Early Path Medical Consultation Services

Early Path Medical Consultation Services
Pathology Services Working for Safer Pregnancies

Abstract
Recurrent Obstetric Compromise
Kathryn A. Starzyk and Carolyn M. Salafia

The single best predictor of obstetric compromise is a prior history of poor pregnancy outcome. However, the risk for subsequent pregnancies is not outcome specific; patients with early recurrent pregnancy loss are at risk for problems later in gestation including preeclampsia, spontaneous prematurity, fetal growth restriction and late fetal death if they maintain pregnancy past the first trimester. It would follow, therefore, that although the clinical manifestations may vary, there may be some pathophysiological links among these conditions that are potentially influenced by environmental and temporal factors, resulting in outcome variability. There is comparatively little documentation detailing the pathology of successive pregnancies with different sub-optimal pregnancy outcomes. It would seem logical that identification of the underlying pathophysiology would facilitate cost-effective clinical intervention to improve subsequent pregnancy outcome. The frustration and, in some cases, desperation, of patients with recurrent pregnancy loss has fostered the proliferation of interventions that are at the very least hotly contested both as far as scientific basis and efficacy. In order to create a sound strategy for patient management in cases of recurrent obstetric compromise, it is our thesis that diagnostic schemes should be established utilizing not only clinical, genetic but also histopathologic assessment.

The mechanisms by which pregnancy loss and/or compromise are effected are imprecisely understood and probably only indirectly assessed by current laboratory modalities. However, the goal of this perinatal pathology group has been to identify broad pathophysiologic processes that are biologically reasonable, including lesions that have been well documented in the placental histology literature. We acknowledge that there is neither complete consensus nor lack of inter-observer variance regarding the diagnosis of these lesions. Nevertheless, we present a framework for the classification of placental histopathologic diagnosis. This framework we use, and propose that such a framework, which permits identification of general pathophysiologic mechanisms underlying placental histopathology, is clinically relevant to the determination of causes of recurrent obstetric compromise.

Text

The mechanisms by which pregnancy loss and/or compromise are effected are imprecisely understood and probably only indirectly assessed by current laboratory modalities. However, our goal has been to identify broad pathophysiologic processes that are biologically reasonable, including lesions that have been well documented in the placental histology literature. We acknowledge that there is neither complete consensus nor lack of inter-observer variance regarding the diagnosis of these lesions. Nevertheless, we present a framework for the classification of placental histopathologic diagnosis. This framework we use, and propose that such a framework, which permits identification of general pathophysiologic mechanisms underlying placental histopathology, is clinically relevant to the determination of causes of recurrent obstetric compromise.

A. Acute inflammation

1. Lesions

The correlation between neutrophil invasion of choriodecidua, amnion, chorionic plate and fetal umbilical and chorionic vessels, and microbial invasion of the amniotic cavity has been clearly documented. An ascending organism may either colonize the extraplacental membranes or cross the membranes into the amniotic fluid. Necrotizing deciduitis occurs when the membranes become infected and neutrophils are recruited out of the decidual capillary bed by locally generated cytokines, to remain in the decidua and participate in decidual destruction. If an ascending pathogen accumulates in the amniotic fluid, however, there is no local decidual destructive inflammation and neutrophil migration is directed out of the decidua and toward the amnion. Although some degree of intraamniotic bacterial contamination may normally occur with normal labor and delivery, clinically relevant acute inflammatory pathology is identified by histologic evidence of neutrophil infiltration of the amnion and umbilical cord. The overwhelming majority of cases with histologic evidence of acute intraamniotic infection are clinically "silent", i.e., have no ante-partum or post-partum clinical manifestations of infection.

2. Evidence for recurrence and role in obstetric compromise

The cascade(s) by which intraamniotic infections may lead to preterm membrane rupture and/or preterm labor and delivery have been widely described. Women with a history of preterm birth have a 5-fold risk increase for another preterm birth. In a recent review of intervention effectiveness, Villar et al concluded that treatment of asymptomatic bacteriuria reduces the incidence of preterm labor and low birth weight. Evidence exists that, in patients with certain cervicovaginal flora (e.g., bacterial vaginosis) and/or specific microorganism types (e.g., group B streptococcus), eradication of infection may improve subsequent outcome. In a study of women with recurrent pregnancy loss, bacterial vaginosis was found in 21% (27/130) of women with a history of late fetal death [as opposed to 8% (31/370) of women with a history of early loss]. Such clinical data supports the hypothesis that recurrent infection underlies a subset of patients with recurrent but clinically variable midtrimester pregnancy complications.

