Cytotrophoblast invasion CAMs and preeclampsia

Pre-eclampsia is associated with failed trophoblast invasion. Immunocytochemical studies have shown that pre-eclampsia is associated with abnormal expression of integrins by invasive cytotrophoblasts. Zhou et al. (1993) reported that in pre-eclampsia cytotrophoblasts in floating villi, in contrast to normal pregnancy, failed to down-regulate a6b4 and up-regulate a1b1 in distal columns and in the uterine wall. Expression of cytotrophoblast-associated ECM appeared to be generally unaltered. In...

Coagulation and fibrinolytic systems in preeclampsia

Pregnancy is a state of chronic intravascular coagulation (McKay, 1981) and pre-eclampsia appears to be an exaggerated state of this phenomenon. Pre-eclampsia is accompanied by endothelial injury, increased platelet activation with platelet consumption in the microvasculature and enhanced clotting (Saleh et al., 1992). Activated protein C resistance (caused by the Leiden factor V mutation) has been implicated (Lindoff et al., 1997). Increases in cellular fibronectin concentrations and platelet...

The maternal circulation to the placenta

Before considering oxygen concentrations within the intervillous space it is worthwhile reviewing the basic features of the maternal intraplacental circulation in order to appreciate the likely impact of the endometrial vascular abnormalities that are associated with pre-eclampsia. The main uterine arteries give off branches which extend inward for about a third of the thickness of the myometrium without significant branching and then subdivide into an arcuate wreath encircling the uterus...

Evidence of maternal oxidative damage in preeclampsia

Investigations of marker molecules in the maternal circulation in pre-eclampsia have shown varying results however, most are indicative of oxidative stress. Reports of increased generation of peroxy-nitrite radicals suggest higher oxidative damage (Hubel, 1999 Roggensack et al., 1999). MDA, a major breakdown product of lipid peroxides, was one of the first biomarkers found to be raised (Ishihara, 1978). Numerous studies have confirmed that serum MDA levels or the amounts of thiobar-bituric acid...

Matrix metalloproteinases and their tissue inhibitors

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes which play a pivotal role in invasion processes by degrading basement membranes and ECM components (Nawrocki et al., 1997). The MMPs are secreted into the ECM as inactive preforms and therefore must be cleaved to be activated. There are four main groups of MMPs (Hulboy et al., 1997). Collagenases (e.g. MMP-1, MMP-8, MMP-13), which primarily degrade fibrillar collagens I, II and III gelatinases (e.g. MMP-2, MMP-9), which...

Conclusions

While some aspects of trophoblast invasion resemble tumor invasion, the striking difference between the two is that trophoblast invasion of the uterus is tightly controlled by a plethora of factors expressed within the decidua and on the trophoblasts themselves. These include CAMs and the ECM, proteinases and their inhibitors, growth factors, cytokines and others. Abnormalities in any one of these mechanisms may have the potential to lead to impaired cytotrophoblast invasion. The precise...

Placental macrophages

Macrophages can be found within the fetal villi from week 4 until term. Their role in the placenta is still largely unclear. They can express class II major histocompatibility complex (MHC) antigens and Fc receptors and, when activated, can produce various potent cytokines and interleukins. In addition to phagocytic activity, there is evidence for their involvement in (i) substrate transport across the stroma, (ii) the regulation of angiogenesis, and (iii) fetal immunological defence. Their...

Invading cytotrophoblast cells express endothelial CAMs

More recent studies have suggested that cytotrophoblast cells that invade spiral arteries switch their adhesion molecule repertoire so as to mimic an endothelial phenotype (Zhou et al., 1997a). Immunohistochemistry performed on chorionic villi and placental bed biopsies demonstrated the following in second-trimester tissue, of the av integrins, av 5 was detected on cytotrophoblast on chorionic villi and av 6 was detected at sites of column formation and on the first cell layers. However, av 3...

A master regulator of inflammation

Many aspects of the inflammatory response are coordinated by a single transcription factor, nuclear factor kappa-B (NF-kB). Genes that contain NF-kB binding elements include those for inflammatory cytokines, acute phase proteins and adhesion molecules (Haddad, 2002). There is uncertainty about the relationship between NF-kB and oxidative stress (Hayakawa et al., 2003 Li and Karin, 1999). Indirect activation by way of the inflammatory responses to lipid peroxides or other products of cell damage...

Cardiorespiratory pathology and pathophysiology

Patients with severe pre-eclampsia are predisposed to the development of pulmonary edema because of low oncotic pressure and altered capillary permeability with or without left ventricular dysfunction (systolic or diastolic) (Belfort et al., 1991 Visser and Wallenberg, 1991). Left ventricular diastolic dysfunction increases the risk of pulmonary edema following rapid plasma volume expansion even small aliquots of intravenous fluids have been shown to cause a sharp rise in left-sided filling...

Acknowledgment Of Placentation

We are grateful to Tom Pijnenborg for producing an artistic representation of the physiological change of spiral arteries in Figure 1.2. Aardema, M. W., Oosterhof, H., Timmer, A., van Rooy, I. and Aarnoudse, J. G. (2001). Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses. Placenta, 22, 405-11. Ashton, S.V., Whitley, G. StJ., Dash, P.R., Wareing, M., Crocker, I.P., Baker, P.N....

Definition of exposure maternal characteristics and events

A key reason why studies may differ in the nature and strength of associations described with hypertensive disorders in pregnancy is the definition of the exposure. Different study designs are likely to have different methods of definition. Generally, small studies and prospective studies will tend to have more precise definitions. Studies involving a retrospective review of case notes will depend on the degree of standardization of clinical care to allow comparison between women. The inclusion...

Apoptosis

This article would not be complete without mentioning apoptosis. Apoptosis (programmed cell death) is a physiological and pathological process which regulates the number of cells in tissues (Thompson, 1995). Because apoptotic cells are degraded in a short time (1 2h), small changes in the number of apoptotic cells in a tissue may have important biological significance. Little is known about apoptotic events in the placental bed of women with pre-eclampsia. One study (DiFederico et al., 1999)...

