Human Reproduction, Vol. 15, No. 8, 1830-1833,
August 2000
© 2000 European Society of Human Reproduction and Embryology
Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?
University Department of Obstetrics and Gynaecology, Liverpool Women's Hospital, UK
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Abstract |
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We examined the relationship between placental histology and thrombophilia status in women who were admitted with severe pre-eclampsia/eclampsia, placental abruption, intrauterine growth restriction or unexplained stillbirth. All women had thrombophilia screen at least 10 weeks after delivery (antithrombin III, protein C, protein S, activated protein C resistance, anticardiolipin antibodies, lupus anticoagulant, fasting plasma homocysteine and specific mutations to methylenetetrahydrofolate reductase C677T, G20210A prothrombin gene and factor V Leiden. Placental histology reports were examined to identify the frequency of thrombotic lesions in the placenta including fetal stem vessel thrombosis, fetal thrombotic vasculopathy, placental infarction, perivillous fibrin deposition, intervillous thrombosis and placental floor infarction. During a 17 month period, a cohort of 79 women met the study criteria. Thirty (70%) out of 43 women with abnormal thrombophilia screen had abnormal placental histology. Twenty-eight (78%) out of 36 women with negative thrombophilia screen had abnormal placentae. No specific histological pattern could be identified when thrombophilia positive and thrombophilia negative groups were compared. We propose that there is a poor correlation between thrombophilia status and pathological changes of the placenta in women with severe pregnancy complications.
Key words: adverse pregnancy outcome/placental thrombosis/thrombophilia
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Introduction |
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Thrombotic lesions of the placenta are a common finding in women with major complications of pregnancy such as pre-eclampsia (Kitzmiller and Benirschke, 1973
), stillbirth (Fujikura and Benson, 1964; Naeye, 1977), fetal growth restriction (Fox, 1976; Salafia et al., 1992; Salafia et al., 1995), and placental abruption (Goddijn-Wessel et al., 1996). Histological evidence of placental thrombosis may also indicate the presence of subclinical congenital or acquired haemostatic defects (Kraus, 1993). However, clinical significance of morphological changes in the placenta is still a matter of controversy (Driscoll and Langston, 1991). We were particularly interested in frequency and significance of placental lesions in women with adverse pregnancy outcome and abnormal thrombophilia state. Arias et al. (1998) found that women with a history of adverse pregnancy outcome and thrombotic lesions of the placenta exhibit laboratory abnormality consistent with a thrombophilic state. Khong and Hague (1999) examined pathological changes of the placenta in women with maternal hyperhomocysteinaemia and found that placental changes are non-specific and could not be identified in every placenta. The aim of the present study was to provide additional data on the relationship between placental changes and thrombophilia status in women with serious pregnancy complications.
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Materials and methods |
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The placental histology reports and results were studied of complete thrombophilia screen for women who were admitted to Liverpool Women's Hospital with pregnancies complicated by: (i) severe pre-eclampsia (PET)/eclampsia requiring obstetric intensive care; (ii) placental abruption requiring immediate delivery; (iii) antenatally diagnosed intrauterine growth restriction (IUGR) requiring delivery before 36 weeks; or (iv) unexplained stillbirth after 23 completed weeks of gestation.
Cases with fetal congenital malformation, abnormal karyotype or known maternal history of deep venous thrombosis or pulmonary embolism were excluded.
Thrombophilia screen
All blood tests were done at least 10 weeks after delivery and included assays of antithrombin III, protein C activity, antigen protein S free and total, activated protein C resistance (APCR), anticardiolipin antibodies (IgG and IgM), lupus anticoagulant by activated partial thromboplastin time (APTT) and dilute Russell's viper venom test (DRVVT) and fasting plasma homocysteine. Results were considered abnormal only if two consecutive tests were outside the reference range for the local population. Because these tests are subject to widespread inter-laboratory variation, specific cut-off points for abnormal dynamic thrombophilia have deliberately not been given: local reference ranges were derived from the local normal population and cannot and should not be extrapolated to other settings.
Genetic studies were performed to look for specific mutations to methylenetetrahydrofolate reductase (MTHFR C677T), G20210A prothrombin gene and factor V Leiden.
