approximately 90%).The ovary, the abdominal cavity, and the intrauterine portion of the fallopian tube (cornual pregnancy).
1/ 150 pregnancies.
The most important predisposing condition in 35% to 50% of patients is PID with chronic salpingitis.
Other factors: peritubal adhesions due to appendicitis or endometriosis, leiomyomas, and previous surgery.
Intrauterine devices may also increase risk.

8. Morphology
In tubal pregnancy, the placenta is poorly attached to the wall of the tube. Intratubal hemorrhage may thus occur from partial placental separation without tubal rupture
Tubal pregnancy is the most common cause of hematosalpinx and should always be suspected when a tubal hematoma is present.
More often- causes tubal rupture and intraperitoneal hemorrhage
Less commonly- the tubal pregnancy may undergo spontaneous regression and resorption of the entire gestation.
Less commonly, the tubal pregnancy is extruded through the fimbriated end into the abdominal cavity (tubal abortion).

9. Potential sites for ectopic pregnancy, including the fallopian tube, ovary, cornu, and (rarely) abdominal viscera.
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10. Disorders of Late Pregnancy
Umblical cord-knods- compression
Ascending inflammation
Retroplacental hemorrhage
Intervillous hemorrhage
Abnormal placentation

11. A, Diagram of placental anatomy
A, Diagram of placental anatomy. Within the outer boundary of myometrium is a layer of decidua, from which the maternal vessels originate and deliver blood to and from the intervillous spaces. Umbilical vessels branch and terminate in placental villi, where nutrient exchange takes place.
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12. B, Normal term placenta (fetal surface) with umbilical cord.
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13. Placenta accreta
Caused by partial or complete absence of the decidua with adherence of the placenta directly to the myometrium.
Important for two reasons:
(1) postpartum bleeding, often life-threathening, occurs because of failure of placental separation
(2) in up to 60% of cases, it is associated with placenta previa, a condition in which the placenta implants in the lower uterine segment or cervix, often with serious antepartum bleeding and premature labor.
Many cases of placenta previa-associated accreta occur in patients with cesarean section scars.

14. Twin pregnancies
arise from fertilization of two ova (dizygotic) or from division of one fertilized ovum (monozygotic).
There are three basic types of twin placentas:
1-dichorionic diamnionic (which may be fused),
2- monochorionic diamnionic,
3- monochorionic monoamnionic.
One complication of twin pregnancy is twin-twin transfusion

15. Diagrammatic representation of the various types of twin placentation and their membrane relationships.
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16. Twin-twin transfusion syndrome resulting in the death of both fetuses because of excessive (left) or deficient (right) blood volume.
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17. PLACENTAL INFLAMMATIONS AND INFECTIONS
Placenta (placentitis, villitis)
the fetal membranes (chorioamnionitis)
the umbilical cord (funisitis).
They reach the placenta by two pathways:
(1) ascending infection through the birth canal -- most often bacterial-premature rupture of membranes - Sexual intercourse has been implicated in enhancing ascending infections.
(2) hematogenous (transplacental) infection
The amniotic fluid may be cloudy with purulent exudate, and the chorion-amnion histologically contains a leukocytic polymorphonuclear infiltration with accompanying edema and congestion of the vessels

18. Placental infections derived from ascending and blood-borne routes
Placental infections derived from ascending and blood-borne routes. Acute chorioamnionitis. A, On gross examination, the placenta contains greenish opaque membranes
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19. . B, A photomicrograph illustrates a dense bandlike inflammatory exudate on the amniotic surface (top).
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20. C, Acute necrotizing intervillositis, from a fetal-maternal infection by listeria.
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21. Bacterial infections of the placenta and fetal membranes may arise by the hematogenous spread of bacteria directly to the placenta.
The villi are most often affected histologically (villitis)
Classically, TORCH (toxoplasmosis and others [syphilis, tuberculosis, listeriosis], rubella, cytomegalovirus, herpes simplex) should be considered, although the cause is usually obscure and may involve immunologic phenomena

22. TOXEMIA OF PREGNANCY (PREECLAMPSIA AND ECLAMPSIA)
Toxemia of pregnancy refers to a symptom complex characterized by hypertension, proteinuria, and edema (preeclampsia).
6% of pregnant women, usually in the last trimester and more commonly in primiparas than in multiparas.
More seriously ill, developing convulsions; this more severe form of toxemia is termed eclampsia.
Patients with eclampsia develop disseminated intravascular coagulation (DIC) with lesions in the liver, kidneys, heart, placenta, and sometimes the brain.