Endothelin in the maternal circulation in preeclampsia

Studies in isolated omental ( Vedernikov et al., 1995 Wolff et al., 1996a) and myometrial arteries No Notches Notches Notches notches normal with IUGR with PE outcome 0 1 2 3 4 5 6 7 (c) ADMA (micromol L) Figure 4.5 Correlation between ADMA and FMD in women who later developed pre-eclampsia. (Wolff et al., 1996b) have shown similar responses to ET-1 in arteries from normal and preeclamptic women, suggesting that enhanced sensitivity to ET-1 is unlikely to contribute to vasoconstriction of the...

The circulating RAS in preeclampsia early and late roles

Normal pregnancy is a state of activation of the RAS, which is one of the earliest systems to recognize pregnancy. There is activation of the circulating system in the luteal phase of every ovulatory menstrual cycle and, should conception occur, this activation is maintained and rapidly amplified. It is thought that the activation is initially a response to the increased progesterone , which is natriuretic, but it may also be a response to the perceived underfilling of the circulation in very...

Periventricular leukomalacia

This is a significant cause of brain injury in premature infants. Hypotension results in poor cerebral perfusion in premature infants due to an inability to autoregulate the cerebral circulation. PVL may occur in utero if there is poor placental function or fetal blood loss, such as may result from antepartum hemorrhage. Antenatal chor-ioamnonitis has been shown to cause release of cytokines, which are known to damage the white matter of the premature brain. Post-natal events such as cerebral...

Endotheliumderived relaxing factors

Stimulation of intact endothelial cells by circulating neurotransmitters, hormones and substances derived from platelets and the coagulation system causes the release of a substance that induces relaxation of the underlying vascular smooth muscle (Furchgott and Zawadzki, 1980). Furthermore, mechanical forces such as shear stress, which are generated by changes in blood flow, induce endothelium-dependent vasodilatation, an important adaptive response during exercise. Table 4.1....

Natural history of eclampsia

Almost half of all cases of eclampsia occur preterm and over one-fifth occur before 31 weeks' gestation (Douglas and Redman, 1994). Of those occurring at term, the majority (approximately 75 ) occur either intrapartum or within 48 h of delivery. Traditionally, convulsions occurring more than 48 h after delivery were not considered eclampsia. However, it is now clear that late postpartum eclampsia i.e. seizures developing greater than 48 h but before 4 weeks' postpartum does indeed exist and may...

Waveform indices

Measurement of absolute blood flow is dependent on multiple factors including angle of insonation, blood viscosity, and vessel diameter. The latter is difficult to measure and precludes accurate assessment of volume flow, especially in small fetal vessels. Instead, angle-independent non-dimensional analysis of the pulsatility of the flow velocity waveform (FVW) spectrum is used. The commonly used FVW indices are resistance index (RI), systolic diastolic ratio (S D or A B) or pulsatility index...

Link between the endothelium and immune factors in preeclampsia

Pre-eclampsia is likely to result from an interaction between immunological, cardiovascular and metabolic factors. Defective cytotrophoblast invasion of the maternal spiral arteries leads to reduced uteroplacental perfusion and hence placental ische-mia hypoxia. Placental ischemia results in the release of a variety of factors including inflammatory cytokines and reactive oxygen species that cause maternal endothelial dysfunction. Neutrophils and platelets are activated in normal pregnancy and...

Measurement of peptide hormones as markers of placental function

The ischemic hypoxic injury suffered by tropho-blast in pre-eclampsia may alter its functional activity manifest as changes in production of peptide or steroid hormones and help predict the disease. While there are potential circulating markers of trophoblast invasion that can be measured as yet none have been correlated with invasion hence hormone measurements in maternal plasma more likely reflect villous trophoblast function. Concentrations of corticotro-phin-releasing hormone (CRH)...

Normal hemostasis

The primary initiator of coagulation is tissue factor. Tissue factor (TF) is expressed by epithelial, stromal and perivascular cells throughout the body but not normally by cells in contact with the circulation. Following vascular damage, membrane-bound TF complexes with factor VII (FVII). Cleavage of FVII results in the formation of activated FVIIa. Thereafter TF FVIIa complex can directly activate factor X (FX). TF FVIIa complex may also activate FX indirectly via activation of factor IX...

The genetics of the RAS in preeclampsia

The M235T polymorphism is a common polymorphism of the Aogen gene. Although there are considerable population differences in allele frequency, a recent meta-analysis of 45,267 nonpregnant patients showed a stepwise increase in both plasma Aogen and in the odds ratio for hypertension with increasing dosage of the T allele (Sethi et al., 2003). In the first published study of pre-eclamptic patients (Ward et al., 1993), the variant M235T was found in significantly increased frequency in 45...

Long interbirth interval

In a recent retrospective study of over 500,000 women over a period of 30 years, Skjaeren and colleagues (2002) demonstrated that the risk of pre-eclampsia in a second or third pregnancy was directly related to time elapsed since the previous delivery. After controlling for change of partner, maternal age and year of delivery there was an approximately 12 increase in the risk of pre-eclampsia for each year between pregnancies RR per year 1.12 (95 CI, 1.11-1.13) . The risk of pre-eclampsia in...

Umbilical artery

Umbilical artery (UA) FVW are readily obtained transabdominally. Acquisition of waveforms, especially in the second trimester, is facilitated by color Doppler. Waveform indices are higher at the fetal than the placental end of the cord, and therefore the sample gate should be placed over a free loop of cord considered equidistant from the two insertion points (Arduini and Rizzo, 1990). All fetal Doppler measurements should be performed in the absence of fetal breathing and gross body movements...

