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Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome
BJOG: an International Journal of Obstetrics and Gynaecology May 2002, Vol. 109, pp. 570– 573
SHORT COMMUNICATION
Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome N.J. Sebirea,*, M. Backosb, R.D. Goldina, L. Reganb We present three pregnancies in which massive perivillous fibrous deposition (MPVFD) and maternal floor infarction (MFI) occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and who were treated with low dose aspirin and heparin. We hypothesise that PAPS may be a predisposing factor to the development of this condition. The increased prevalence of late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Some patients with PAPS may therefore be prone to suffer either the previously reported complications of the uteroplacental vasculature, such as pre-eclampsia, and/or specific complications related to the environment of the intervillus space, such as MPVFD/MFI. Introduction Massive perivillous fibrin deposition (MPVFD) and maternal floor infarction (MFI) are pregnancy complications of unknown aetiology, characterised by extensive deposition of fibrin either within the intervillous space or primarily within and around the basal plate. Significant areas of chorionic villi become entrapped by fibrin, with obliteration of the intervillous space, resulting in secondary villous atrophy, with or without cytotrophoblast proliferation1. The clinical and pathological features of MPVFD and MFI may exhibit some overlap, and there is uncertainty in the literature whether they represent different, distinct entities, or are simply different manifestations of a common underlying pathophysiology, as evidenced by the suggestion that the term ‘massive basal plate fibrin deposition (MBPFD) may be more appropriate than MFI2 – 4. In unselected populations, the prevalence of these conditions is around 1/200 – 1/1000 pregnancies2 and both MPVFD and MFI have been associated with fetal death, preterm birth and intrauterine growth restriction5. Furthermore, women in whom MFI is diagnosed are more likely to have experienced similar obstetric complications previously, and recurrence in subsequent pregnancies has been reported5,6.
a
Department of Histopathology, Imperial College School of Medicine, St Mary’s Hospital, London, UK b Department of Obstetrics and Gynaecology, Imperial College School of Medicine, St Mary’s Hospital, London, UK * Correspondence: Dr N. Sebire, Department of Histopathology, St Mary’s Hospital, Paddington, London W2, UK. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 2 ) 0 0 0 7 7 - 0
It has been suggested that the primary underlying event is platelet aggregation and fibrin deposition from maternal blood, and an immunological basis for the activation of this process has been proposed2,4,7. We present three cases in which partial or complete MPVFD/MFI occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and hypothesise that in some women, PAPS may be a predisposing factor to the development of this condition.
Case 1 A 30 year old woman had a history of one previous live birth at term with no complications followed by an intrauterine death from severe intrauterine growth restriction (IUGR) at 32 weeks of gestation and nine subsequent first trimester pregnancy losses. She tested persistently positive for both lupus anticoagulant and IgG anticardiolipin antibodies. She was offered low dose aspirin plus heparin treatment in her 12th pregnancy according to published protocols8, which was complicated with pre-eclampsia and intrauterine growth restriction (IUGR) requiring induction of labour at 37 weeks resulting in the birth of a baby boy weighing 2.1 kg who was admitted to the special care baby unit for hypoglycemia, hypothermia and polycythaemia. In her 13th (index) pregnancy she was again treated with low dose aspirin and heparin. This pregnancy was uneventful until week 29, when IUGR was again diagnosed on ultrasound examination. There were bilateral uterine artery notches on Doppler flow examination. Although the umbilical artery Doppler flow velocity waveforms were normal at this time, multiple cystic areas were visualised within the www.bjog-elsevier.com
SHORT COMMUNICATION
571
Fig. 1. Placenta from Case 1 showing marked thickening of the basal plate with prominent septae and extensive areas of massively increased perivillus fibrin deposition.
placenta, which appeared to have a variable architecture with multiple echoes. The umbilical artery pulsatality index subsequently became abnormal and emergency lower segment caesarean section was performed at 32 weeks with delivery of a live female infant weighing 1.2 kg with Apgar scores of 6 and 10 at one and five minutes, respectively. The baby was admitted to the special care baby unit for further monitoring but was discharged home in a good condition six weeks later. The placenta measured 18 14 3.5 cm with 8 cm of umbilical cord which inserted centrally. The maternal surface was complete but with markedly increased basal plate fibrin deposition. There were also numerous thick, white, subchorionic fibrin plaques present and serial sectioning revealed a diffuse ‘lobular’ appearance of the entire placenta with prominent septae and areas of massive fibrin depostion but no infarcts. Cystic areas were also present within the placental parenchyma (Fig. 1). The villous maturity was normal for gestation with predominant terminal villi, but approximately 40% of the placental parenchyma showed extensive perivillous and basal plate fibrin deposition with entrapped degenerate villi. The intervening areas showed villi with increased syncytial knot formation and massive subchorionic fibrin deposition was also present.
