35. Gestational Disorders.pdf

GESTATIONAL DISORDERS. Arben Santo, Irushi Dissanayake. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1028-1033. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pag...

GESTATIONAL DISORDERS. Arben Santo, Irushi Dissanayake. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1028-1033. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages 646-650. CASE PRESENTATION: LYNETTE MITCHELL. A 35-year-old primigravid woman developed headaches along with a 3-kg weight gain over one week during the 7th month of an otherwise unremarkable pregnancy. She was brought into the emergency department because of generalized seizures which lasted for one minute accompanied with frothing of mouth, up rolling of eyes, and cyanosis. At admission, she was afebrile, and her blood pressure was 200/120 mm Hg. On physical examination, she had edema involving her head and all extremities. Fetal heart tones were 140 per minute and fetal movements were present. Laboratory studies showed hemoglobin of 12.5 g/dL (normal: 10-16 g/dL), hematocrit of 37 % (normal: 36-48%), platelet count of 199,000 cells/mm3 (normal: 140,000-450,000 cells/mm3), serum creatinine of 1 mg/dL (normal: 0.7-1.4 mg/dL), and fasting blood glucose of 101 mg/dL (normal: 70-100 mg/dL). Urinalysis showed 2+ proteinuria, but no erythrocytes, leukocytes, or casts. A diagnosis of eclampsia was made. At 38 weeks, a cesarean section was performed for fetal distress. A girl weighing 1,700 g was born showing evidence of growth retardation. SPONTANEOUS ABORTION. 1. Definition. Spontaneous abortion (synonymous with “miscarriage”) is the pregnancy loss before 20 weeks’ gestation without outside intervention. • About 10-15% of clinically recognized pregnancies terminate in spontaneous abortion. When highly sensitive β-hCG assays are used early, the magnitude of miscarriage significantly increases to about 60%70%. Many pregnancies are lost spontaneously before a woman recognizes that she is pregnant. Clinical signs of miscarriage are mistaken for heavy menses. 2. Risk factors. Common risk factors for pregnancy loss include increasing maternal age (>35 years), medical conditions (infection, diabetes, obesity, thyroid disease), and teratogenic medications (ACE inhibitors, isotretinoin, alcohol, lithum, etc.). 3. Etiology. In most instances, the mechanisms leading to early loss of pregnancy are unknown. Chromosomal abnormalities are noted in 70% of all miscarriages. The most common abnormalities associated with miscarriage include trisomies (trisomy 16), followed by triploidies (69 chromosomes, two sperm fertilize an egg), and monosomy X (Turner syndrome). • Mendelian disorders account for 30-50% of miscarriages that show no chromosomal abnormalities. Examples include miscarriages caused by homozygous mutations of the autosomal-dominant polycystic kidney disease (ADPKD) gene. • Physical defects of the uterus, such as submucosal leiomyomas, uterine polyps, or uterine malformations, may prevent or disrupt implantation. 1 4. Pathology. Tissues obtained by uterine evacuation after miscarriage reveals the presence of placental tissue (chorionic villi and trophoblast) and decidua (background gestational changes in the endometrium). In the pathological report, placental tissues are reported as “products of conception”. 5. Clinical presentation. The typical symptoms are crampy pelvic pain and vaginal bleeding, which ranges from scant brown spotting to heavy bleeding. Vaginal bleeding may include fetal tissue, which is solid and appears as a white mass covered with blood. Pelvic ultrasound reveals absence of fetal cardiac activity. 6. Laboratory studies. Serum levels of the β-subunit of human chorionic gonadotropin (β-hCG), which is secreted by syncytiotrophoblasts, in a normal pregnancy rise until about 10-11 weeks, and then decline until reaching a plateau in the second and third trimesters. In failed pregnancies, a decline in serum βhCG is usually apparent based upon two measurements at least two days apart. ECTOPIC PREGNANCY. 1. Definition. Ectopic pregnancy refers to implantation of the fertilized ovum outside the uterine cavity. It occurs in 1–2% of pregnancies. The most common site is within the fallopian tubes (∼90%). Other sites include ampulla (80%), isthmus (12%), fimbriae (5%), ovary (0.2%), intramural part or interstitium (2%), abdominal cavity (1.4%), and uterine cervix (0.2%). 2. Risk factors. Various risk factors for ectopic pregnancy have been identified: pelvic inflammatory disease, previous pelvic surgery, increasing age, vaginal douching, smoking, and intrauterine devices. 