Oxidative stress in normal pregnancy

Normal pregnancy is a mild state of oxidative stress. Despite the presence of antioxidant systems such as SOD, catalase, GPX and GSTPi, and the co-factors glutathione and cysteine that are present from early pregnancy onwards (Jauniaux et al., 2000 Raijmakers et al., 2001a), a low level of oxidative modification occurs in placental tissue of uncomplicated pregnancies (Qanungo et al., 1999 Raijmakers et al., 2002). Also maternal factors lead to increased generation of O2* and other ROS during...

Metabolism and the systemic inflammatory response

Systemic inflammation has complex effects on metabolism, of which many are stimulated by components of the acute phase response. Inflammatory responses, stimulated by endotoxin, TNF-a or other pro-inflammatory factors cause insulin resistance and hyperlipidemia. The hyper-lipidemia of sepsis has been known for many years (Harris etal., 2001). TNF-a is an important mediator of these changes because it induces insulin resistance and inhibits lipogenesis while increasing lipolysis (Sethi and...

Postoperative care

After labor and delivery, all pre-eclamptic patients should be monitored in the recovery room or the Neuromuscular blocking agent + 0.1 mg ml of magnesium sulfate Figure 30.8 Dose-response curves of D-tubocurarine chloride and succinylcholine with and without added magnesium using a rat phrenic nerve preparation. Each point represents the mean of five observations with the standard error represented. Magnesium sulfate (0.1 mgml-1) is a subminimal dose. The magnitude of the potentiation by...

Counseling the woman who has preeclampsia

Unfortunately, few if any of the molecular genetic observations regarding pre-eclampsia are ready for use in predictive, diagnostic, or prognostic protocols (Khoury and Wagener, 1995). For instance, even though angiotensinogen T235 is associated with a several-fold increased risk of pre-eclampsia in the Utah population, and even though most patients with pre-eclampsia are homozygous or heterozygous for T235, over 60 of the obstetric population has T235 and only 5 8 will develop pre-eclampsia....

Preeclampsia oxidative stress and other metabolic changes

Pre-eclampsia is associated with increased markers of oxidative stress in placental tissue, as described in the chapter by Raijmakers and Poston. As already mentioned, inflammation and oxidative stress are closely related. The oxidative stress of pre-eclampsia is not localized to the placenta but disseminated in the maternal circulation (Hubel, 1998) and is an expected part of the systemic inflammatory response. Just as normal pregnancy is associated with increased circulating markers of...

Triglycerides oxidative stress and vascular dysfunction

There is strong support for a causal relationship between cholesterol and coronary artery disease. Nevertheless, up to half of patients with coronary artery disease have cholesterol levels in the normal range, suggesting involvement of other factors (Lamarche and Lewis, 1998 Lamarche et al., 1998). Hypertriglyceridemia is emerging as a major risk factor (Krauss, 1991, 1997 Lamarche et al., 1998 Lewis and Steiner, 1996 Reaven, 1994). Elevated triglycerides compromise vascular function in several...

Summary

In a series of investigations spanning more than a decade, the hypothesis that maternal physiological changes of pregnancy at high altitude would be intermediate between those observed in normal sea level pregnancy, and those observed in pre-eclampsia has been largely supported. What is important to remember is that none of the variables discussed above, in and of themselves, are sufficient to cause pre-eclampsia. Rather, they are correlates of the syndrome, perhaps markers of a single...

Cyclic guanosine monophosphate cGMP

Circulating levels of cGMP, the second messenger for NO, has been used as a surrogate marker for NOS activity. Studies on pregnant rats have demonstrated an increase in both plasma and urinary cGMP levels as renal blood flow increases with advancing gestation (Conrad and Vernier, 1989). Renal vasodilatation and hyperfiltration is abolished by inhibition of NOS (Danielson and Conrad, 1995). In human pregnancy, there is agreement that urinary concentrations of cGMP increase early in pregnancy and...

Enzymatic antioxidants

Superoxide dismutases (SOD) provide a first line defense against free radicals through conversion of O2*, to H2O2 and oxygen (Zelko et al., 2002). The rapid cellular response to oxidative stress leads to a defensive increase in expression of SOD (Mates et al., 1999). SOD works in concordance with H2O2-removing enzymes such as glutathione peroxidase (GPX) and catalase (Mates etal., 1999). Selenium-dependent glutathione peroxidase (SeGPX) catalyzes the reduction of H2O2 and organic hydroperoxides...

Metabolic changes and the inflammatory response in normal pregnancy

The metabolic adaptations of systemic inflammation, namely an acute phase response (as discussed above), oxidative stress, hyperlipidemia and insulin resistance, also occur during normal pregnancy. Markers of oxidative stress (Morris et al., 1998 Zusterzeel et al., 2000) are increased at least in the third trimester. In normal pregnancy insulin resistance develops early and persists until delivery (Stanley et al., 1998). To some extent this parallels the development of systemic inflammation...

Renal handling of protein

In the healthy nonpregnant individual the glomer-ulus is relatively impermeable to large proteins and although smaller proteins (radius < 30 A) are freely filtered there is almost complete reabsorption in the proximal tubule such that daily renal excretion of protein is only 20 80 mg, 40 of which is albumin. In normal pregnancy, both the total protein excretion (TPE) and the urinary albumin excretion (UAE) are increased after 20 weeks gestation, attaining 200mg24h 1 (upper limit 300 mg) and...

APC resistance and factor V Leiden

Because increased APC resistance and FV Leiden are the most prevalent thrombophilias in Caucasian populations, much attention has been directed toward studying the association, if any, of these defects with pre-eclampsia. In an early study, 8 of 50 women with a history of severe, early pre-eclampsia were found to have increased APC resistance (Dekker et al., 1995). No controls were included, but in a further study the same group later reported that FV Leiden was more common in women with a...

The systemic inflammatory response in normal pregnancy is not a form of immune rejection

It is important to appreciate, especially in the context of the remarks above about the relation between innate and adaptive immunity, that these responses do not imply that there is some form of alloimmune recognition of the fetus with either antigen-specific tolerance or conversely immune rejection. The key issue is that the major interface between mother and fetus, the syncytiotropho-blast, expresses no known polymorphic major histocompatibility (HLA) antigens. It is possible that it...

