—  SHORT COURSE #06  —

Placental Development, Indications for and Methods of Examination

Section 3 - Maternal Diseases

Phyllis C. Huettner, M.D.


Case 3: Preeclampsia with acute atherosis
In many of the placentas that pathologists are called upon to evaluate, the pregnancy has been complicated by underlying maternal disease. Many of the most common and clinically significant maternal diseases affecting women during pregnancy have the shared features of low uteroplacental blood flow, a characteristic set of changes in the placenta and a growth retarded fetus. Preeclampsia is by far the most common and most clinically important of these underlying maternal diseases. In order to understand the placental changes in preeclampsia and many other maternal diseases, one must understand the changes that occur in normal pregnancy in the uterine blood vessels that supply the placenta.

Normal Vascular Remodeling in Pregnancy
In the first trimester, extravillous (intermediate) trophoblast invades through the walls and into the lumens of the intradecidual portions of the spiral arteries beneath the developing placental disk. The smooth muscle and elastic tissue are replaced by fibrinoid material derived from maternal plasma constituents and trophoblast. The endothelium is also replaced by intermediate trophoblast. This trophoblast shows down regulation of certain integrins and E cadherin characteristic of an epithelial phenotype and shows upregulation of other integrins and E cadherin characteristic of an endothelial phenotype so that tophoblast eventually functions more like endothelium in the lining of these maternal blood vessels. Between weeks 14 and 16 a second, retrograde, wave of endovascular trophoblast continues this process in the intramyometrial segments of the spiral arteries. This process, termed physiologic transformation or change, serves to convert the thick-walled, muscular spiral arteries into flaccid, low-resistance, dilated tubes termed uteroplacental arteries. This in turn serves to increase the blood flow to the placenta by up to ten fold. It is important to note that the smaller basal arteries of the uterus and the spiral arteries that are not beneath the placental disk, such as those of the decidua capsularis (underlying the free fetal membranes), do not undergo this physiologic transformation.

Decidual Vasculopathy
When physiologic transformation of maternal spiral arteries, described above, does not occur normally, the musculoelastic media is retained and the vessels continue to respond to vasomotor influences and therefore do not dilate, reducing blood flow to the fetoplacental unit. In preeclampsia, physiologic changes do not occur in the intramyometrial segments of the spiral arteries but do occur in the decidual segments of most, but not all spiral arteries. This lack of physiologic transformation in the spiral arteries is one form of decidual vasculopathy and is most common in women who are preeclamptic, but may also be seen in normotensive women whose fetuses develop idiopathic intrauterine growth retardation or who deliver small for gestational age infants. There is recent evidence that failure of spiral arteries to undergo physiologic transformation is more commonly seen in the placentas of patients with preterm labor and intact membranes and in patients with preterm premature rupture of membranes compared to a normal control population. Acute atherosis is another form of decidual vasculopathy, with features of necrotizing vascular injury, occurring in vessels in which physiologic remodeling has not occurred. Fibrinoid necrosis is the earliest lesion that can be recognized by light microscopy. Established lesions also show lipid-laden macrophages and a perivascular or vascular chronic inflammatory infiltrate. Vessels with acute atherosis may or may not have superimposed acute thrombi. The free membrane roll is an excellent place to find this lesion. Like absence of physiologic transformation, acute atherosis is most common in preeclampsia, but even in this situation it may be focal and can be demonstrated in only about half of cases despite extensive sampling of the basal plate of the placenta and the decidua capsularis (membrane roll). The presence of acute atherosis is related to the severity of preeclampsia. Acute atherosis may be seen in conditions other than preeclampsia such as intrauterine growth retardation even in the absence of hypertension, small for gestational age infants, scleroderma, systemic lupus erythematosus and antiphospholipid antibody syndrome without lupus. Atherosis may further narrow the already narrowed vessel lumens, which may be still further narrowed or occluded by superimposed thrombus, the result of which is a severe decrease in the flow of blood to the fetoplacental unit.