3. Pathophysiology. After tubal implantation, the proliferating trophoblast invades the tubal wall. Tubal rupture due to ectopic pregnancies is more likely in the isthmus (the narrowest part of the tube), but 2 unusual in the ampullary (the widest portion). Chorionic villi invade the tubal wall and large blood vessels in the broad ligament. With vascular disruption, bleeding takes place that fills fallopian tube with blood (hematosalpinx), stretches the serosa, and causes pain. If left untreated, spontaneous tubal abortion will cause tubal rupture resulting in massive intraperitoneal hemorrhage. 4. Clinical presentation. The signs and symptoms of an ectopic pregnancy when unruptured mimic that of a normal pregnancy: women are asymptomatic, or they have amenorrhea, nausea, and vomiting. • When symptomatic, patients with ectopic pregnancy manifest the classic clinical triad of pain, amenorrhea, and vaginal bleeding. These symptoms typically appear 6-8 weeks after the last menstrual period, but can occur later, especially if the pregnancy is intraabdominal. These symptoms overlap with those of spontaneous abortion. Unfortunately, only about 50% of patients present with all three symptoms. • Progression of symptoms to severe abdominal pain, peritoneal signs, and hemorrhagic shock is indicative of a ruptured ectopic pregnancy. Rupture of a tubal pregnancy is a medical emergency. 5. Laboratory studies. Although women with an ectopic pregnancy tend to have lower β-hCG levels than those with an intrauterine pregnancy, there is considerable overlap. Serial β-hCG measurement cannot confirm the location of the gestational sac. Intrauterine pregnancies are characterized by doubling of the β-hCG levels every 48-72 hours. In most of cases, a plateau level or a rising β-hCG concentration that fails to reach 50% suggests a failing or ectopic pregnancy. 6. Pathology. Diagnostic laparoscopy is the ‘gold standard’ diagnostic test for ectopic pregnancy. Pelvic ultrasound is inconclusive. The endometrium undergoes pregnancy related changes (decidualization) regardless of the location of the pregnancy. Decidualization consists of proliferation and transformation of the endometrial stromal cells into large cells with abundant pale granular cytoplasm, and bland nuclei. Decidual changes are seen in very early pregnancy; they are essential to allow the establishment of pregnancy. • Endometrial curettage can help differentiate between an intrauterine or ectopic pregnancy. Chorionic villi are seen in endometrial curettage specimens in a nonviable intrauterine pregnancy. If villi are not seen, the diagnosis of ectopic pregnancy is made. ABNORMALITIES OF PLACENTAL IMPLANTATION. 1. Placenta previa. Placenta previa is a condition in which the placenta implants in the lower uterine segment or cervix, often with serious third-trimester bleeding. Placenta previa is one of the most feared adverse maternal and fetal-neonatal complications in obstetrics. Placenta usually implants at fundus. The blood supply at the fundus is better than the one at lower uterus. • The pathogenesis of placenta previa is unknown. There is an association between endometrial damage and uterine scarring and subsequent placenta previa. It is believed that suboptimally vascularized endometrium in the upper uterine cavity resulting from previous surgery or multiple pregnancies promote implantation of trophoblast in the lower uterine cavity. 3 • There are two types of placenta previa: (i) complete placenta previa, in which the cervical os is covered by placental tissue, and (ii) marginal placenta previa, in which the placenta lies within 2 to 3 cm of the cervical os but does not cover it. • Placenta previa occurs in 0.5% of all pregnancies. • Bleeding is induced when uterine contractions result in partial detachment of placenta at the cervix. • Patients with placenta previa present with painless vaginal bleeding in the 2nd or 3rd trimester, due to disruption of the placental attachment to the lower uterine segment. Most cases are diagnosed incidentally at mid-trimester transabdominal ultrasound. Cesarean delivery is indicated for all patients with sonographic evidence of placenta previa. • Because of the inherent risk of hemorrhage, placenta previa causes serious morbidity and mortality to both the fetus and the mother. The neonate is at increased risk of preterm birth, and lower birth weight. Massive vaginal bleeding can lead to a maternal blood transfusion, and peripartum hysterectomy. 