The immunology of preeclampsia

An immunologic cause of pre-eclampsia was proposed in 1902 and profound alterations in immunologic function in women with preeclampsia have been shown (see the Moffett chapter). Alterations in T cell and macrophage function during pre-eclampsia may result in altered regulation of cytokine production. There are many reports of alterations of cytokines in pre-eclampsia, for example increased concentrations of tumor necrosis factor a, interleukin-6 and tumor necrosis factor receptors (Vince et...

Introduction

Eclampsia is one of the most severe forms of central nervous system (CNS) involvement in the pre-eclampsia syndrome. Although pre-eclampsia has been known to be a multisystem disorder for over 100 years, much of the pathophysiology, including its molecular manifestations, has only come to light in the past 20 years. This is exemplified by the fact that the prominent causative role of endothelial activation has only been recently appreciated (Redman et al., 1999 Roberts and Redman, 1993 Roberts...

Cerebral palsy

Cerebral palsy is the end result of damage to the developing brain, resulting in problems with movement, tone and posture. Despite public misconception, intellect is often not affected. The major cause in premature infants is PVH and PVL. As noted below these complications can also affect sight and hearing. In most cases the newborn will leave the nursery with no apparent movement disorder. As the child becomes older and the nervous system matures, changes in tone become obvious. A picture of...

History of blood pressure measurement

The first blood pressure recording was done in 1733 by the Reverend Stephen Hales (1677-1761). He inserted a brass tube into the crural artery of a restrained mare and observed the column of blood that rose in the tube. Pioseuille used the first mercury sphygmomanometer in 1828 when he measured direct arterial pressure in a dog. Using mercury considerably reduced the height of the pressure column required (by a factor of 13.6). This study was the origin of the units for measuring blood...

The sympathetic nervous system in preeclampsia

It has been suggested that the pathological increase in vascular tone evident in pre-eclampsia occurs secondary to changes in the autonomic nervous system. Women with pre-eclampsia have been found to have increased sympathetic nerve activity in muscle-nerve fascicles of the peroneal nerve (Schobel et al., 1996) and higher plasma noradren-aline levels compared with normotensive women (Manyonda etal., 1998). In this latter study, tyrosine hydroxylase activity and mRNA levels were greater in...

Maternal antioxidant status in preeclampsia

The total peroxyl radical-trapping ability of plasma has been found to be higher in women with pre-eclampsia (Kharb, 2000c Uotila et al., 1994), unsurprising, perhaps, since this assay includes the antioxidant uric acid, which has frequently been reported to be raised (Chappell et al., 2002 Kharb, 2000c Many et al., 1996 Zusterzeel et al., 2002). As explained above, this may reflect increased XO activity with subsequent generation of O2', rather than an elevation of functional antioxidant...

Maternal and placental preeclampsia

This concept was first proposed to distinguish between pre-eclampsia caused by an abnormal placenta and that caused by an increased maternal susceptibility, owing to the predisposing conditions discussed in the preceding section (Ness and Roberts, 1996). They summarized the evidence that the maternal and placental causes converge downstream from the effects of reduced placental perfusion, at the point of maternal endothelial injury. This extremely useful concept is here extended in four ways....

Magnesium toxicity

Plasma magnesium levels maintained at 4 7mEql 1 are believed to be therapeutic in preventing eclamptic seizures. Patellar reflexes usually are lost at 8 10mEql 1, and respiratory arrest may occur at 13mEql 1 (Pritchard, 1955). Urine output, patellar reflexes, and respiratory rates should be routinely monitored during magnesium administration. Serial serum magnesium levels are advised for patients with renal dysfunction. Calcium gluconate should be available in the event of magnesium toxicity a...

Conclusion Of The Precelampsia

Recently, in the understanding of the etiology of pre-eclampsia, clinical (epidemiological) studies have been found to be fundamental in order to reorient the debate toward the potential for immunological mechanisms. The term ''primipaternity'' (Robillard et al., 1993) has been chosen to challenge the dogma that ''preeclampsia is a disease of primigravidas promulgated in most of the last century's obstetrical textbooks. Nevertheless, this term ''primipaternity carries some ambiguity....

Introduction the placental bed

The placental bed underlies the fetal placenta and includes the decidua basalis and the underlying myometrium containing the uterine spiral arteries. In order to establish human hemochorial placentation and to provide a progressive increase in blood supply to the growing fetus, the placental bed spiral arteries must undergo considerable alterations. These physiological modifications are thought to be brought about by the interaction of invasive cytotrophoblast with the spiral artery vessel...

Toward a rational fetal monitoring strategy in preeclampsia

With improvements in neonatal management clinicians have been willing to deliver high-risk pregnancies at earlier gestations, particularly where there is evidence of both maternal and fetal compromise. Clinicians should avoid early delivery in the belief that in pre-eclampsia fetal maturation is accelerated in a large cohort of preterm infants delivered to women with pre-eclampsia matched to preterm deliveries to normotensive mothers there were no differences in the rates of mortality, RDS,...

Systemic lupus erythematosus and antiphospholipid syndrome

Pregnancy in systemic lupus erythematosus (SLE) is associated with an increased risk of preeclampsia (Khamashta and Hughes, 1997). However, this risk is largely attributable to the presence of certain risk factors, particularly the presence of antiphospholipid antibodies (APAs), renal involvement of the lupus with or without hypertension, and active disease at the time of conception (Nelson-Piercy and Khamashta, 2003). Thus for women with SLE without antiphospholipid antibodies, lupus...

James C Cross

While the disease has been studied for decades, the pathogenesis of pre-eclampsia remains mysterious. However, studies of the disease in humans are confounded by the fact that while the disease manifests in the second and third trimester its origins likely begin in the first trimester (Cross, 1996 Roberts and Cooper, 2001 Roberts and Lain, 2002). This makes defining both the etiology and the subsequent pathological events rather difficult, and researchers are limited to making inferences from...