2.47 kg. Her postoperative course was complicated with persistent hypertension requiring anti-hypertensive medication. The couple declined infant postmortem examination, but karyotyping confirmed a normal female karyotype. The placenta measured 15 13 3.5 cm with 53 cm of macroscopically normal three-vessel umbilical cord which inserted paracentrally. The membranes showed mild green discolouration but were otherwise unremarkable and there were numerous small, white subchorionic plaques. The maternal surface was complete but approximately 35% of the maternal area, towards the periphery, had lost its normal appearance and was firm, white and lobular, consistent with MPVFD (Fig. 2). Serial sectioning revealed this area to be solid white with numerous further pale solid lesions and cystic spaces throughout the remaining placenta with prominent septae. The villous maturity was normal for third trimester with predominant terminal villi and normal villous vascularity. The basal plate in the large white area showed markedly increased fibrin deposition with overlying entrapped fibrosed villi with cytotrophoblast proliferation, and there were numerous further areas throughout
Case 2 A 38 year old woman with a history of live birth at term followed by four first trimester miscarriages was investigated for recurrent pregnancy loss and tested persistently positive for IgG anticardiolipin antibodies. She was offered treatment with low dose aspirin and heparin in her next pregnancy which was uneventful until the 38th week of gestation when she developed mild gestational hypertension (blood pressure 140/95mmHg). Subsequently, persistent fetal bradycardia was noted on cardiotocograph (CTG) and an emergency lower segment caesarean section delivery carried out but the baby was fresh stillborn, weighing D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
Fig. 2. Placenta from Case 2 showing the maternal surface with marked pale, firm areas of fibrin deposition, histological examination of which demonstrated the features of MPVFD/MFI.
572
SHORT COMMUNICATION
the placenta showing MPVFD. Old and recent intervillus thrombi were also noted.
Case 3 A 34 year old woman had experienced three previous mid-trimester pregnancy losses at 14, 14 and 16 weeks of gestation, respectively. Her first and second miscarriages were preceded by spontaneous rupture of membranes but no postmortem examinations were performed. In her third pregnancy, prophylactic cervical cerclage was carried out at 14 weeks of gestation but two weeks later an ultrasound scan confirmed an intrauterine death of a fetus with abnormal male karyotype (trisomy 21). Following the third miscarriage she was investigated and found to have persistently positive tests for IgG anticardiolipin antibodies. Accordingly she was offered treatment with low dose aspirin and heparin in her next pregnancy. This was initially a twin pregnancy but at 13 weeks she miscarried the first twin and a rescue cervical cerclage was inserted. Serial ultrasound examinations of the surviving fetus were satisfactory until at 29 weeks she presented with a small antepartum haemorrhage with an abnormal CTG. The cervical suture was removed and an emergency lower segment caesarean section was performed to deliver a female infant weighing 1.2 kg with Apgar scores of 7 and 8 at one and five minutes, respectively. An apparent retroplacental clot was noted at delivery. The baby was immediately intubated and admitted to the special care baby unit and had an uncomplicated neonatal course. The placenta measured 13 13 4 cm with 31 cm of macroscopically normal three vessel umbilical cord which inserted paracentrally, 2 cm from the closest placental margin. The maternal surface was ragged but appeared complete with a loosely adherent marginal clot, 5 5 cm,
Fig. 3. Photomicrograph of the placenta from Case 3 showing excessive fibrin deposition in and around the basal plate and an area of massive perivillus fibrin deposition in which numerous villi are entrapped (original magnification 40).
present at one periphery, with no overlying parenchymal compression. Separate from the clot, there was an area measuring 7 3 2 cm towards the periphery, which was firm and white with the macroscopic appearance of partial MFI. Serial sectioning revealed approximately 25% of the placental volume to be affected by massive basal plate fibrin deposition with overlying prominent septae and massive fibrin deposition with small areas of macroscopically uninvolved villi. Microscopic examination showed early third trimester maturity. The basal plate demonstrated extensive fibrin deposition with overlying MPVFD encasing large areas of villi (Fig. 3). The sections of macroscopically unremarkable placenta away from the main lesion showed no specific histological abnormalities. Mild histological chorioamnionitis was also present.