B. Chronic Inflammation

1. Lesions

Lesions of chronic inflammation include chronic villitis of unknown etiology (no known clearly identified viral source), chronic destructive anchoring villitis, chronic choriodeciduitis/amnionitis, massive chronic intervillositis and chronic uteroplacental vasculitis. Chronic villitis is characterized by infiltration within the chorionic villi, primarily by maternal macrophages and T lymphocytes. It has been suggested that in areas of villitis seen in conjunction with trophoblast necrosis and destruction of its basal membrane the inflammatory response may include a mixture of maternal and fetal cells. Chronic inflammatory placental lesions are classically considered to reflect a congenital viral infection. More recently, a materno-fetal immune pathology has also been proposed, due in part to the recognition of these lesions' presence in clinical conditions known to recur. In this context, chronic placental inflammatory lesions are believed to be "markers" of abnormal immune recognition or rejection of the fetal allograft.

2. Evidence of recurrence and role in obstetric compromise

Many chronic inflammatory lesions most likely represent an auto- or allo-immune response of maternal lymphocytes to trophoblast or placental stromal, viral or even bacterial antigens. Most intriguing as far as the nature of the antigenic stimulus to chronic villitis may be the documentation of discordant placental involvement in dichorionic twins with discordant birthweights. While such studies do not a priori exclude the possibility of discordant congenital viral infection, follow-up of these mother-infant groups could clarify the inciting stimuli.

It also must be considered that some chronic inflammatory lesions may represent effects of tissue injury and normal repair processes (which commonly invoke lymphocytes), especially in term deliveries. This may be consistent with a trigger for villitis located in the placental antigens expressed in the villus stroma; Labarrere et al have proposed that the causative factor(s) is present in all pregnancies.

Chronic inflammatory lesions are associated with a broad range of clinical outcomes known themselves to be recurrent. Not surprisingly, documentation of the actual recurrence of the chronic inflammatory histopathology in serial compromised pregnancies is spotty. The best data pertains to chronic villitis and intervillositis, documented primarily in case reports. In 1985, Redline reported a small series of patients showing a 17% recurrence of chronic villitis (10 of 59 patients in whom villitis had been diagnosed in an initial pregnancy), with a reproductive loss rate of 60% in the group with recurrent villitis. Data from the Michigan Placental Tissue Registry indirectly supports the recurrence of chronic villitis in serial reproductive compromise.

Less documentation of recurrence exists for other chronic inflammatory lesions. Chronic uteroplacental vasculitis has been identified in placental bed biopsies in the context of recurrent phospholipid antibody- associated loss; a causal relationship between the vasculitis and pregnancy compromise was speculated, but has not been proven. Among 17 cases of chronic "chorioamnionitis", 7 (41%) had experienced at least one previous spontaneous abortion, fetal death in utero or preterm birth. Whether either of these lesions has a potential either for recurrence or for serial pregnancy compromise separable from chronic villitis is not known.

It has been well established that antiphospholipid antibodies (and specifically anticardiolipin antibodies and lupus anticoagulant) are associated with recurrent early fetal loss (for a recent review, see Kutteh, 1997). General immune-associated reproductive compromise is identifiable by abnormalities of the process of uteroplacental vascular conversion and evidence of abnormal immune recognition and abnormal coagulation. It has been speculated that chronic villitis results from alloreactive maternal autoantibodies causing trophoblast and intervillous and intravillous macrophage recruitment. We identified a clustering of chronic villitis, "chorioamnionitis", and uteroplacental vasculitis in phospholipid antibody associated pregnancy compromise; chronic villitis and chronic uteroplacental vasculitis have been separately confirmed to be prominent lesions in this type of recurrent pregnancy loss.