Placental fibroblasts

A variety of methods for the isolation of fibroblasts from villous mesenchyme have been described and compared (Garcia-Lloret et al., 1994 Haigh et al., 1999). Villous extracellular matrix (ECM) is produced by these cells. First-trimester cells synthesize higher amounts of several ECM components than term cells. Production of the ECM components collagen IV and fibronectin increases with lower oxygen partial pressure (Chen and Aplin, 2003) and, correspondingly, basement membrane thickness...

Transforming growth factors and trophoblast invasion in normal pregnancy and preeclampsia

Transforming growth factor- s (TGF- s) are members of a large superfamily of cytokines (Pepper, 1997). The TGF family is composed of three related proteins, TGF- 1, 2 and 3. TGF- s act through receptors designated types I, II and III. TGF- , produced primarily by the decidua, may regulate trophoblast invasion (Lala and Hamilton, 1996). Expression of TGF- 3 in placental villous tissue was reported to be low at 5 6 weeks' gestation, peaking at 7 8 weeks' gestation and virtually undetectable by 9...

AT1 receptor autoantibodies

The presence of agonistic auto-antibodies against the angiotensin II AT1 receptor have been reported in the serum of individuals with PE (Xia et al., 2003). The antibody also downregulates the AT1 receptor in a similar manner to angiotensin II but stimulates superoxide production from placental or vascular tissue (Dechend et al., 2003). They also inhibit trophoblast invasion in an in vitro assay and increase trophoblast PAI-1 production (Xia et al., 2002, 2003) and thus may account for two...

Relationship of uterine artery waveforms to placental bed morphology

During the first half of pregnancy, extravillous trophoblast (TB) cells invade the decidua and myometrium (interstitial TB) and the uterine spiral arteries (endovascular TB). Invasion results in ''physiological transformation of the spiral arteries characterized by a loss of normal musculo-elastic structure and replacement by amorphous fibrinoid material in which TB cells are embedded. In pre-eclampsia and FGR there is failure of TB invasion and consequent spiral artery transformation (Lyall...

Preanesthetic evaluation

It is important for the anesthesiologist to be involved early so as to help with control of the hypertension, stabilization of the hemodynamic status, and optimization of intravascular resuscitation. It is also prudent to have a well thought out, Table 30.5. Assessment parameters to evaluate extent of disease process Platelet count platelet function Studies PT, PTT, fibrinogen, FDP Peripheral smear SGOT Alkaline phosphatase Serum bilirubin (Indirect) Serum glucose Abdominal sonogram Magnetic...

Placental development

Establishment of the placenta requires that fetal cytotrophoblast stem cells invade the decidua and penetrate into the maternal spiral arteries. Trophoblasts replace maternal endothelium as far as the inner third of the myometrium transforming their phenotype and adopting characteristics such as the presence of von Willebrand factor, CD31 markers, adhesion molecules and coagulation components so as to resemble the endothelium they replace. The invasion of syncytiotrophoblasts into the spiral...

Preeclampsia Background

Unique to humans, pre-eclampsia is a multiorgan disease of unknown origin. Symptoms present themselves in a normotensive woman after the twentieth week of gestation. However, pre-eclampsia can occur in normotensive patients with trophoblastic disease (e.g. molar pregnancy) prior to the twentieth week (Ness and Roberts, 1996). The risk of developing pre-eclampsia is greater in women with pre-existing conditions such as chronic hypertension, diabetes, anti-phospholipid syndrome and collagen...

Treatment

Hospitalization and bed rest may provide effective treatment for women with mild pre-eclampsia. Initially the primary goals of management include (1) prevention of convulsions (2) control of hypertension (3) stabilization of cardiovascular status and optimization of intravascular volume. Initially, the primary therapeutic goal is to prevent convulsions. Magnesium sulfate (Mg2+) remains the treatment of choice for seizure prophylaxis in North America and is gaining popularity in the United...

Placental hyperoxia and preeclampsia

The oxygen concentration within the intervillous space will be determined by the balance of supply from the spiral arteries and extraction by the fetus and the placenta. Each spiral artery delivers its blood into the central cavity of a placental lobule and the blood disperses in a classic smoke-ring pattern, passing between the villi and exchanging respiratory gases before finally entering the uterine veins. Consequently, it was proposed that an oxygen gradient exists across a lobule...

Diagnosis of superimposed preeclampsia in chronic hypertension renal disease and diabetes

In contrast to gestational hypertension and preeclampsia that occur in the second half of pregnancy, hypertension that is evident before 20 weeks' gestation is diagnosed as chronic hypertension. The Australasian and American classifications are consistent in their definitions of chronic hypertension, blood pressure > 140 mmHg systolic and or > 90 mmHg diastolic pre-conception or in the first half of pregnancy (Anonymous, 2000 Brown et al., 2000). Rare exceptions include hydatidiform molar...

Longitudinal changes in fetal Doppler indices and relationship to perinatal outcome

Several studies have reported that increased MCA PI precedes changes in other vessels (Arduini et al., 1992 Ferrazzi et al., 2002). While observational studies have shown a relationship between elevated MCA PI and perinatal morbidities (e.g. low Apgar scores and neonatal complications), positive predictive values are generally poor (Hornbuckle and Thornton, 1998). Fong et al. (1999) confirmed that UA PI was a better predictor of major adverse perinatal outcome (e.g. death, hypoxic-ischemic...

MMPs and TIMPs in preeclampsia

There is much less known about pre-eclampsia. The inactive MMP-9 is the principle MMP secreted from cytotrophoblast cultures prepared from cases of pre-eclampsia whereas the active form is more abundant in uncomplicated pregnancies (Lim et al., 1997). Purified cytotrophoblast cells from the cases of pre-eclampsia showed reduced invasive potential and failed to modulate expression of MMP-9. In vivo data are also limited a study of two placenta with attached decidua reported that in...