Discussion These cases suggest a possible association between PAPS and development of MPVFD/MFI. Low dose aspirin and heparin therapy achieves a successful pregnancy in more than 70% of patients who have suffered recurrent miscarriages in association with PAPS, but such pregnancies have an increased risk of developing complications such as intrauterine growth restriction, pre-eclampsia and placental abruption9. The majority of these complications are believed to be a consequence of uteroplacental disease but some adverse outcomes may be due to an increased risk of the MPVFD/MFI spectrum of abnormalities. It is suggested that in most cases of MPVFD there is platelet aggregation with subsequent maternal fibrin deposition around chorionic villi within the intervillous space. The small amounts of perivillous fibrin present in all normal term placentas probably occur as a result of areas of turbulent intervillous blood flow2. In cases of MPVFD the process is much more extensive, and the distribution of fibrin deposition is not apparently related to areas of turbulent flow, suggesting that diffuse trophoblastic damage, possibly immunological in nature, may be the underlying pathological process4,7. Rand et al.10 have previously reported that antiphospholipid antibodies can downregulate trophoblast expression of the endogenous anticoagulant annexins leading to a localised hypercoagulable state in the placenta. Additionally, MPVFD/MFI has been reported in patients with other maternal autoimmune diseases, consistent with an autoantibody mediated mechanism11,12. In the present series, the histological features of MPVFD were present in all cases, but the extent of placental involvement varied from total to apparently partial. If the underlying aetiology were binding of circulating antibodies to trophoblast, it might be expected that the placenta/intervillous space should be uniformly affected. It is therefore likely that these cases represent different stages of an evolving condition, the expression of which, may be further modified by regional alterations in maternal uteroplacental flow. D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
SHORT COMMUNICATION
For example, in Case 3, there was apparent partial placental involvement, which, in the absence of surveillance and early delivery, may have subsequently presented classically as a third trimester intrauterine death with extensive and more uniform placental MPVFD. The underlying mechanism of pregnancy loss in PAPS remains undetermined with a wide range of reported histological features and suggested pathophysiologies, including decidual vasculopathy with placental infarction, unspecified placental thrombosis and direct embryotoxic effects13. Patients treated with aspirin and heparin have an improved prognosis suggesting that the mechanism of action of these agents is either due to a direct effect on platelet aggregation/activation, or alternatively, to a modification of endothelial cell function. The finding of increased late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity or alters the disease expression. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Patients with PAPS may therefore be prone to suffer both complications of the uteroplacental vasculature, such as pre-eclampsia, and/or complications directly related to the environment of the intervillus space, as in the present series. The majority of ongoing pregnancies in patients with PAPS do not, however, develop MPVFD and therefore further investigation of the specific antibodies present in such cases, including epitope specificity, may allow more accurate prediction of the likelihood of complications in such pregnancies following treatment. Furthermore, since fetal growth restriction, oligohydramnios and increased placental echogenicity may allow prenatal diagnosis of MPVFD/MFI14, particularly in cases at high risk due to previous obstetric history, antenatal surveillance in such cases may allow delivery prior to the development of critical fetal distress.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
573