23. Pathogenesis The many theories on the nature of toxemia of pregnancy
Three events that seem to be of prime importance in this disorder are addressed:
1-Placental ischemia
2-Hypertension
3-DIC

24. Proposed sequence of events in the pathogenesis of toxemia of pregnancy. The main features are (1) decreased uteroplacental perfusion; (2) increased vasoconstrictors and decreased vasodilators, resulting in local and systemic vasoconstriction; and (3) disseminated intravascular coagulation (DIC).

25. An abnormality of placentation- placental ischemia- involve defects in both trophoblast invasion and the development of the physiologic alterations in the placental vessels required to perfuse the placental bed adequately
Immunologic, genetic, and other factors have been postulated as causes of these abnormalities.
The net effect is a shallow implantation with incomplete conversion of decidual vessels to vessels adequate for the pregnancy state.
Investigators have hypothesized that an intrinsic defect in the invading trophoblast may contribute to altered vascular flow
- the inability of the invading cytotrophoblast-influence remodeling of uterine vasculature, reducing blood flow and leading to placental ischemia, the basis for the toxemic placenta.
- decreased uteroplacental perfusion induces stimulation of vasoconstrictor substances (thromboxane, angiotensin, endothelin)
the inhibition of vasodilator influences (prostaglandin I2, prostaglandin E2, nitric oxide ) from the ischemic placenta.
DIC, hypertension, and organ damage then develop

26. During toxemia, the placental ischemia leads to a higher output of thromboplastic substances, and antithrombin III levels are reduced.
The characteristic lesions in eclampsia are in large part due to thrombosis of arterioles and capillaries throughout the body, particularly in the liver, kidneys, brain, pituitary, and placenta.

27. One mechanism involves renin-angiotensin and prostaglandins.
Normal pregnant women develop a resistance to the vasoconstrictive and hypertensive effects of angiotensin, but women with toxemia lose such resistance, developing a tendency to hypertension.
Prostaglandins of the E series, produced in the uteroplacental vascular bed during pregnancy, are thought to mediate the normal resistance of pregnant women to angiotensin, and prostaglandin production is indeed decreased in the placenta of toxemic women.
Thus, the increase in angiotensin hypersensitivity, characteristic of toxemia, may be due to decreased synthesis of prostaglandin by the toxemic placenta. There is also evidence that renin production by the toxemic placenta is increased, another potentially vasoconstrictive event.

28. The liver lesions- irregular, focal, subcapsular, and intraparenchymal hemorrhages.
On histologic examination, there are fibrin thrombi in the portal capillaries with foci of characteristic peripheral hemorrhagic necrosis.
The kidney lesions are variable. Glomerular lesions are diffuse, when assessed by electron microscopy. They consist of striking swelling of endothelial cells, the deposition of fibrinogen-derived amorphous dense deposits on the endothelial side of the basement membrane, and mesangial cell hyperplasia. - bilateral renal cortical necrosis
The brain may have gross or microscopic foci of hemorrhage along with small-vessel thromboses.
Similar changes are often found in the heart and the anterior pituitary.