Clinical and research implications of the twostage model

The two-stage model of pre-eclampsia proposes that there is more to pre-eclampsia than reduced placental perfusion. It is clear that reduced perfusion of the intervillus space is not sufficient for the development of pre-eclampsia and that a maternal contribution is also necessary. The identification of such maternal factors raises the possibility of preventive therapy for pre-eclampsia directed at countering specific abnormalities present in specific women. Is it possible, for example, that...

Control of severe hypertension

The objective of treating acute severe hypertension is to prevent potential cerebrovascular and cardiovascular complications such as encephalopathy, hemorrhage, and congestive heart failure (National High Blood Pressure Working Group, 2000). For obvious ethical reasons, there are no randomized trials to determine the level of hypertension to treat in order to prevent these complications. The point at which to begin antihyperten-sive drug therapy is not clear. Antihypertensive therapy is...

Gastrointestinal laboratory findings

Elevated liver function tests (LFTs) The liver is frequently involved in women with severe pre-eclampsia and eclampsia. Although transaminases may be elevated to 2000-3000 Ul-1, they are usually < 500Ul-1. Bilirubin levels may be modestly elevated (2-3mg , occasionally to 5mg ) women with pre-eclampsia are not obviously jaundiced. Intrahepatic and subcapsular hemorrhage may occur and can lead to hepatic rupture. The description and popularization of the subset of women with severe...

Can dyslipidemia during pregnancy flag laterlife cardiovascular risk

Recent data have linked maternal vascular, metabolic, and inflammatory complications of pregnancy (including gestational diabetes, pre-eclampsia, and low birthweight) with an increased risk of cardiovascular disease in later life (Hubel et a ., 2000 Sattar and Greer, 2002). As mentioned previously, the insulin resistance syndrome is a key factor underlying non-pregnancy cardiovascular disease. The maternal physiologic response to normal pregnancy includes a transient excursion into several...

Maternal fetal interactions in preeclampsia

Although reduced placental perfusion may be necessary, it is certainly not sufficient to invariably result in stage 2 of pre-eclampsia. Reduced uterine perfusion also accompanies intrauterine growth restriction (IUGR) not associated with infection or chromosomal anomalies. Despite the reduced perfusion, most women with IUGR infants do not manifest the maternal syndrome of pre-eclampsia. Perhaps the most compelling evidence that reduced placental perfusion does not invariably result in...

Can we predict an eclamptic seizure

The relationship between hypertension, symptoms and signs of cortical irritability (headache, visual disturbances, nausea, vomiting, fever, hyperre-flexia) and seizures remains unclear and unpredictable. That said, the majority of women do have one or more antecedent symptoms prior to an eclamptic seizure. In a retrospective analysis of 383 cases of eclampsia in the United Kingdom, Douglas and Redman (1994) reported that 59 (227 383) of eclamptic patients experienced either a prodromal...

Hemodynamic profile

Women with pre-eclampsia may present with a wide spectrum of cardiovascular changes. Thus, Table 30.1. Hemodynamic changes in nonpregnant and healthy term pregnant women Table 30.1. Hemodynamic changes in nonpregnant and healthy term pregnant women Data from Clark, S., Cotton, D.B. and Lee, W. (1989). Central hemodynamic assessment of normal term pregnancy. Am. J. Obstet. Gynecol., 161, 1439-42, with permission. Data from Clark, S., Cotton, D.B. and Lee, W. (1989). Central hemodynamic...

References

M., Hays, J. M. and Anderson, G. D. (1984). Relationship of hypertensive disease to abruption placentae. Obstet. Gynecol., 63, 365-70. Anonymous Infant v. Anonymous Midwife and Anonymous OB Gyn. (2000). Case No. Withheld, 7 November 2000. The Massachusetts, Connecticut, Rhode Island Verdict Reporter. JAS Publications 2001. Arias, F. (1978). Intrauterine resuscitation with terbutaline a method for the management of acute fetal distress. Am. J. Obstet. Gynecol., 131,...

Cardiovascular

Chest pain is a symptom that is universally recognized as abnormal by patients as well as by their friends and families. Chest pain invokes concerns about myocardial ischemia. While myo-cardial ischemia can occur in association with pre-eclampsia, it is rare and usually occurs in women with underlying predisposing risks (age, hypertension or other vascular diseases, etc.). The pain associated with myocardial ischemia is typically described as ''pressure'' or ''squeezing,'' often radiates to the...

Followup of highrisk infants and longterm outcome

Neonatologists are faced with a dilemma as some complications arising during the neonatal period may not become apparent until the child is much older. All neonatal units must have a system to monitor neonatal unit graduates. Over a period either a problem will be identified and dealt with, or there will no longer be any significant risk of the problem occurring. In effect this means a follow-up program for 2 years as most children will be speaking and walking at this age. Without such...

Hypertension as a predisposing factor for preeclampsia

In humans, the risk factors of essential hypertension and pre-eclampsia overlap considerably and, indeed, pre-existing hypertension increases the risk of pre-eclampsia (Eskenazi et al., 1991 Sibai et al., 1995). It is therefore not surprising that some genes that have been implicated as risk factors for pre-eclampsia, AGT (encoding angiotensinogen, a precursor of the vasoconstrictor angiotensin) (Ward et al., 1993) and NOS3 (encoding endothelial nitric oxide synthetase, eNOS) (Arngrimsson et...

Conclusion Fetal Circulation

The increasing technical capabilities of ultrasound machines allow specific interrogation of vessels from the placental and fetal circulation. Uterine and UA Doppler are important clinical utilities to identify high-risk pregnancies. Once identified as high-risk, women can be counseled about the need for enhanced fetal surveillance using UA Doppler. In women with pre-eclampsia, the loss or reversal of EDF in the UA signals the need for daily surveillance by experienced clinicians working in...