References 1. Naeye RL. Maternal floor infarction. Hum Pathol 1985;16:823 – 828. 2. Fox H. Macroscopic abnormalities of the placenta. In: Fox H, editor. Pathology of the Placenta. London: WB Saunders, 1997:102 – 150. 3. Benirschke K, Kaufmann P. Nonvillous parts of the placenta. In: Benirschke K, Kaufmann P, editors. Pathology of the Human Placenta. New York: Springer-Verlag, 1995:182 – 267. 4. Rushton DI. Pathology of placenta. In: Wigglesworth JS, Singer DB, editors. Textbook of Fetal and Perinatal Pathology. London: Blackwell Science, 1998:145 – 199. 5. Andres RL, Kuyper W, Resnik R, Piacquadio KM, Benirschke K. The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol 1990;163:935 – 938. 6. Clewell WH, Manchester DK. Recurrent maternal floor infarction: a preventable cause of fetal death. Am J Obstet Gynecol 1983;147: 346 – 347. 7. Salafia CM, Pijnenborg R. Diseases of the decidua and maternal vasculature. In: Lewis SH, Perrin E, editors. Pathology of the Placenta. Philadephilia: Churchill Livingstone, 1999:185 – 212. 8. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin versus aspirin plus heparin in pregnant women with recurrent miscarriage associated with antiphospholipid antibodies. BMJ 1997;314:253 – 257. 9. Backos M, Rai R, Chilcott I, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol 1999;106:102 – 107. 10. Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome — a possible thrombogenic mechanism. N Engl J Med 1997;337:154 – 160. 11. Benirschke K, Kaufmann P. Maternal diseases complicating pregnancy: diabetes, tumors, preeclampsia, lupus anticoagulant. In: Benirschke K, Kaufmann P, editors. Pathology of the Human Placenta. New York: Springer-Verlag, 1995:476 – 536. 12. Bendon RW, Hommel AB. Maternal floor infarction in autoimmune disease: two cases. Pediatr Pathol 1996;16:293 – 297. 13. Fox H. The placenta in abortion. In: Fox H, editor. Pathology of the Placenta. London: WB Saunders, 1997:270 – 293. 14. Mandsager NT, Bendon R, Mostello D, Rosenn B, Miodovnik M, Siddiqi TA. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol 1994;83:750 – 754. Accepted 5 February 2002
SHORT COMMUNICATION
Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome N.J. Sebirea,*, M. Backosb, R.D. Goldina, L. Reganb We present three pregnancies in which massive perivillous fibrous deposition (MPVFD) and maternal floor infarction (MFI) occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and who were treated with low dose aspirin and heparin. We hypothesise that PAPS may be a predisposing factor to the development of this condition. The increased prevalence of late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Some patients with PAPS may therefore be prone to suffer either the previously reported complications of the uteroplacental vasculature, such as pre-eclampsia, and/or specific complications related to the environment of the intervillus space, such as MPVFD/MFI. Introduction Massive perivillous fibrin deposition (MPVFD) and maternal floor infarction (MFI) are pregnancy complications of unknown aetiology, characterised by extensive deposition of fibrin either within the intervillous space or primarily within and around the basal plate. Significant areas of chorionic villi become entrapped by fibrin, with obliteration of the intervillous space, resulting in secondary villous atrophy, with or without cytotrophoblast proliferation1. The clinical and pathological features of MPVFD and MFI may exhibit some overlap, and there is uncertainty in the literature whether they represent different, distinct entities, or are simply different manifestations of a common underlying pathophysiology, as evidenced by the suggestion that the term ‘massive basal plate fibrin deposition (MBPFD) may be more appropriate than MFI2 – 4. In unselected populations, the prevalence of these conditions is around 1/200 – 1/1000 pregnancies2 and both MPVFD and MFI have been associated with fetal death, preterm birth and intrauterine growth restriction5. Furthermore, women in whom MFI is diagnosed are more likely to have experienced similar obstetric complications previously, and recurrence in subsequent pregnancies has been reported5,6.
a
Department of Histopathology, Imperial College School of Medicine, St Mary’s Hospital, London, UK b Department of Obstetrics and Gynaecology, Imperial College School of Medicine, St Mary’s Hospital, London, UK * Correspondence: Dr N. Sebire, Department of Histopathology, St Mary’s Hospital, Paddington, London W2, UK. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 2 ) 0 0 0 7 7 - 0
It has been suggested that the primary underlying event is platelet aggregation and fibrin deposition from maternal blood, and an immunological basis for the activation of this process has been proposed2,4,7. We present three cases in which partial or complete MPVFD/MFI occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and hypothesise that in some women, PAPS may be a predisposing factor to the development of this condition.