Levels of annexin V, a phospholipid-binding protein with potent anticoagulant activity, are markedly reduced on placental villi in antiphospholipid-affected women. Decreased levels of annexin V prevent the cell membrane phophatidylserine flip involved in trophoblast differentiation and normal implantation, and its absence leads to increased thrombosis. It would appear that antiphospholipid antibodies cause pregnancy failure via an induction of deleterious cellular immune responses, rather than via direct initiation of coagulation. The prevalence of extensive chronic inflammatory lesions in failed pregnancies treated with anticoagulants has led to redirection of treatment to immune-mediated pathologic processes, with anecdotal success (Salafia CM, unpublished observations). Excessive perivillous fibrin or fibrinoid deposition is common in antiphospholipid patients who 'fail' coagulation therapy and may reflect immune-associated trophoblast injury. Although an early loss may be averted in some pregnancies treated with anticoagulants, the underlying pathology that was not a treatment target may persist and result in a preterm and/or growth-restricted neonate. The efficacy of IVIg therapy for antiphospholipid-related obstetric compromise, however, has yet to be fully established.

C. Coagulopathy

1. Lesions

Coagulation-related lesions in the uteroplacental, intervillous and/or fetoplacental vasculature may lead to uteroplacental malperfusion or primary coagulopathy, and be secondary to abnormal uteroplacental vascular conversion or immune responses. These lesions include fetal stem vessel thrombi, decidual hemosiderin deposition, uteroplacental thromboses, fibrin/fibrinoid deposition in the basal plate, maternal floor infarct (which is not a true infarct but rather massive fibrin deposition involving the decidua basalis and the nearby villi), and perivillous fibrin deposition.

2. Evidence for recurrence and role in obstetric compromise

Although a relatively uncommon lesion, Andres et al (1990) found that given the risk of growth restriction, preterm birth and fetal death in subsequent pregnancies, the identification of a potentially recurrent maternal floor infarction merits attention. Gersell (1993) also found maternal floor infarct to be associated with fetal growth restriction and late fetal death and frequently recurrent in successive pregnancies. It has been speculated that this lesion may be a rare complication of maternal autoimmunity due to antibodies against the placental urokinase-plasmin system.

Excessive placental perivillous fibrin deposition, a histologic marker of intraplacental fibrin, has been associated with preeclampsia and pregnancy-induced hypertension. Fibrin deposition in uncomplicated term pregnancies is found at sites of discontinuity in the syncytiotrophoblast of terminal villi, possibly serving as a matrix for trophoblast re-epithelialization.

Defective natural anticoagulation in relation to deficiencies of protein S, protein C or antithrombin III, resistance to activated protein C, and elevated plasma prothrombin has been associated with pregnancy compromise. While these thrombophilic states may be acquired, genetic mutations have been discovered that predispose to the hyper-coagulatory conditions associated with thromboembolic events. For example, increased resistance to activated protein C, a serine protease which acts as a natural anticoagulant by inactivating factor Va and factor VIIIa, has been linked to a point mutation in the factor V Leiden gene. Ridker et al (1998) found the prevalence of factor V Leiden mutation to be increased 2.2 fold (8.0% vs. 3.7%) in a population of women with recurrent spontaneous loss versus women with a successful pregnancy and no prior history of loss. There is normally a change in activated protein C resistance during pregnancy, but in preeclampsia the resistance has been shown to be significantly increased, and within the group with elevated protein C resistance the prevalence of the factor V Leiden mutation was also significantly.

The presence of the factor V Leiden mutation has been shown to be predictive of hereditary protein S deficiency, protein C deficiency and antithrombin deficiency, indicating a potential interaction of risk factors. Recognition of specific coagulation-related vascular pathology in the placenta, especially when coupled with a family history of thrombotic event or disorder, may indicate genetic screening for thrombophilic risk factors. As these conditions (and their physiologic effects on the placenta) are better understood, more specific and more successful anticoagulant therapies may be developed that directly address the aberrant mechanism(s).

D. Uteroplacental vasculature

1. Lesions

Uteroplacental vascular lesions include absent or incomplete uteroplacental vascular adaptation, the presence of fibrinoid necrosis/atherosis, persistence of endovascular trophoblasts in the basal plate, uteroplacental thrombosis and chronic uteroplacental vasculitis. Proper trophoblast invasion of the uterine vasculature proceeds via interstitial and endovascular pathways. The distal ends of spiral arteries, which possess a relatively undifferentiated wall structure, are easily penetrated by interstitial trophoblast which then become endovascular and begin a retrograde migration along the vascular lumen. Histologically, the arterial vessel wall shows disruption of the medial smooth muscle layers and fragmentation of the elastic tissue prior to the arrival of the endovascular trophoblast, emphasizing the importance of both stages of trophoblast invasion. Chronic uteroplacental vasculitis and uteroplacental thrombosis have already been discussed (see above). However, each of these lesions may be either primary immune or coagulopathic lesions, or may develop as secondary effect of another principal vascular injury (such as failed conversion). In this strained environment, the vasculature is highly susceptible to uteroplacental vascular accidents such as abruption and infarction. Chronic uteroplacental malperfusion may be associated with more subtle villous lesions, possibly related to shear stress/deformational effects of maternal malperfusion on the developing villous tree.