2. Placenta accrete spectrum. Placenta accreta refers to an abnormality of placental implantation in which the anchoring placental villi attach to myometrium rather than decidua, resulting in a morbidly adherent placenta. • There are three forms: (i) accreta (63% of cases), (ii) increta (15%); and (iii) percreta (22%). • Placenta accreta occurs when the villi adhere to the superficial myometrium. Placenta increta occurs when the villi extend deeper into the myometrium, but not through its full thickness. Placenta percreta occurs when the villi penetrate the full thickness of the myometrium and may invade neighboring organs such as the bladder or the rectum. • The pathogenesis of placenta accrete is not known with certainty. The most common theory is that defective decidualization (thin, poorly formed decidua) in an area of scarring caused by previous uterine surgery allows the anchoring villi of the placenta to attach directly to or invade the myometrium. • The incidence of placenta accreta is 3 per 1000 deliveries. • Patients with placenta accreta develop severe hemorrhage at the time of attempted manual placental separation. Additional potential sequelae of massive hemorrhage include disseminated intravascular coagulopathy, adult respiratory distress syndrome, renal failure, unplanned surgery, and death. 4 • The first clinical manifestation of placenta accreta is profuse, life-threatening hemorrhage that occurs at the time of attempted manual placental separation. In contrast to a simple retained placenta, part or all of the placenta remains firmly attached to the uterine cavity, and no plane of separation can be developed. 3. Placental abruption. Placental abruption (also referred to as abruptio placentae) refers to partial or complete placental detachment prior to delivery of the fetus. • Approximately 0.4-1% of pregnancies are complicated by placental abruption. • The key factor is the rupture of maternal vessels in the decidua basalis. The accumulating blood separates decidua from its placental attachment. Complete placental separations are caused by high pressure arterial hemorrhage in the central area of the placenta that extensively dissect through the placental-decidual interface. • The cause of placental abruption is often unknown, but multiple risk factors have been identified. • Risk factors in placental abruption include the following: (a) preeclampsia, occurring in 44% of all cases; (b) maternal trauma (e.g., motor vehicle collision, assaults, or falls) accounting for 1.5%-10% of all cases; (c) acute intrauterine infection; and (d) cigarette smoking. • Grossly, a hematoma almost completely separates the placenta from the uterine wall. An overlying intravillous hemorrhage or recent villous infarction are often present. • Patients present with the abrupt onset of vaginal bleeding, mild to moderate abdominal and/or back pain, and uterine contractions. • Maternal consequences include hypovolemic shock with tachycardia, oliguria, and significant changes in mental status, such as confusion or agitation. Fetal consequences include fetal distress such as reduced fetal movement and decreased fetal heart rate, premature labor (25%) and fetal death (15%). The maternal mortality rate is approximately 1% and due to hemorrhagic shock and disseminated intravascular coagulation. PLACENTAL INFECTIONS. 1. Definition. The placenta is composed of three major structures: the placental disc, the chorioamniotic membranes, and the umbilical cord. Acute inflammatory lesions of the placenta show infiltration of neutrophils in each of these structures. The inflammatory process may affect fetal membranes (chorioamnionitis), umbilical cord (funisitis), amniotic fluid (amnionitis), chorionic villi (villitis), or chorionic vessels on the chorionic plate of placenta (chorionic vasculitis). Deciduitis refers to an inflammatory process in the decidualized endometrium. While deciduitis, chorioamnionitis, and amnionitis are evidence of a maternal host response, funisitis and chorionic vasculitis represent fetal inflammatory responses. • The prevalence of placental infections is 9.7 cases per 1000 live births. 2. Etiology. Microorganisms reach the amniotic cavity through: (a) ascending from the lower genital tract (most common); (b) hematogenous transplacental (rare); and (c) accidental introduction during invasive procedures such as amniocentesis or chorionic villus sampling (rare). • The most frequent microorganisms in the amniotic cavity are Ureaplasma species, Gardnerella vaginalis, and Fusobacteria species. 