Low Uteroplacental Flow Changes
One of the characteristic placental findings seen in the setting of reduced blood flow to the placenta, especially in the setting of severe preeclampsia, is a small placenta. The microscopic features of low uteroplacental blood flow include cytotrophoblast proliferation, prominent villous stroma, small fetal capillaries, a thickened trophoblastic membrane, and very small villi with an increased number of syncytial knots, a change that is particularly significant in the placentas of preterm gestations. These low flow changes may be seen in any condition in which physiologic transformation of spiral arteries have not occurred or in which acute atherosis is present.

Preeclampsia
Preeclampsia is the most common maternal disease to occur in pregnancy and is the most important for both baby and mother. Preeclampsia complicates 2% to 7% of all pregnancies. It is defined as the development of hypertension with proteinuria or generalized edema or both after 20 weeks gestation. Eclampsia is diagnosed when seizures develop in the setting of preeclampsia. Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. The etiology of preeclampsia is not well understood and a detailed review is beyond the scope of this discussion. We know that this disease is pregnancy-specific and trophoblast-dependent as there is marked improvement of signs and symptoms soon after delivery of the placenta. Recent concepts of the etiology have focused on hypotheses involving placental ischemia, an abnormal immune response with abnormal expression of adhesion molecules by trophoblast, altered lipid metabolism and genetic factors. It appears that the final common pathway, whatever the etiology, is diffuse endothelial dysfunction leading to edema, platelet consumption, renal effects (hypertension, proteinuria), CNS effects (hyperreflexia, seizures) and hepatic effects (elevated liver enzymes, abdominal pain). Recent studies have shown that soluble fms-like tyrosine kinase 1 (s-flts-1) is increased in pregnancy. It is known that trophoblast stimulated by hypoxia secrete s-flt-1. This factor binds to vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) resulting in an overall anti-angiogenic effect. Introducing adenovirus encoding s-flts-1 into pregnant rats causes the clinical features of preeclampsia, providing an animal model for this disease. Retrospective data on humans show that increased serum s-flts-1 and decreased active VEGF and PlGF in women with preeclampsia that could be detected weeks before the onset of overt disease. This gives the possibility of a diagnostic test for this condition very early in its course enabling careful follow up for effected patients. Injection of VEGF in pregnant rats caused reversal of preeclampsia opening a window into therapies based on the underlying pathogenesis. While this pathogenetic scheme is still preliminary and probably only explains some cases of preeclampsia, the possibilities it offers for early diagnosis and therapy are exciting. The placentas of preeclamptic women are significantly more likely to show decidual vasculopathy, villous changes related to low uteroplacental blood flow, infarcts, retroplacental hematomas and in some studies, intervillous thrombohematomas and thrombi in the fetal vascular system. The rates of vasculopathy, central infarction and changes of low uteroplacental flow are more common in the placentas delivered earlier in gestation. These pathologic changes, although characteristic, are not specific for preeclampsia and do not always occur with the clinical syndrome.

HELLP Syndrome and Acute Fatty Liver of Pregnancy
The HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count) complicates about 4% to 12% of pregnancies with severe preeclampsia. Most cases occur in the late second and early third trimester but up to one-third occur postpartum. No difference in placental pathology was observed in a study of 56 cases of preeclampsia and 31 cases of HELLP. The presence of abruption in HELLP syndrome has been significantly associated with death of the fetus and acute renal failure and pulmonary edema in the mother. Overall, the perinatal mortality rate is 35% and this is dependant on the severity of the abnormalities as well as the gestational age. The maternal mortality rate is 1% to 3%. Acute fatty liver of pregnancy is related to the HELLP syndrome but is much less common and is associated with an even higher fetal and maternal mortality rate. Patients usually present late in the third trimester with nausea, vomiting and right upper quadrant pain. Liver biopsy shows microvesicular steatosis. Treatment primarily involves rapid delivery. One cause of both acute fatty liver of pregnancy and the HELLP syndrome is a pregnancy in which the fetus has an enzyme deficiency in one of the enzymes in the pathway of beta-oxidation of long chain fatty acids and in which the mother is heterozygous for this enzyme deficiency. Between 49% and 70% of woman who carried an affected fetus had acute fatty liver of pregnancy and 11% had HELLP syndrome. The most common deficiency appears to be the result of a specific mutation in the long chain 3 hydroxyacyl-coenzyme A dehydrogenase gene, but recently deficiencies in various other enzymes involved in fatty acid oxidation have been implicated in maternal liver disease as well, making disorders of fatty acid oxidation one of the most common inborn errors of metabolism. The placenta, which shares the genotype of the fetus, is known to express six of the enzymes in the beta-oxidation pathway, and therefore presumably also has deficient enzyme activity leading to the accumulation in the mother of toxic intermediates of fatty acid metabolism. The exact mechanism by which these toxic intermediates cause damage in the mother is still unclear. In addition to HELLP syndrome and acute fatty liver of pregnancy, nearly two-thirds of woman carrying affected fetuses deliver prematurely and about 40% of these infants are growth restricted. Currently, 36 states require screening of newborns for fatty acid oxidation disorders. This can be done with tandem mass spectrometry on a small spot of blood. Diagnosis of these disorders before symptoms develop and initiation of an appropriate diet can prevent neonatal and infant deaths, myopathy, neuropathy, retinopathy and arrhythmias and has been shown to be cost effective.