Coagulation investigations
Antithrombin III, protein C activity, APCR without predilution with factor V deficient plasma, lupus clotting screens [prothrombin time (PT), APTT, DRVVT] with phospholipid neutralisation procedure (PNP) were all measured on the multidiscrete analyser (MDA-180 Organon-Teknika) with a variety of reagents according to the manufacturer's instructions. Protein S assay was performed using Diagnostica Stago free and total Protein S kits (Asnieres, France) by an enzyme-linked immunosorbent assay (ELISA) method.
Homocysteine and anticardiolipin antibodies
Homocysteine was quantified by ELISA using Axis Homocysteine EIA® (Bio-Rad, Hemel Hempstead, UK). Anticardiolipin antibodies were measured using the Cambridge Life Science Melisa kit (Cambridge Life Science, Huntingdon, UK). Results were read on multiscan reader (Titertek Multiscan II MCC/340®; from Laboratories Ltd, Finland) at 450 nm and calculated using the manufacturer's software.
DNA extraction and genetic analysis
Genomic DNA was extracted from 400 µl of whole blood using the Puregene kit® (Gentra, MN, USA) (floegen) according to the manufacturer's instructions. DNA sequences of factor V gene, prothrombin gene and MTHFR gene were amplified by the polymerase chain reaction (PCR) using primers (Bertina et al., 1994; Frosst et al., 1995; Poort et al., 1996).
Definition of placental lesions
The histological examination of the placenta was performed as a routine clinical practice in pregnancies with severe adverse outcome.
Fetal stem vessel thrombosis was diagnosed when a major placental vessel was completely or partially occluded by a thrombus. The vessel could be located either in the chorionic plate or in one of the stem vessel branches (arterial) or tributaries (vein).
Fetal thrombotic vasculopathy was identified by foci of more than five terminal villi showing lack of villous capillaries and with a hyalinized fibrotic stroma. The adjacent villi were normally vascularized and the distribution of avascular villi conformed to a single villous tree (Redline and Pappini, 1995).
Placental (villous) infarctions were diagnosed in the presence of an area of ischaemic necrosis of the placental villi with collapse of the intervillous space and tight clustering of the villous tree.
Perivillous fibrin deposition was diagnosed in the presence of increased and excessive accumulations of fibrin-like material in the intervillous space surrounding multiple villi that remained separated. Trophoblastic cells may have migrated into the fibrin deposits and the villous capillaries may be normal.
Intervillous thrombosis was diagnosed when a villous-free nodular thrombus was found in the intervillous space.
Placental floor infarction was diagnosed when the maternal surface of the placenta was extensively thickened and stiffened due to accumulation of excessive fibrinoid material which expands the basal plate, envelops anchoring villi and surrounds large numbers of basal and periseptal villi (Kraus, 1996).
Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for comparison of frequencies. Chi-square (
2) test, Fisher's exact test, Student's t-test were used where appropriate and P < 0.05 was taken as significant. Statistical analyses were performed using the statistical package of Arcus Quickstat 1.0 (Iain Buchan, 1997).
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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In the period from July 1997 to November 1998, there were 102 women who delivered at the Liverpool Women's Hospital with pre-eclampsia/eclampsia, intrauterine growth restriction, unexplained stillbirth or placental abruption as defined by our protocol. Placental histology and full thrombophilia screen were available for 79 of them who were studied in detail. There were no demographic differences between the 79 women included in the study and the 23 women in whom placental histology or thrombophilia screen was either incomplete or not performed. The general characteristics and pregnancy outcome of the study group (n = 79) are described in Table I
. Forty-three (54%) women had abnormal thrombophilia screen. There were no significant differences between the two groups regarding maternal age, gestational age at delivery, onset of labour, mode of delivery, and pregnancy outcome. The incidence of placental abruption was lower in women with abnormal thrombophilia (14 versus 36%, P = 0.04).