Cerebral blood flow in pregnancy

Pregnancy results in increased maternal cardiac output to allow for the increased demands of the placental fetal unit. With the increased maternal cardiac output and blood flow to the gravid uterus, it is expected that other maternal organs such as brain, adrenals, kidneys and heart maintain metabolic equilibrium. These vascular beds are thought to have relatively low vascular resistance to ensure adequate perfusion throughout most of the cardiac cycle, in order to maintain the high oxygen...

The pathological renal characteristics of preeclampsia

It has been recognized for almost a century that pre-eclampsia is associated with morphological renal changes. Lohlein in 1918 noticed that glomeruli in autopsy specimens from pre-eclamptic patients were enlarged and had a thickened basement membrane. The precise nature of the pathological lesion was not determined until the introduction of the electron microscope. The classical pathology we now recognize to be associated with pre-eclampsia is that of endothelial vacuolization and hypertrophy...

Evidence of increased systemic free radical generation in preeclampsia

Pre Eclampsia Pics

Stimulated O2* generation with receptor-mediated agonists is higher in isolated neutrophils from affected than normotensive pregnant women (Tsukimori et al., 1993). However, stimulation with phorbol esters that directly activate protein Figure 8.2 Consequences of maternal systemic O2 generation on oxidative stress and vascular function in pre-eclampsia. Figure 8.2 Consequences of maternal systemic O2 generation on oxidative stress and vascular function in pre-eclampsia. kinase results either in...

Comparison of pregnancy in rodents and humans

Many of the features of pregnancy in rodents are different than in humans, such as a gestation length of 3 weeks versus 9 months and the fact that rodents usually give birth to litters rather than singletons. Despite these obvious differences, however, the fact that rodents can develop pre-eclampsia shows that there is more in common between rodents and humans than is widely appreciated. A number of anatomical and physiological features of pregnancy are similar in humans and rodents (Table...

MMPs and TIMPs in normal pregnancy

Both protein and mRNA for MMP-1 are found in trophoblast columns and invading trophoblast. MMP-1 protein is present on invasive trophoblast in the second and third trimester. MMP-1 staining was more intense in deeply invaded trophoblast where cells are more in contact with decidual tissue rich in interstitial collagens (Huppertz et al., 1998a Vettraino et al., 1996). Cultured first-trimester cytotrophoblast cells secrete MMP-2 and MMP-9 and this secretion...

Malignant hypertension

In the previously normotensive patient, cerebral autoregulation is lost and the risk of intracranial bleeding increases when the mean arterial pressure (MAP) exceeds 140 150mmHg (Zimmerman, 1995). Intracranial hemorrhage may result from the combination of severe hypertension and hemostatic compromise (Hobbins et al., 1988). Belfort and colleagues hypothesize that uncontrolled cerebral perfusion pressure may cause barotrauma and vessel damage, leading to hypertensive encephalopathy and...

Prostanoids in the maternal circulation in preeclampsia

Prostaglandins are now known to play an important role in the adaptive changes associated with normal pregnancy, with inadequate synthesis being a likely contributory factor to the development of pre-eclampsia (Davidge, 2001). In contrast to normal pregnancy, pre-eclampsia is associated with relative underproduction of PGI2 and the over-abundance of TxA2 (Fitzgerald et al., 1990). A reduction in the PGI2 TxA2 ratio increases the likelihood of hypertension (Granger et al., 2001). The imbalance...

Severe preeclampsia immediate delivery vs expectant management

The clinical course of severe pre-eclampsia maybe characterized in some patients by progressive deterioration in both maternal and fetal condition. Pregnancies complicated by severe pre-eclampsia are associated with increased rates of perinatal mortality, and increased risks of maternal morbidity and mortality. As a result, there is universal agreement that all such patients should be delivered if the disease develops after 34 weeks' gestation, or prior to that time if there is evidence of...

Prevention of recurrent convulsions

Without treatment, approximately 10 of eclamptic women will have repeated seizures (Prichard et al., 1984). Although there is agreement that patients with eclampsia require anticonvulsant therapy to prevent further seizures, complications of repeated seizure activity (neuronal death, rhabdomyolysis, metabolic acidosis, aspiration pneumonitis, neurogenic pulmonary edema and respiratory failure, and possible cerebrovascular accident), the choice of agent has been controversial. Alternative...

White coat hypertension

The anxiety caused by the measurement itself or the environment in which it is taken can influence blood pressure by what is known as a defense reaction (Mancia et al., 1983, 1987). When the blood pressure of the patient is constantly higher when measured in the clinical environment than at home, it is known as white coat hypertension, i.e. patients who have white coat hypertension have a blood pressure that is within the normal range outside the clinic setting (Pickering et al., 2002). This...

Angiotensinases in normal and preeclamptic pregnancy

Angiotensin-converting enzyme (ACE) is a specialized angiotensinase. Concentrations of circulating ACE fall in the first half of normotensive human pregnancy, and then rise significantly over the third trimester towards non-pregnant levels (Oats et al., 1981). In pre-eclamptic pregnancy, levels remain low in the third trimester (Rasmussen et al., 1983). Plasma ACE is of endothelial origin, and these depressed concentrations may relate to the generalized endothelial dysfunction of pre-eclampsia....

Impaired physiological change in spiral arteries

Although pre-eclampsia eclampsia has been recognized for a long time in history as an important pregnancy complication (Lindheimer et al., 1999), a possible histopathological basis for this condition was only identified in the late 1960s. The idea that maternal perfusion of the placenta is disturbed in pre-eclampsia is an old one, and was based on the regular occurrence of placental infarcts in such cases (reviewed by Robertson et al., 1967). Searching for associated vascular pathologies,...

Other heritable abnormalities

Natural anticoagulant deficiencies are rare or uncommon. Although early studies suggested protein S deficiency may be associated with an increased risk of pregnancy vascular complication including pre-eclampsia, no large studies including carefully characterized patients confirming these findings have been reported. In a case-control study of 404 women with a history of pre-eclampsia, 303 with a history of gestational hypertension and 164 control women, Table 21.2. FN G20210A and pre-eclampsia...