2. Evidence of recurrence and role in obstetric compromise

The magnitude of placental insufficiency and its effect on clinical outcome is determined by the presence, severity and combination of uteroplacental vascular lesions. There is no single uteroplacental arterial lesion that distinguishes among the different clinical conditions associated with uteroplacental vascular disease. There may be mitigating factors that determine the ultimate endpoint, such as a particular combination of lesions, a difference in the degree of the insult or the timing of onset. In addition, there may be intrinsic differences in the level and/or nature of a fetoplacental response to any specific uteroplacental vascular pathology; this may in part influence which of the variety of clinical presentations may be manifest. The clinical complications that are associated with poor uteroplacental vascular conversion include preterm preeclampsia, late fetal growth restriction, prematurity and early pregnancy loss.

In some compromised pregnancies, "normal" uteroplacental vascular adaptation takes place only partially within any one vessel, and/or not to the maximum depth, and/or in a more limited total number of placental bed arteries. At 16-18 weeks only one third of the arteries have been invaded, and a failure to complete the invasion process may result in a compromised pregnancy. In preterm preeclampsia, the placenta, and often the fetus, demonstrate clinical and histologic evidence of chronic uteroplacental malperfusion, consistent with an early failure to establish a normal uteroplacental vascular environment. Unconverted vessels retain high-resistance/low-capacitance properties and uteroplacental blood flow is severely restricted, which may explain the frequent association with fetal growth restriction.

It has become increasingly clear that the heritable and acquired conditions that affect the maternal systemic vasculature have ramifications for the development and maintenance of the maternal-fetal nutrient exchange of pregnancy. Through either structural damage and/or functional alteration of the uteroplacental vasculature, these mechanisms may affect the ability of the maternal system to regulate blood flow and effectively provide for the increasing demands of the fetus. The genetic basis for these conditions is important in relation to recurrent materno-placental vascular pathologies as they are a persistent attribute of the mother, and gone untreated their physiological manifestations in the placenta should, in theory, recur given similar environmental parameters.

Recent research has shown a correlation between established genetic cardiovascular risk factors and a compromised uteroplacental vascular environment. Markers of accelerated atherosclerosis, including elevated maternal plasma lipoprotein(a) and hyperhomocysteinemia (associated with the mthfr gene polymorphism), have been implicated in recurrent early fetal loss, fetal growth restriction and preeclampsia. The homozygous state for the MTHFR (5,10 methylenetetrahydrofolate) gene is associated with premature athersclerosis and thrombosis, and even the moderately elevated homocysteine levels seen in heterozygotes appear to carry increased risk cardiovascular sequelae. Hyperhomocyteinemia has also been associated with unexplained recurrent early pregnancy, with the suggestion that correction of the maternal homocysteine levels (via folate/B6 supplementation) may favor pregnancy success. Fully 31% of women with placental abruption or placental infarct were reported to be hyperhomocysteinemic. The precise mechanism of homocysteine-associated vascular injury is not clear, but most likely involves direct effects on the endothelium via generation of hydrogen peroxides, enhanced endothelial factor V activity, and impaired endothelial thrombomodulin expression. Hyperhomocysteinemia may also stimulate proliferation of vascular smooth muscle cells in vitro, contributing to the vascular dysfunction of this condition.

Conclusion

Given the scarcity of pathological data in serial obstetric compromise of varied outcome, we are restricted to general hypotheses regarding the potential recurrent pathophysiologies that should underlie serial obstetric compromise. We further hypothesize that identification of the underlying pathology of recurrent obstetric compromise will lead to improved outcome in subsequent pregnancies by precipitating an earlier diagnosis of both risk for recurrence and the cause of compromise, more diligent surveillance and earlier intervention. Histologic evidence of acute inflammation (as a marker of ascending infection), chronic inflammation (marking viral or allo/auto-immune pathology), coagulation related lesions, and maternal vascular pathology would support specific plans of obstetric evaluation and management, ranging from microbial surveillance to potentially endometrial Doppler ultrasonography. The evolving role of the placental pathologist may be to identify the targets of tissue injury and use clinical, genetic and pathologic findings to propose a mechanism and/or timetable for fetal compromise for use by clinicians in devising future obstetric interventions.