Chronic Hypertension
Surprisingly, there is little information available about the pathologic features of isolated chronic hypertension in the placenta. The pathologic changes are probably very similar to those of preeclampsia even at the ultrastructural level. The placentas of women with chronic hypertension may also show a vascular lesion termed hyperplastic arteriosclerosis that consists of proliferation of all layers of the vessel wall, intimal hyperplasia and luminal narrowing. These changes are most pronounced in the myometrial segments of the spiral arteries, vessels rarely available for examination unless a placental bed biopsy or hysterectomy is obtained. Hyperplastic arteriosclerosis may show superimposed acute atherosis when preeclampsia complicates the pregnancy. A recent large, population-based cohort study found that chronic hypertension was an independent risk factor for the development of preeclampsia, severe preeclampsia, gestational diabetes mellitus, and placental abruption. Therefore, in addition to the changes seen in preeclampsia and the vascular changes mentioned above, placental examination may show changes consistent with diabetes and with placental abruption, such as retroplacental hematoma.

Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Scleroderma
The rate of pregnancy complications including stillbirth, intrauterine growth retardation, and prematurity is increased in women with systemic lupus erythematosus (SLE). About 30% to 40% of women with SLE have antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibody. These are a heterogeneous group of autoantibodies directed against negatively charged phospholipids that are frequently found in healthy people, but the presence of which is strongly associated with thromboembolic events, both arterial and venous, thromobocytopenia and fetal loss (the antiphospholipid antibody syndrome), especially in women who also have SLE. Whether recurrent pregnancy loss should be attributed to the presence of antiphospholipid antibodies is still debated, but there is a strong association between continued positivity of these antibodies throughout gestation and fetal loss. The pathologic lesions seen in preeclampsia may also be seen in the placentas of women with SLE. In contrast to preeclampsia, which occurs in the second and third trimesters, these placental changes may occur in the first trimester in SLE. SLE alone is associated with decreased placental weight, low uteroplacental flow changes, decidual vasculopathy, decidual thrombi, fetal thrombi and villitis of unknown etiology. These findings do not appear to correlate with disease activity. Women with SLE who also have antiphospholipid antibodies may have an increased rate of low flow changes, extensive infarction and fetal death. Although the number of cases studied is small, Ogishima et al have found that women who are positive for both lupus anticoagulant and anticardiolipin antibody had a high rate of decidual vasculopathy, decidual thrombosis, extensive infarction and fetal death. It is thought that the poor pregnancy outcomes are caused by thrombosis of placental vessels leading to ischemia, infarction, growth retardation and in some cases, fetal death, but the exact mechanism by which antiphospholipid antibodies cause thrombosis is not well established. Scleroderma is another connective tissue disease associated with intrauterine growth retardation, preterm birth and perinatal loss. Findings in the placenta include decidual vasculopathy, infarcts, intervillous thrombohematomas, increased intervillous fibrin and villitis of unknown etiology.