29. Morphology
The placenta is the site of variable changes, most of which reflect ischemia and vessel injury.
(1) Placental infarcts, which occur in normal full-term placentas, are larger and more numerous.
(2) There is increased frequency of retroplacental hematomas.
(3) There is evidence of increased villous ischemia; formation of prominent syncytial knots, thickening of trophoblastic basement membrane, and villous hypovascularity
(4) A characteristic finding in the walls of uterine vessels is striking fibrinoid necrosis and intramural lipid deposition (acute atherosis)

30. Acute atherosis of uterine vessels in eclampsia
Acute atherosis of uterine vessels in eclampsia. Note fibrinoid necrosis of the vessel walls, subendothelial macrophages and perivascular lymphocytic infiltrate.
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31. Clinical Course
Preeclampsia usually starts after the 32 nd week of pregnancy but begins earlier in patients with hydatidiform mole or pre-existing kidney disease or hypertension.
The onset is typically insidious, characterized by hypertension and edema, with proteinuria following within several days.
Headaches and visual disturbances are common.
Eclampsia is suspected by central nervous system involvement, including convulsions and eventual coma.
Mild and moderate forms of toxemia can be controlled by bed rest, a balanced diet, and antihypertensive agents, but induction of delivery is the only definitive treatment of established preeclampsia and eclampsia.
Proteinuria and hypertension usually disappear within 1 or 2 weeks after delivery except in patients in whom these findings predate the pregnancy.

32. INTRAUTERINE GROWTH RESTRICTION
Intrauterine growth restriction is an important cause of infant mortality and morbidity and is defined as a birth weight below the 10th percentile
Major causes:fetal disorders such as chromosomal abnormalities and malformations (20%)
maternal vascular disease- toxemia (30%).
Other causes include thrombolytic disorders, maternal and fetal infections, autoimmune disorders (chronic villitis), fetal vascular disorders (fetal thrombosis), and other metabolic

33. Gestational Trophoblastic Disease
Gestational trophoblastic disease constitutes a spectrum of tumors and tumor-like conditions characterized by proliferation of pregnancy-associated trophoblastic tissue of progressive malignant potential.
The hydatidiform mole (complete and partial)
The invasive mole
The frankly malignant choriocarcinoma.

34. The hydatidiform mole is a common complication of gestation, occurring about once in every 1000 to 2000 pregnancies in the United States
It has become possible, by monitoring the circulating levels of human chorionic gonadotropin, to determine the early development of persistent trophoblastic disease.
Choriocarcinoma, once a dreaded and uniformly fatal complication, is now highly responsive to chemotherapy.

35. HYDATIDIFORM MOLE (COMPLETE AND PARTIAL)
Hydatidiform mole is characterized by cystic swelling of the chorionic villi, accompanied by variable trophoblastic proliferation.
The most important reason for the correct recognition of true moles is that they may precede choriocarcinoma.
Most patients present in the fourth or fifth month of pregnancy with vaginal bleeding and with a uterus that is usually, but not always, larger than expected for the duration of pregnancy.
These moles can occur at any age during active reproductive life, but the risk is higher in pregnant women in their teens or between the ages of 40 and 50 years.

36. Trophoblast proliferation Diffuse; circumferential Focal; slight
Feature
Complete Mole
Partial Mole
Karyotype
46,XX (46,XY)
Triploid
Villous edema
All villi
Some villi
Trophoblast proliferation
Diffuse; circumferential
Focal; slight
Atypia
Often present
Absent
Serum hCG
Elevated
Less elevated
HCG in tissue
++++ +
Behavior
2% choriocarcinoma
Rare choriocarcinoma
fetal parts no may be present

37. Morphology
Moles develop within the uterus, but they may occur in any site, including ectopic pregnancies.
Partial moles may be diagnosed in early spontaneous abortions or later, following fetal development. Careful dissection may disclose a small, usually collapsed amniotic sac. Fetal parts are frequently seen in partial moles but are never found in complete moles (unless there is a twin pregnancy).
Currently, complete moles are being diagnosed and removed at an earlier mean gestational age (8.5 versus 17.0 weeks) due to routine ultrasound and close monitoring of early pregnancy, combined with more efficient histologic recognition of early complete hydatidiform mole.
The classic presentation is a uterine cavity filled with a delicate, friable mass of thin-walled, translucent, cystic, grapelike structures consisting of swollen edematous (hydropic) villi