Finally, we believe the controversies regarding appropriate therapy for complex- and pathologically heterogeneous- clinical disorders will be simplified by better categorization of "at-risk" patients by underlying pathologic anatomy. Cost, let alone the potential complications of certain widely advocated therapies (e.g., IVIg, heparin), demands better triage of patients for treatment protocols. In treated pregnancies, placental examination is essential to assess most fully treatment "success" or "failure"; delivery of a living, but chronically compromised or preterm, neonate could reasonably be considered less "successful" than delivery at term of a well-grown infant. The placentas of women with "partial successes" may demonstrate "new" pathologies that were masked by an overwhelming, but now treated pathology. For example, we have found destructive chronic inflammation commonly in complicated pregnancies following anticoagulant therapy for phospholipid antibody syndrome; such patients have benefited from inclusion of anti-inflammatory therapy in subsequent regimens. Current evidence documenting the recurrence of specific placental histopathologic features remains sketchy. However, the data supports the premise that general pathophysiologic processes underlie complicated pregnancies, and when subsequent pregnancies also fail, the underlying processes are similar.

Altemani AM (1992) Immunohistochemical study of the inflammatory infiltrate in villitis of unknown etiology. A qualitative and quantitative analysis. Pathol Res Pract, 188(3), 303-9. Andres RL, Kuyper W, Resnik R, Piacquadio KM, Benirschke K (1990) The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol, 163(3), 935-8

Bendon RW, Hommel AB. (1996) Maternal floor infarction in autoimmune disease: two cases. Pediatr Pathol Lab Med 16(2), 293-7.

Benirschke K, Kaufmann P (1995) Infectious Diseases: Viral Infections and Villitides. In Pathology of the Human Placenta, 3rd Ed. New York: Springer-Verlag. Chapter 20.

Bertina RM, Koeleman BPC, Koster T, et al (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature, 369, 64-67.

Brenner B, Blumenfeld Z (1997) Thrombophilia and fetal loss. Blood Rev, 11(2), 72-79.

Clarke R, Daly L, Robinson K, Naugthen E, Cahalane S Fowler B, Graham I (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med, 324, 1149-1155.

Coulam CB (1991) Epidemiology of recurrent spontaneous abortion. Am J Reprod Immunol, 26(1), 23-7.

Cusick W, Salafia CM, Ernst L, Rodis J, Campbell W, Vintzileos AM. (1995) Low dose aspirin therapy and placental pathology in women with poor prior pregnancy outcomes. Am J Reprod Immunol 34, 141-7.

Dekker GA, de Vries JIP, Doelitzsch PM, Huigens PC, von Blomberg BME, Jakobs C, van Gejin HP (1995) Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol, 173, 1042-8.

Doss BJ, Greene MF, Hill J, Heffner LJ, Bieber FR, Genest DR (1995) Massive chronic intervillositis associated with recurrent abortions. Hum Pathol, 26(11), 1245-51.

Dudley DJ, Branch DW, Edwin SS, Mitchell MD. (1996) Induction of preterm birth in mice by RU486. Biol Reprod 55(5), 992-5.

Erlendsson K, Steinsson K, Johannsson JH, Geirsson RT (1993) Relation of antiphospholipid antibody and placental bed inflammatory vascular changes to the outcome of pregnancy in successive pregnancies of 2 women with systemic lupus erythematosus. J Rheumatol, 20(10), 1779-85.

Gersell DJ (1993) Chronic villitis, chronic chorioamnionistis, and maternal floor infarction. Semin Diagn Pathol, 10(3), 251-66.

Gersell DJ, Phillips NJ, Beckerman K. (1991) Chronic chorioamnionitis: a clinicopathologic study of 17 cases. Int J Gynecol Pathol 10(3), 217-29.

Girling J, de Swiet M (1998) Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol, 10(2), 135-44.

Goddijn-Wessel TAW, Wouters MGAJ, v.d. Molen EF, Spuijbroek MDEH, et al (1996) Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynaecol Reprod Biol, 66, 23-29.