3. Pathogenesis. Microorganisms gaining access to the uterine cavity from the lower genital tract are localized in the decidua of the supracervical region, where they cause a local deciduitis. Subsequent bacterial propagation leads to chorioamnionitis and amnionitis. • Amnionitis leads to fetal infection: involving fetal skin through direct contact with the amniotic fluid, fetal gut by swallowing amniotic fluid, and fetal lung. Ultimately, fetal invasion may lead to a systemic inflammatory response termed the fetal inflammatory response syndrome (FIRS). The hallmark of FIRS is fetal leukocytosis and elevation in the fetal circulation of IL-6. FIRS is followed by the spontaneous onset of preterm labor. 5 • The end-result is the focal weakening of the fetal membranes at the internal cervical os, premature membrane rupture, and induction of pre-term contractions, which would culminate in pre-term birth. 4. Pathology. Grossly, chorioamniotic membranes are dull, opaque with yellow green discoloration and cloudy amniotic fluid, possibly with purulent exudate (chorioamnionitis). The surface of the umbilical cord shows multiple, small, white or yellow plaques (funisitis). Histologically, diffuse infiltration of neutrophils is seen in the chorioamnionic membranes, decidua, placenta parenchyma, and fetal vessels of chorionic plate or umbilical cord. 5. Clinical presentation. Patients present with fever, uterine tenderness, abdominal pain, purulent foulsmelling fluid coming from the cervical os, maternal tachycardia, fetal tachycardia, and maternal leukocytosis. • Chorioamnionitis is complicated by preterm premature rupture of membranes (pPROM), i.e., prior to 31 weeks’ gestation. One of the most common complications of preterm PROM is early delivery soon after membrane rupture. The pPROM can lead to significant perinatal morbidity, including respiratory distress syndrome, neonatal sepsis, and fetal death. HYPERTENSIVE DISORDERS OF PREGNANCY. 1. Definition. Elevated blood pressure in pregnancy may represents preexisting chronic hypertension, gestational hypertension, preeclampsia, and eclampsia. Preexisting chronic hypertension is associated with preeclampsia in 20% of cases. • Gestational hypertension, preeclampsia, and eclampsia form a spectrum of disorders that represent progressive manifestations of a single process and share a common etiology. • Hypertensive disorders affect up to 10% of pregnancies in the United States. Gestational hypertension is seen in 6%, preeclampsia in 1%-3%, and eclampsia in 0.1% of pregnancies. Chronic hypertension is rare. 2. Chronic/preexisting hypertension. Chronic/preexisting hypertension is defined as blood pressure ≥130/80 mm Hg that predates pregnancy or presents before the 20th week of pregnancy or persists longer than 12 weeks postpartum. Chronic/preexisting hypertension is estimated to be present in 3-5% of pregnancies. The majority of women with chronic/preexisting hypertension do well in pregnancy, but a few of them develop complications such as superimposed preeclampsia. 3. Gestational hypertension. Gestational hypertension is the development of new arterial hypertension (i.e., blood pressure >130/80 mm Hg) in a pregnant woman after 20 weeks gestation. These patients display no proteinuria or signs of end-organ dysfunction. Preeclampsia develops in 25% of women with gestational hypertension. Final diagnosis of gestational hypertension is made only postpartum. The pathogenesis is unknown. 4. Preeclampsia. Preeclampsia is characterized by high blood pressure (≥140/90 mm Hg) accompanied by proteinuria and/or end-organ dysfunction after 20 weeks of gestation. Proteinuria is defined as 6 urinary excretion of at least 300 mg of protein in a 24-hour specimen. This correlates with 1+ dipstick reading or more in a random urine test. Proteinuria is associated by peripheral edema. (A) Risk factors. Risk factors of preeclampsia include: (i) age >40 years or <18 years; (ii) nulliparity; (iii) preeclampsia in a previous pregnancy; (iv) family history of preeclampsia; (v) pre-existing hypertension, diabetes mellitus, and obesity. (B) Pathophysiology. IMPAIRED VASCULAR REMODELING. Preeclampsia is induced by the placental ischemia which is the result of failed remodeling of the uterine spiral arteries in the first half of pregnancy. Spiral arteries are distributed in the decidua basalis and provide nutrients to the placenta and fetus. For this purpose, they are remodeled into highly dilated vessels in a process called ‘physiological change’. Remodeling consists of removal of vascular