Case 1 A 30 year old woman had a history of one previous live birth at term with no complications followed by an intrauterine death from severe intrauterine growth restriction (IUGR) at 32 weeks of gestation and nine subsequent first trimester pregnancy losses. She tested persistently positive for both lupus anticoagulant and IgG anticardiolipin antibodies. She was offered low dose aspirin plus heparin treatment in her 12th pregnancy according to published protocols8, which was complicated with pre-eclampsia and intrauterine growth restriction (IUGR) requiring induction of labour at 37 weeks resulting in the birth of a baby boy weighing 2.1 kg who was admitted to the special care baby unit for hypoglycemia, hypothermia and polycythaemia. In her 13th (index) pregnancy she was again treated with low dose aspirin and heparin. This pregnancy was uneventful until week 29, when IUGR was again diagnosed on ultrasound examination. There were bilateral uterine artery notches on Doppler flow examination. Although the umbilical artery Doppler flow velocity waveforms were normal at this time, multiple cystic areas were visualised within the www.bjog-elsevier.com
SHORT COMMUNICATION
571
Fig. 1. Placenta from Case 1 showing marked thickening of the basal plate with prominent septae and extensive areas of massively increased perivillus fibrin deposition.
placenta, which appeared to have a variable architecture with multiple echoes. The umbilical artery pulsatality index subsequently became abnormal and emergency lower segment caesarean section was performed at 32 weeks with delivery of a live female infant weighing 1.2 kg with Apgar scores of 6 and 10 at one and five minutes, respectively. The baby was admitted to the special care baby unit for further monitoring but was discharged home in a good condition six weeks later. The placenta measured 18 14 3.5 cm with 8 cm of umbilical cord which inserted centrally. The maternal surface was complete but with markedly increased basal plate fibrin deposition. There were also numerous thick, white, subchorionic fibrin plaques present and serial sectioning revealed a diffuse ‘lobular’ appearance of the entire placenta with prominent septae and areas of massive fibrin depostion but no infarcts. Cystic areas were also present within the placental parenchyma (Fig. 1). The villous maturity was normal for gestation with predominant terminal villi, but approximately 40% of the placental parenchyma showed extensive perivillous and basal plate fibrin deposition with entrapped degenerate villi. The intervening areas showed villi with increased syncytial knot formation and massive subchorionic fibrin deposition was also present.
2.47 kg. Her postoperative course was complicated with persistent hypertension requiring anti-hypertensive medication. The couple declined infant postmortem examination, but karyotyping confirmed a normal female karyotype. The placenta measured 15 13 3.5 cm with 53 cm of macroscopically normal three-vessel umbilical cord which inserted paracentrally. The membranes showed mild green discolouration but were otherwise unremarkable and there were numerous small, white subchorionic plaques. The maternal surface was complete but approximately 35% of the maternal area, towards the periphery, had lost its normal appearance and was firm, white and lobular, consistent with MPVFD (Fig. 2). Serial sectioning revealed this area to be solid white with numerous further pale solid lesions and cystic spaces throughout the remaining placenta with prominent septae. The villous maturity was normal for third trimester with predominant terminal villi and normal villous vascularity. The basal plate in the large white area showed markedly increased fibrin deposition with overlying entrapped fibrosed villi with cytotrophoblast proliferation, and there were numerous further areas throughout
Case 2 A 38 year old woman with a history of live birth at term followed by four first trimester miscarriages was investigated for recurrent pregnancy loss and tested persistently positive for IgG anticardiolipin antibodies. She was offered treatment with low dose aspirin and heparin in her next pregnancy which was uneventful until the 38th week of gestation when she developed mild gestational hypertension (blood pressure 140/95mmHg). Subsequently, persistent fetal bradycardia was noted on cardiotocograph (CTG) and an emergency lower segment caesarean section delivery carried out but the baby was fresh stillborn, weighing D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
Fig. 2. Placenta from Case 2 showing the maternal surface with marked pale, firm areas of fibrin deposition, histological examination of which demonstrated the features of MPVFD/MFI.
572
SHORT COMMUNICATION
the placenta showing MPVFD. Old and recent intervillus thrombi were also noted.