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Frequency of placental lesions and their relationship with abnormal thrombophilia screen is shown in Table II
. Pathological changes in the placentae were identified in 30/43 (70%) women with abnormal thrombophilia compared to 28/36 (78%) women with negative thrombophilia screen (not significant). Placental infarction was the most common lesion and was identified in 48% of placentae of the study population, but there was no significant increase in the number of specific placental lesions in women with abnormal thrombophilia.
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We compared the incidence of six types of pathological lesions of the placenta in women with single (n = 23) and multiple (n = 20) abnormal laboratory tests and found no difference between the two groups (Table III
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The distribution of placental lesions according to state of thrombophilia screen and obstetric complications is shown in Tables IV and V
. Odds ratios and 95% CI were calculated for all comparisons (Table II–V
) but the differences were not statistically significant and therefore not shown in the tables.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The results of our study show that there is a poor correlation between thrombophilia state and placental pathological changes in women with adverse pregnancy outcome. The six types of placental lesions were selected based on previous reports suggesting that they are common in pregnant women with thrombophilia (Arias et al., 1998
; Magid et al., 1998). It is important to emphasize that our study does not address the incidence of these patterns in all births, but rather shows their relative frequency and possible clinical implications in a high-risk obstetric population.
Placental infarction was the most common abnormal histological finding in our cohort and this finding is consistent with previous reports (Laurini et al., 1994). Small placental infarctions are common in uncomplicated pregnancies at term and of no importance, but extensive infarction, i.e. necrosis of >10% of the placenta, is associated with fetal hypoxia, growth retardation and fetal death, particularly in the second and early third trimester (Fox, 1997; Rodriguez et al., 1997).
Although it is claimed that fetal thrombotic vasculopathy and fetal stem vessel thrombosis are common findings in women with adverse pregnancy outcome (Arias et al., 1998), we were unable to confirm this observation.
The incidence of maternal floor infarction in unselected pregnancies is <1% (Naeye, 1985; Andres et al., 1990). The incidence in our cohort was much higher (15%) confirming the previously observed association between maternal floor infarction of the placenta and adverse pregnancy outcome (Andres et al., 1990). As expected, perivillous fibrin deposition and intervillous thrombosis were quite common, but their clinical significance remains questionable (Fox, 1998).
Low activated protein C resistance (APCR) was the most common abnormal finding in this cohort. It is important to stress that only two women in our cohort had factor V Leiden mutation. Despite that, placental infarction was demonstrated in 50% of cases of low APCR ratio. The significance of this finding remains uncertain.
Placental changes in women with abnormal anticardiolipin antibodies and lupus anticoagulants are consistent with previous reports (Out et al., 1991; Magid et al., 1998). Non-specific placental changes in women with hyperhomocysteinaemia were recently reported (Khong and Hague, 1999) and were confirmed in our study. It is noteworthy that four women with hyperhomocysteinaemia had normal placentae. This suggests that placental changes may not be the only factor responsible for adverse pregnancy outcome in these women.
In summary, we found a poor correlation between thrombophilia status and pathological changes of the placenta in women with severe pregnancy complications. If there is a causal link between currently known thrombophilias, placental pathological changes and severe pregnancy complications, more sophisticated methods are required to prove it.
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Acknowledgments |
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Placental histopathology was performed by Lynette Moore and Grant McBride from the Department of Histopathology, Central Manchester Healthcare Trust. Thrombophilia screening was performed by the team from the Department of Haematology, Royal Liverpool Hospital, led by Vanessa Martlew, Cheng Toh and Margo Perez.
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Notes |
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1 To whom correspondence should be addressed at: University Department of Obstetrics and Gynaecology, University of Liverpool, Liverpool L69 3BX, UK. E-mail: zarko{at}liv.ac.uk
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Andres, R.L., Kuyper, W., Resnik, R. et al. (1990) The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am. J. Obstet Gynecol., 163, 935–938.[Medline]
Arias, F., Romero, R., Joist, H. et al. (1998) Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in placenta. J. Mat. Fet. Med., 7, 277–286.
Bertina, R.M., Koeleman, B.P., Koster, T. et al. (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature, 369, 64–67.[Medline]
Driscoll, S.G. and Langston C. (1991) College of American Pathologists Conference XIX on the examination of the placenta: report of the working group on methods for placental examination. Arch. Pathol. Lab. Med., 115, 704–708.[Web of Science][Medline]
Fox, H. (1976) The histopathology of placental insufficiency. J. Clin. Path., 10, 1–8.