smooth muscle cells and endothelial cells by invasive extravillous trophoblast cells and their replacement with endovascular trophoblast. Spiral artery remodeling begins in the first few weeks of pregnancy and modifies the arteries from low-flow, high-resistance to high-flow, lowresistance vessels capable of meeting the demands of the developing fetus. Failed remodeling results in an abnormally small placenta or in blood vessels that still retain some of their muscle fibers. When these contract, blood flow to the placenta becomes intermittent. This is the first stage of preeclampsia, which occurs prior to the development of any clinical signs or symptoms. SOLUBLE PLACENTAL FACTORS. The second stage of preeclampsia occurs during the second half of pregnancy. As the growing fetus puts additional demands on the placenta, it struggles with its inadequate blood flow. The resulting hypoxia and oxidative stress cause the trophoblasts to release soluble placental factors: fms-like tyrosine kinase (sFlt-1) - soluble form of the VEGF receptor, and the soluble endoglin (sEng) - soluble form of the TGF-β receptor, into the maternal circulation. These substances lead to inappropriate, exaggerated activation of the endothelium that produce the clinical signs and symptoms of preeclampsia. The endothelium lines the entire maternal circulatory system, and its dysfunction leads to increased vascular reactivity (hypertension) and other abnormalities (such as proteinuria, glomerular endotheliosis). (C) Pathology. The root cause of preeclampsia is the placenta; hence it subsides with the delivery of the placenta. Preeclamptic placentas have lower mean weights, thicknesses, diameters, and surface areas compared to healthy placentas. The number of terminal chorionic villi is reduced leading to increasing branching of the intermediate villi. However, the blood flow remains reduced causing the formation of small, avascular and sclerotic villi. Syncytiotrophoblastic knots (called syncytial knots) are another indication of reduced placental perfusion. Syncytial knots are aggregates of syncytial nuclei at the 7 surface of terminal villi. The number of knots is positively correlated with the length of time and the severity of the hypertensive diseases of pregnancy. • Acute atherosis is a pregnancy specific arterial lesion observed in non-transformed spiral arteries. It is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis of the arterial wall, perivascular lymphocytic infiltration, and it is histologically similar to early-stage atherosclerosis. Atherosis is rare in normal pregnancies but is frequently observed in non- transformed spiral arteries in preeclampsia. • Placental malperfusion may give rise to placental infarcts and retroplacental hematomas. • Cerebral edema is commonly seen in eclampsia. The severe acute rise in systemic blood pressure exceeds the individual's cerebral autoregulatory range, causing generalized vasodilatation, hydrostatic leakage across the capillaries, and cerebral edema. • Liver abnormalities (subcapsular, and intraparenchymal hemorrhages, hemorrhagic necrosis) are due to reduced hepatic blood flow and fibrin thrombi in portal capillaries. • Renal glomeruli are enlarged and completely fill Bowman capsule and there are virtually no red blood cells in the capillary tuft. The lumens of capillary loops are extremely narrowed and occluded due to enlargement of the endothelial cells. The podocytes are not altered. These changes are collectively called glomerular capillary endotheliosis. The glomerular lesions are reversible after delivery. • In advanced cases, fibrin thrombi deposit in the cortical capillaries and may lead to bilateral cortical necrosis. (D) Clinical presentation. Pre-eclampsia is arbitrarily divided into mild (75%) and severe (25%) forms. Blood pressures between 140/90 - 160/110 mm Hg are considered mild while ≥160/110 mm Hg are considered severe. • Initially, pre-eclampsia is associated with hypertension and proteinuria. As pre-eclampsia progresses, it may cause severe headaches, vision problems (blurring or seeing flashing lights), pain in the epigastric area or in the right upper abdominal quadrant, vomiting, generalized edema. • Severe pre-eclampsia is associated with renal insufficiency (elevated creatinine), impaired liver function (elevated AST), pulmonary edema, ischemic or hemorrhagic stroke, consumption thrombocytopenia, and disseminated intravascular coagulation (DIC) • Without immediate treatment, pre-eclampsia may lead to eclampsia or HELLP syndrome. 