Maternal Thrombophilic Disorders
The heightened interest in the last decade in the relationship between hereditary thrombophilic conditions in the mother or baby and pregnancy complications has been the subject of recent reviews. Some case-control studies have reported a significantly increased prevalence of factor V Leiden, protein S deficiency and homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase (leading to hyperhomocysteinemia) in women with severe preeclampsia compared to controls. Other studies have not found such an association. An association between thrombophilic conditions, both inherited and acquired, and late pregnancy loss has also been reported. Whether thrombophilic disorders are associated with intrauterine growth restriction is controversial. Also unclear is the relationship of various hereditary thrombophilic disorders and lesions in the placenta. Although many studies are hampered by imprecise use of terminology for placental lesions and problems with study design, it appears that various hereditary thrombophilic conditions, alone and in combination, are associated with an increased number and larger infarcts, acute atherosis, spiral artery thrombi, retroplacental hematoma (abruption), and fetal thrombotic vasculopathy.

Diabetes Mellitus
The placental findings in women with diabetes mellitus are variable, probably because the disease itself is quite variable. Some women are affected for just a few weeks during pregnancy and controlled by diet while others may have had longstanding, insulin-dependent disease years before becoming pregnant. Sometimes the placenta is normal but in over half of cases it is larger and heavier than normal for gestational age. In one large, controlled study of gestational diabetes diagnosed between 28 and 32 weeks gestation, women with gestational diabetes were significantly older, taller, had a higher prepregnancy weight and a higher body-mass index. These women also delivered significantly heavier placentas and had a significantly lower fetal:placental weight ratios than control women without diabetes. The histologic findings in the placentas of women with diabetes are not specific but certain findings are characteristic of this disease. Often the villi are immature for gestational age. They may also be edematous. The cytotrophoblast is unusually prominent and the trophoblastic basement membranes shows irregular thickening. Sometimes deposits of fibrinoid material can be seen between the trophoblast and the basement membrane. Chorangiosis and avascular terminal villi appear to be more common in the placentas of diabetic women. The umbilical cord in women with diabetes may have an increased diameter and is more likely to have single umbilical artery. These placental changes do not vary significantly between diabetic women who deliver infants with an appropriate weight for gestational age and those who deliver large for gestational age infants. Also most studies find no differences in histologic findings between diabetes with good control versus those with poor control of blood sugar. Interestingly, in one study the histologic abnormalities of control women who delivered large for gestational age infants but did not have diabetes were quite similar to those of diabetics. In women with diabetes complicated by vascular disease the placental findings may be similar to those seen in preeclampsia, showing acute atherosis of the spiral arteries and small placentas with an increased number of infarcts. A second pattern of vascular change in uterine vessels of diabetic women has been described. This is characterized by arteriolar medial hypertrophy with hyalinization and onion skinning. Woman with diabetes, particularly type 1 diabetes, are at increased risk for delivering infants with congenital malformations, macrosomia and to experience "unexplained" fetal deaths. There is no clear-cut relationship between the presence or severity of the above-mentioned pathologic findings and these adverse outcomes, however.

Sickle Cell Disease
Maternal sickle cell disease is associated with a high rate of pregnancy complications including spontaneous abortion, stillbirth, premature delivery and fetal growth retardation. Mothers experience increased infections during pregnancy such as urinary tract infections and pneumonia which may contribute to premature delivery. Also the number of painful crises is increased and the degree of anemia is worsened during pregnancy with possible implications for the fetus. Evidence of sickle cell disease is often present in histologic sections of the placenta. Sickled maternal red blood cells can often be seen in the intervillous space, which is a modified maternal blood vessel. Apart from the presence of sickled red cells, the findings in sickle cell disease are nonspecific. The placenta may be small and may have an increased number of infarcts. Woman with sickle trait have no increase in pregnancy complications or placental abnormalities.

References

Normal Vascular Remodeling and Decidual Vasculopathy
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Essential Hypertension
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Maternal Thrombophilic Disorders
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Diabetes Mellitus
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Sickle Cell Disease
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