Consequences of oxidative stress in preeclampsia

As discussed above, the products of oxidative stress from the placenta may contribute to the maternal inflammatory response. These will be compounded by local generation of ROS in the mother. Indeed, it is possible the characteristics of pre-eclampsia could be explained on the basis of oxidative stress (Hubel, 1999). Vascular function may be altered by oxidative stress (Davidge, 1998). Lipid peroxides can interact and alter endothelial cell function (Davidge, 1998 Hubel et al., 1989 Taylor et...

Adaptive cardiovascular changes of healthy pregnancy

Renal Blood Flow Distribution

The maternal cardiovascular system undergoes profound physiological changes during pregnancy (Williams, 2003). Blood flow to each maternal organ changes at different stages and by different amounts (Figure 4.4). Ultimately, the aim of these gestational changes is to ensure that the mother can meet the metabolic demands of the growing conceptus. The mechanisms of these widespread and variable cardiovascular changes are incompletely understood. One of the earliest manifestations of this adaptive...

Preeclampsia litigation

To identify the cases described in this section of the chapter, a search was done in Lexis-Nexis using the words pre-eclampsia, eclampsia, and pregnancy-induced hypertension for the period 1 January 1998 through 31 December 2003. The search identified 61 cases involving pre-eclampsia related to litigation. An overview of the maternal and perinatal outcomes for these 61 cases is listed in Table 34.5. These cases support the observations of the Harvard Study (Brennan et al., 1996) that law suits...

Dangerous partner

There are data that provide evidence for the existence of the so-called ''dangerous'' father. Lie et al. (1998) published a Norwegian population study (1967-1992 about 60,000 births per year) in which they identified 363,758 pairs of first and second pregnancies where the two children had the same mother and father 14,266 pairs of pregnancies where the children had the same mother but different fathers and 26,152 pairs where the children had the same father but different mothers. One of the...

Amaurosis temporary blindness

Temporary blindness may complicate 1 3 of cases of pre-eclampsia and has been reported in 15 of women with eclampsia at Parkland Hospital cases of permanent visual impairment have been reported (Cunningham et al., 1995a Do et al., 2002 Ekbladh et al., 1980 Moseman and Shelton, 2002). Pregnancy-related blindness has been associated with eclampsia, cavernous sinus thrombosis, hypertensive encephalopathy, and occipital lobe edema (Beal and Chapman, 1980 Beck et al., 1980 Beeson and Duda, 1982...

Fluid management

Image Oliguria Eclampsia

The peripartum period is associated with considerable volume fluxes in the maternal circulation and meticulous fluid management in pre-eclamptic patients is crucial in management at this time. In pre-eclampsia, altered capillary permeability favors an increased interstitial volume and a 10 15 reduction in intravascular volume (Brown and Gallery, 1994 Davison, 1997). In addition, plasma oncotic pressure, already reduced in normal pregnancy, is lower secondary to proteinuria, thus contributing...

Relationship of fetal Doppler indices to hypoxemia and acidemia

Data from direct animal experiments and indirect animal and human studies using Doppler techniques have demonstrated circulatory adaptations to impaired placental function and progressive hypoxemia (Hornbuckle and Thornton, 1998). Most of the human studies have been conducted on fetuses with fetal growth restriction (FGR) but are of direct relevance to pre-eclampsia, where FGR frequently coexists. An overview of Doppler changes is shown in Figure 32.2. Under hypoxic conditions there is...

Prediction of preeclampsia by uterine artery Doppler at 1824 weeks gestation

Uterine Artery With Gestation Age

Based on a review of 19 studies, Papageorghiou et al. (2002) found an overall sensitivity of uterine artery Doppler for predicting pre-eclampsia of 55 but this ranged from 24 to 89 . The pooled likelihood ratio (LR) for a positive result (LR+) was 5.90 (5.30, 6.52) while the pooled LR for a negative result was 0.55 (0.50, 0.60). Lees et al. (2001) subsequently showed that likelihood of severe adverse pregnancy outcome (fetal death, abruption Figure 32.4 Prediction of adverse outcome by uterine...

Pregnancyinduced changes in lipid metabolism

The diverse effects of pregnancy include a profound impact upon lipid metabolism. Several comprehensive reviews deal with the changes in lipid metabolism that occur with normal pregnancy and their importance for fetal development (Herrera, 2002). This section summarizes some of these aspects to provide a framework for discussion of lipid abnormalities and pre-eclampsia. Maternal metabolism is disposed toward adipose tissue fat accumulation during early gestation. In marked contrast, a shift to...

Conclusion

One of the most fascinating series of papers linking the RAS to pre-eclampsia has recently come from Luft's group in Berlin. In 1999 they demonstrated the existence of circulating stimulatory autoantibodies to the second extracellular loop of the AT1R in all pre-eclamptic patients studied (Wallukat et al., 1999) an observation subsequently confirmed by others (Xia et al., 2003). Such autoantibodies have also been found in a proportion of patients with non-pregnant hypertension (Fu et al.,...

Conclusion Of Precelampsia

The critical care management of severe pre-eclampsia is essentially quite simple, although these cases are probably better managed by clinicians and nursing staff familiar with this disease. Gratifyingly, women afflicted by preeclampsia usually make a complete recovery on these grounds alone, there can be no better justification for investing resources and time in teaching and upgrading the standard of care provided to these unfortunate victims of a disease that has remained an enigma for...

Ductus venosus

Reversed Ductus Venosus Waveform

A number of sites have been used to assess venous return to the fetal heart. Waveform indices vary substantially in the inferior vena cava, depending on the sampling site, and the ductus venosus (DV) has emerged as the most clinically useful vessel. The DV originates from the intrahepatic portion of the umbilical vein (UV) and allows shunting of oxygenated blood to the left side of the heart via the foramen ovale. In an oblique transverse section of the fetal abdomen the DV can be identified...