38. Histologic examination
partial moles demonstrate villous hydrops and architectural disturbances in only a proportion of villi. The trophoblastic proliferation is minimal and limited to the syncitiotrophoblast.
In contrast, complete moles show hydropic swelling of most chorionic villi and virtual absence or inadequate development of vascularization of villi.
More advanced complete moles exhibit the classic spectrum of diffuse villous swelling, central cavitation (cisterns) and extensive concentric villous and extravillous trophoblastic proliferation.

39. Complete hydatidiform mole suspended in saline showing numerous swollen (hydropic) villi.
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40. A, Photomicrograph of partial hydatidiform mole revealing swollen villi and slight hyperplasia of the surface trophoblast.
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41. B, Complete hydatidiform mole with extensive cytotrophoblastic hyperplasia (lower field) (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.).
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42. C, Complete moles lack expression of p57 in the cytotrophoblast (arrowheads) and villous stroma (arrow).
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43. D, Normal placenta immunostained for p57 exhibits staining in both stromal (arrows) and cytotrophoblast (arrowheads) nuclei. (Courtesy of Dr. Diego C. Castrillon, Brigham and Women's Hospital, Boston, MA.)
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44. Clinical Course
Most patients with partial and early complete moles present with spontaneous pregnancy loss or undergo curettage due to abnormalities in ultrasound.
Watery fluid and bits of tissue seen as small, grapelike masses may be seen in the uterine contents. Ultrasound examination will confirm the diffuse villous enlargement.
In complete moles, quantitative analysis of human chorionic gonadotropin shows levels of hormone greatly exceeding those produced by a normal pregnancy of similar age.
The vast majority of moles are removed by thorough curettage.
Virtually no partial and only 2.5% of complete moles evolve into a malignant trophoblastic neoplasm (choriocarcinoma).
10% of complete moles develop into invasive moles. Because unattended complete moles may persist and recur, distinction of these moles from non-molar hydropic and partial molar gestations is important.

45. INVASIVE MOLE
This is defined as a mole that penetrates and may even perforate the uterine wall.
There is invasion of the myometrium by hydropic chorionic villi, accompanied by proliferation of both cytotrophoblast and syncytiotrophoblast
The tumor is locally destructive and may invade parametrial tissue and blood vessels.
Hydropic villi may embolize to distant sites, such as lungs and brain, but do not grow in these organs as true metastases,
The tumor is manifested clinically by vaginal bleeding and irregular uterine enlargement.
It is always associated with a persistent elevated human chorionic gonadotropin level and varying degrees of luteinization of the ovaries.
The tumor responds well to chemotherapy but may result in uterine rupture and necessitate hysterectomy.

46. A, Invasive mole presenting as a hemorrhagic mass adherent to the uterine wall.
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47. B, On cross-section, the tumor invades into the myometrium
B, On cross-section, the tumor invades into the myometrium. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.)
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48. CHORIOCARCINOMA
Gestational choriocarcinoma is an epithelial malignant neoplasm of trophoblastic cells derived from any form of previously normal or abnormal pregnancy.
Although most cases arise in the uterus, ectopic pregnancies provide extrauterine sites of origin.
Choriocarcinoma is a rapidly invasive, widely metastasizing malignant neoplasm, but once it is identified, it responds well to chemotherapy.

49. Incidence In 1 in 20,000 to 30,000 pregnancies in the United States.
It is much more common in some African countries; for example, it occurs in 1 in 2500 pregnancies in Ibadan, Nigeria.
It is preceded by several conditions:
50% arise in hydatidiform moles,
25% in previous abortions,
approximately 22% in normal pregnancies (intraplacental choriocarcinoma).
The remainder occur in ectopic pregnancies and genital and extragenital teratomas.
About 1 in 40 hydatidiform moles may be expected to give rise to a choriocarcinoma, in contrast to 1 in approximately 150,000 normal pregnancies.