Hasegawa I, Takakuwa K, Adachi S, Kanazawa K (1990) Cytotoxic antibody against trophoblast and lymphocytes present in pregnancy with intrauterine fetal growth retardation and its relation to anti-phospholipid antibody. J Reprod Immunol, 17(2), 127-39.

Jacques SM, Qureshi F (1994) Chronic villitis of unknown etiology in twin gestations. Pediatr Pathol, 14(4), 575-84.

Kanfer A, Bruch JF, Nguyen G, He CJ, Delarue F, Flahault A, Nessman C, Uzan S (1996) Increased placental antifibrinolytic potential and fibrin deposits in pregnancy-induced hypertension and preeclampsia. Lab Invest, 74(1), 253-8.

Karimu AL, Burton GJ. (1994) Significance of changes in fetal perfusion pressure to factors controlling angiogenesis in the human term placenta. J Reprod Fertil 102(2), 447-50. Kimberlin DF, Andrews WW. (1998) Bacterial vaginosis: association with adverse pregnancy outcome. Semin Perinatol 22(4), 242-50.

Kristensen J, Langhoff-Roos J, Kristensen FB (1995) Implications of idiopathic preterm delivery for previous and subsequent pregnancy. Obstet Gynecol, 86(5), 800-4.

Koeleman BP, Reitsma PH, Allaart CF, Bertina RM (1994) Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood, 84, 1031-5. Kutteh WH.( 1997) Antiphospholipid antibodies and reproduction J Reprod Immunol 35(2), 151-71.

Labarrere C, Althabe O (1985) Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies. Eur J Obstet Gynecol Reprod Biol, 20(1), 1-11.

Labarrere C, Althabe O (1987) Chronic villitis of unknown aetiology in recurrent intrauterine fetal growth retardation. Placenta, 8(2), 167-73.

Labarrere CA, Catoggio LJ, Mullen EG, Althabe OH (1986) Placental lesions in maternal autoimmune diseases. Am J Reprod Immunol Microbiol, 12(3), 78-86.

Labarrere CA, McIntyre JA, Faulk WP (1990) Immunohistologic evidence that villitis in human normal term placentas is an immunologic lesion. Am J Obstet Gynecol, 162(2), 515-22.

Lentz SR (1997) Minireview: Homocysteine and vascular dysfunction. Life Sciences, 61, 1205-15.

Llahi-Camp JM, Rai R, Ison C, Regan L, Taylor-Robinson D (1996) Association of bacterial vaginosis with a history of second trimester miscarriage. Hum Reprod , 11(7), 1575-8.

Magid MS, Kaplan C, Sammaritano LR, Peterson M, Druzin ML, Lockshin MD (1998) Placental pathology in systemic lupus erythematosus: a prospective study. Am J Obstet Gynecol, 179(1), 226-34.

Mallozzi-Eberle A, Levesque D, Vintzileos AM, Egan JFX, Tsapanos V, Salafia CM. (1993) Placental pathology in discordant twins. Am J Obstet Gynecol 169, 931-935.

Martius J, Eschenbach DA. (1990) The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity--a review. Arch Gynecol Obstet 247(1), 1-13.

Mimuro S, Lahoud R, Beutler L, Trudinger B. (1998) Changes of resistance to activated protein C in the course of pregnancy and prevalence of factor V mutation. Aust N Z J Obstet Gynaecol 38(2), 200-4.

Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, et al. (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet, 37, 1-31.

Nelson DM (1996) Apoptotic changes occur in syncytiotrophoblast of human placental villi where fibrin type fibrinoid is deposited at discontinuities in the villous trophoblast. Placenta, 17(7),387-91.

Okada T, Matsuzaki N, Sawai K, Nobunaga T, Shimoya K, Suzuki K, Taniguchi N, Saji F, Murata Y. (1997) Chorioamnionitis reduces placental endocrine functions: the role of bacterial lipopolysaccharide and superoxide anion. J Endocrinol 155(3), 401-10.

Peek MJ, Nelson-Piercy C, Manning RA, de Sweit M, Letsky EA (1997) Activated protein C in normal pregnancy. Br J Obstet Gynecol, 104, 1084-86.

Quere I, Bellet H, Hoffet M, Janbon C, Mares P, Gris J-C (1998) A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages. Fertil Steril, 69,152-4.

Rand JH, Wu XX, Guller S, Scher J, Andree HA, Lockwood CJ (1997) Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am J Obstet Gynecol, 177(4), 918-23.