5. Eclampsia. Eclampsia is a complication of severe pre-eclampsia. Eclampsia is defined as new onset of grand mal seizure activity and/or coma during pregnancy or postpartum in a woman with pre-eclampsia. • Eclampsia occurs in 2-3% of women with pre-eclampsia. Most cases of eclampsia present in the third trimester of pregnancy; about 60% of seizures occur antepartum, 20% occur intrapartum and 20% occurs postpartum, mainly within the first week of delivery. • Two mechanisms may explain the development of seizures: (i) areas of cerebral vasospasm cause focal ischemia, which may in turn lead to seizures, and (ii) breakdown of the autoregulatory system of the cerebral circulation, leading to brain edema. 8 • Typically, patients develop hypertension and proteinuria before the onset of a convulsion. Frequent signs/symptoms preceding seizure are persistent headaches, visual disturbances (scotomata, blurred vision), or epigastric pain. • Eclampsia is manifested by a generalized tonic-clonic seizure. Seizure begins with an abrupt loss of consciousness without any aura. The tonic phase starts with a scream and generalized stiffening of the body. Clonic jerking follows the initial tonic phase. Postictal sleepiness, confusion, or agitation occur after the seizure and patient begin to recover responsiveness within 10-20 minutes post-convulsion. Focal neurologic deficits are generally absent. • Neuroimaging findings include bilateral areas of white matter edema in the posterior cerebral hemispheres with sparing of the cortical gray matter (see Block 4 SDL: Arterial hypertension, Hypertensive encephalopathy). • Histological findings include perivascular edema, petechial hemorrhages in the occipital lobe, small vessel thrombosis, and small areas of parenchymal necrosis. • Maternal complications occur in up to 70% of women with eclampsia. The most frequent complications are placental abruption, disseminated intravascular coagulation, pulmonary edema, and acute renal failure. • The maternal mortality rate in preeclampsia-eclampsia is 0%-1.8%. The newborn mortality is 5.6%11.8%. Intracerebral hemorrhage has been found in 10%-60% of all maternal deaths. 6. HELLP syndrome. HELLP syndrome is a severe form of preeclampsia and involves hemolytic anemia, elevated liver function tests, and thrombocytopenia. • HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome is a microangiopathic hemolytic anemia in pregnant and postpartum women that is characterized by hemolysis, elevated liver enzymes, and a low platelet count. • HELLP syndrome develops in 0.1-1% of pregnancies overall. The majority of cases develop before delivery between 28 and 37 weeks of gestation; the remainder occurs within 48 hours after delivery. • The most frequent symptoms are hypertension, proteinuria, pain in the epigastric area or right upper abdominal quadrant, nausea, and vomiting. Less common symptoms include headache, ocular manifestations (i.e., blurred vision, retinal edema, and hemorrhages, retinal detachment), jaundice, and ascites. • Pathophysiology is similar to preeclampsia, including vascular spasms, vascular endothelial injury, platelet aggregation, thrombocytopenia due to platelet consumption, fibrin deposition, and end-organ ischemia. • Hemolysis is the main finding. Red blood cells become fragmented when passing through small blood vessels with endothelial damage and fibrin deposits. Peripheral blood smear shows schistocytes (fragmented red blood cells), burr cells (contracted red cells with spicula)), and polychromatic red cells (blueish due to residual ribosomes). Decreased hemoglobin and elevated serum LDH indicate hemolysis. Hemoglobinemia or hemoglobinuria are macroscopically recognizable in 10% of patients. Serum levels of unconjugated bilirubin are elevated. Haptoglobin levels are low or undetectable. Elevated levels of AST and ALT indicate liver injury. • Thrombocytopenia (platelet count <100,000 cells/mm3) is seen as platelets are activated and adhere to damaged vascular endothelial cells, resulting in increased platelet turnover with shorter lifespan. • Gross pathological findings include intrahepatic or subcapsular hematoma (30%), hepatic infarction (5%), and capsular rupture (1%). The primary cause of liver damage is secretion of CD95L by placenta, which causes liver cell death. Hepatocyte damage is enhanced by the endothelial damage, microangiopathy, and sinusoidal deposition of fibrin, which impede portal blood flow and cause liver ischemia. • The maternal mortality is about 3.3%, and fetal mortality may be as high as 22%. 9 10