Fox, H. (1997) Pathology of the Placenta, 2nd edn. Saunders, Philadelphia.
Fox, H. (1998) Abnormal placentation. Curr. Obstet. Gynecol., 8, 21–26.
Frosst, P., Blom, H.J., Goyette, P. et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet., 10, 111–113.[Web of Science][Medline]
Fujikura, T. and Benson, R.C. (1964) Placentitis and fibrous occlusion of fetal vessels in the placentas of stillborn infants. Am. J. Obstet. Gynecol., 89, 225–232.[Medline]
Goddijn-Wessel, T.A.W., Wouters, M.G.A.J., Molen, E.F.V.D. et al. (1996) Hyperhomocysteinaemia: a risk factor for placental abruption or infarction. Eur. J. Obstet. Gynecol. Reprod. Biol., 66, 23–29.[Web of Science][Medline]
Khong, T.Y. and Hague, W.M. (1999) The placenta in maternal hyperhomocysteinaemia. Br. J. Obstet. Gynecol., 106, 273–278.[Web of Science][Medline]
Kitzmiller, J.L. and Benirschke, K. (1973) Immunofluorescent study of placental bed vessels in pre-eclampsia. Am. J. Obstet. Gynecol., 115, 248–251.[Medline]
Kraus, F.T. (1993) Placental thrombi and related problems. Semin. Diagn. Pathol., 10, 275–283.[Web of Science][Medline]
Kraus, F.T. (1996) Placenta: thrombosis of foetal stem vessels with foetal thrombotic vasculopathy and chronic villitis. Pediatr. Pathol. Lab. Med., 16, 143–148.[Web of Science][Medline]
Laurini, R., Laurin, J. and Marsal, K. (1994) Placental histology and fetal blood flow in intrauterine growth retardation. Acta Obstet. Gynecol. Scand., 73, 529–534.[Web of Science][Medline]
Magid, M.S., Kaplan, C., Sammaritano, L.R. et al. (1998) Placental pathology in systemic lupus erythmatosus: a prospective study. Am. J. Obstet. Gynecol., 179, 226–234.[Web of Science][Medline]
Naeye, R.L. (1977) Placental infarction leading to fetal or neonatal death. A prospective study. Obstet. Gynecol., 50, 583–588.[Web of Science][Medline]
Naeye, R.L. (1985) Maternal floor infarction. Hum. Pathol., 16, 823–828.[Medline]
Out, H.J., Kooijman, C.D., Bruinse, H.W. et al. (1991) Histopathological findings in placentae from patients with intra-uterine fetal death and antiphospholipid antibodies. Eur. J. Obstet. Gynecol. Reprod. Biol., 41, 179–186.[Web of Science][Medline]
Poort, S.R., Rosendaal, F.R., Reitsma, P.H. et al. (1996) A common genetic variation in the 3'-unsaturated region of the prothrombin gene was associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood, 88, 3698–3703.
Redline, R.W. and Pappini, A. (1995) Fetal thrombotic vasculopathy: the clinical significance of extensive avascular villi. Hum. Pathol., 26, 80–85.[Web of Science][Medline]
Rodriguez, J.G., Poter, H., Andrews, H.S. et al. (1997) Placental lesions: is growth a predictor of bad outcome? Fetal Diagn. Ther., 12, 163–166.[Medline]
Salafia, C.M., Vintzileos, A.M., Silberman, L. et al. (1992) Placental pathology of idiopathic intrauterine growth restriction at term. Am. J. Perinatol., 9, 179–184.[Web of Science][Medline]
Salafia, C.M., Minior, V.K., Pezzullo, J.C. et al. (1995) Intrautrine growth restriction in infants of less than thirty-two weeks' gestation: associated placental pathological features. Am. J. Obstet. Gynecol., 173, 1049–1057.[Web of Science][Medline]
Submitted on February 11, 2000; accepted on May 11, 2000.
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