Redline RW (1996) Recurrent villitis of bacterial etiology. Pediatr Pathol Lab Med, 16(6), 995-1001.

Redline RW, Abromowsky CR (1994) Clinical and pathologic aspects of recurrent placental villitis. Hum Pathol, 16(7), 727-31.

Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA. (1998) Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 128(12 Pt 1), 1000-3.

Romero R, Salafia CM, Athanassiadis AP, Hanaoka S, Mazor M, Sepulveda W, Bracken M. (1992) The Relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. Am J Obstet Gynecol 166, 1382-1388.

Rotmensch S, Liberati M, Mittlemann M, Ben-Rafael Z (1997) Activated protein C resistance and adverse pregnancy.outcome. Am J Obstet Gynecol , 177(1),170-3.

Rush, RW (1979) Incidence of preterm delivery in patients with previous pretrm delivery and/or abortion. S Afr Med J, 56, 1085-7.

Russell P. (1980) Inflammatory lesions of the human placenta. III. The histopathology of villitis of unknown aetiology. Placenta 1(3), 227-44.

Russell P, Atkinson K, Krishnan L (1980) Recurrent reproductive failure due to severe placental villitis of unknown etiology. J Reprod Med, 24(2), 93-8.

Salafia CM, Weigl CA, Silberman L. (1989) The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol 73, 383-9.

Salafia CM, Vintzileos AM, Bantham KF, Vogel CA, Pezzullo J, Silberman L. (1991) Placental pathologic findings in preterm birth. Am J Obstet Gynecol 165, 934-8.

Salafia CM, Maier D, Vogel C, Pezzullo JC, Burns J, Silberman L. (1993) Placental and decidual histology in spontaneous abortion: Detailed description and correlations with chromosome number. Obstet Gynecol 82(2), 295-303.

Salafia CM,Cowchock FS. (1997) Placental pathology and antiphospholipid antibodies: A descriptive study. Am J Perinatol 14(8), 435-41.

Salafia CM, Pezzullo JC, López-Zeno JA, Simmens S, Minior VK, Vintzileos AM. (1995) Placental pathology of preterm preeclampsia. Am J Obstet Gynecol 173,1097-1105.

Sander CH, Kinnane L, Stevens NG, Echt R (1986) Haemorrhagic endovasculitis of the placenta: a review with clinical correlation. Placenta, 7(6), 551-74.

Sander CM, Gilliland D, Flynn MA, Swart-Hills LA (1997) Risk factors for recurrence of hemorrhagic endovasculitis of the placenta. Obstet Gynecol, 89(4), 569-76.

Sibai BM, Ramadan MK, Chari RS, Friedman SA (1995) Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): subsequent pregnancy outcome and long-term prognosis. Am J Obstet Gynecol, 172(1 Pt 1), 125-9.

Thom DH, Nelson LM, Vaughan TL (1992) Spontaneous abortion and subsequent adverse birth outcomes. Am J Obstet Gynecol, 166(1 Pt 1), 111-6.

Todd HM, Dundoo VL, Gerber WR, Cwiak CA, Baldassare JJ, Hertelendy F. (1996 ) Effect of cytokines on prostaglandin E2 and prostacyclin production in primary cultures of human myometrial cells. J Matern Fetal Med 5(4), 161-7.

van Hoeven KH, Anyaegbunam A, Hochster H, Whitty JE, Distant J, Crawford C, Factor SM Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord. Pediatr Pathol Lab Med 1996 Sep-Oct;16(5):731-44.

Villar J, Gulmezoglu AM, de Onis M (1998) Nutritional and antimicrobial interventions to prevent preterm birth: an overview of randomized controlled trials. Obstet Gynecol Surv, 53(9), 575-85.

Vogt E, Ng AK, Rote NS (1997) Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am J Obstet Gynecol, 177(4), 964-72.

Wouters MGAJ, Boers GHJ, Blom HJ, Trijbels FJM, Thomas CMG, Borm GF et al (1993) Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril, 60, 820-4.

Yasuda M, Takakuwa K, Higashino M, Ishii S, Kazama Y, Yoshizawa H, Tanaka K (1993) A typical case of reproductive autoimmune failure syndrome in which a patient experienced recurrent abortion, preeclampsia, and intrauterine growth.retardation. Am J Reprod Immunol, 29(1), 45-7.

Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B (1995) Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood, 85(12), 3518-23.