50. Morphology
Classically a soft, fleshy, yellow-white tumor with a marked tendency to form large pale areas of ischemic necrosis, foci of cystic softening, and extensive hemorrhage
On histologic examination, it is a purely epithelial tumor that does not produce chorionic villi and that grows by the abnormal proliferation of both cytotrophoblast and syncytiotrophoblast
It is sometimes possible to identify anaplasia within such abnormal proliferation, replete with abnormal mitoses.
The tumor invades the underlying myometrium, frequently penetrates blood vessels and lymphatics
some cases extends out onto the uterine serosa and adjacent structures.
In its rapid growth, it is subject to hemorrhage, ischemic necrosis, and secondary inflammation.
In fatal cases, metastases are found in the lungs, brain, bone marrow, liver, and other organs.
On occasion, metastatic choriocarcinoma is discovered without a detectable primary in the uterus (or ovary), presumably because the primary has undergone total necrosis.

51. A, Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall.
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52. A, Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall. B, Photomicrograph of choriocarcinoma illustrating both neoplastic cytotrophoblast and syncytiotrophoblast. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.)
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53. Clinical Course
Irregular spotting of a bloody, brown, sometimes foul-smelling fluid.
This discharge may appear in the course of an apparently normal pregnancy, after a miscarriage, or after a curettage.
Sometimes the tumor does not appear until months after these events.
Usually, by the time the tumor is discovered locally, radiographs of the chest and bones already disclose the presence of metastatic lesions. The titers of human chorionic gonadotropin are elevated to levels above those encountered in hydatidiform moles. Occasional tumors, however, produce little hormone, and some tumors have become so necrotic as to become functionally inactive.
Widespread metastases are characteristic of these tumors. Favored sites of involvement are the lungs (50%) and vagina (30% to 40%), followed in descending order of frequency by the brain, liver, and kidney.

54. The treatment of trophoblastic neoplasms- the uterus, surgery, and chemotherapy.
Chemotherapy consists of the administration of one or more of a group of drugs including methotrexate, actomycin D, and etoposide .
The results of chemotherapy for gestational choriocarcinoma are spectacular and have resulted in up to 100% cure or remission in all patients except some who had high-risk metastatic trophoblastic disease.
By contrast, nongestational choriocarcinomas are much more resistant to therapy.

55. PLACENTAL SITE TROPHOBLASTIC TUMOR
In contrast to syncytial cytotrophoblast, which is present on the chorionic villi, intermediate trophoblast is found in the implantation site and placental membranes.
Intermediate trophoblast is composed of mononuclear cells with abundant cytoplasm that distinguish them from the syncytial cytotrophoblast.
In contrast to syncytiotrophoblasts (which produce human chorionic gonadotropin), intermediate trophoblast cells are weakly immunoreactive for human placental lactogen.
Intermediate trophoblasts compose the placental site trophoblast and residual placental site (implantation site nodule) following pregnancy, and may give rise to placental site trophoblastic tumors (PSTTs)

56. PSTTs comprise less than 2% of gestational trophoblastic neoplasms and present as neoplastic polygonal cells infiltrating the endomyometrium.
PSTTs may be preceded by a normal pregnancy (one-half), spontaneous abortion (one-sixth), or hydatidiform mole (one-fifth).
Beta human chorionic gonadotropin levels may be high.
Overall, about 10% result in disseminated metastases and death.
Distinction of PSTTs from normal exaggerated placental implantation site trophoblast may be difficult and can be achieved by using biomarkers (Mel-Cam and Ki-67) that detect increased proliferation in the trophoblastic cells.

57. A, Placental site trophoblastic tumor, presenting as a discrete mass in the myometrium.
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58. B, Histology of PSTT. (Courtesy of Dr. Bradley J
B, Histology of PSTT. (Courtesy of Dr. Bradley J. Quade, Brigham and Women's Hospital, Boston, MA.)
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