Case 3 A 34 year old woman had experienced three previous mid-trimester pregnancy losses at 14, 14 and 16 weeks of gestation, respectively. Her first and second miscarriages were preceded by spontaneous rupture of membranes but no postmortem examinations were performed. In her third pregnancy, prophylactic cervical cerclage was carried out at 14 weeks of gestation but two weeks later an ultrasound scan confirmed an intrauterine death of a fetus with abnormal male karyotype (trisomy 21). Following the third miscarriage she was investigated and found to have persistently positive tests for IgG anticardiolipin antibodies. Accordingly she was offered treatment with low dose aspirin and heparin in her next pregnancy. This was initially a twin pregnancy but at 13 weeks she miscarried the first twin and a rescue cervical cerclage was inserted. Serial ultrasound examinations of the surviving fetus were satisfactory until at 29 weeks she presented with a small antepartum haemorrhage with an abnormal CTG. The cervical suture was removed and an emergency lower segment caesarean section was performed to deliver a female infant weighing 1.2 kg with Apgar scores of 7 and 8 at one and five minutes, respectively. An apparent retroplacental clot was noted at delivery. The baby was immediately intubated and admitted to the special care baby unit and had an uncomplicated neonatal course. The placenta measured 13 13 4 cm with 31 cm of macroscopically normal three vessel umbilical cord which inserted paracentrally, 2 cm from the closest placental margin. The maternal surface was ragged but appeared complete with a loosely adherent marginal clot, 5 5 cm,
Fig. 3. Photomicrograph of the placenta from Case 3 showing excessive fibrin deposition in and around the basal plate and an area of massive perivillus fibrin deposition in which numerous villi are entrapped (original magnification 40).
present at one periphery, with no overlying parenchymal compression. Separate from the clot, there was an area measuring 7 3 2 cm towards the periphery, which was firm and white with the macroscopic appearance of partial MFI. Serial sectioning revealed approximately 25% of the placental volume to be affected by massive basal plate fibrin deposition with overlying prominent septae and massive fibrin deposition with small areas of macroscopically uninvolved villi. Microscopic examination showed early third trimester maturity. The basal plate demonstrated extensive fibrin deposition with overlying MPVFD encasing large areas of villi (Fig. 3). The sections of macroscopically unremarkable placenta away from the main lesion showed no specific histological abnormalities. Mild histological chorioamnionitis was also present.
Discussion These cases suggest a possible association between PAPS and development of MPVFD/MFI. Low dose aspirin and heparin therapy achieves a successful pregnancy in more than 70% of patients who have suffered recurrent miscarriages in association with PAPS, but such pregnancies have an increased risk of developing complications such as intrauterine growth restriction, pre-eclampsia and placental abruption9. The majority of these complications are believed to be a consequence of uteroplacental disease but some adverse outcomes may be due to an increased risk of the MPVFD/MFI spectrum of abnormalities. It is suggested that in most cases of MPVFD there is platelet aggregation with subsequent maternal fibrin deposition around chorionic villi within the intervillous space. The small amounts of perivillous fibrin present in all normal term placentas probably occur as a result of areas of turbulent intervillous blood flow2. In cases of MPVFD the process is much more extensive, and the distribution of fibrin deposition is not apparently related to areas of turbulent flow, suggesting that diffuse trophoblastic damage, possibly immunological in nature, may be the underlying pathological process4,7. Rand et al.10 have previously reported that antiphospholipid antibodies can downregulate trophoblast expression of the endogenous anticoagulant annexins leading to a localised hypercoagulable state in the placenta. Additionally, MPVFD/MFI has been reported in patients with other maternal autoimmune diseases, consistent with an autoantibody mediated mechanism11,12. In the present series, the histological features of MPVFD were present in all cases, but the extent of placental involvement varied from total to apparently partial. If the underlying aetiology were binding of circulating antibodies to trophoblast, it might be expected that the placenta/intervillous space should be uniformly affected. It is therefore likely that these cases represent different stages of an evolving condition, the expression of which, may be further modified by regional alterations in maternal uteroplacental flow. D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
SHORT COMMUNICATION
For example, in Case 3, there was apparent partial placental involvement, which, in the absence of surveillance and early delivery, may have subsequently presented classically as a third trimester intrauterine death with extensive and more uniform placental MPVFD. The underlying mechanism of pregnancy loss in PAPS remains undetermined with a wide range of reported histological features and suggested pathophysiologies, including decidual vasculopathy with placental infarction, unspecified placental thrombosis and direct embryotoxic effects13. Patients treated with aspirin and heparin have an improved prognosis suggesting that the mechanism of action of these agents is either due to a direct effect on platelet aggregation/activation, or alternatively, to a modification of endothelial cell function. The finding of increased late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity or alters the disease expression. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Patients with PAPS may therefore be prone to suffer both complications of the uteroplacental vasculature, such as pre-eclampsia, and/or complications directly related to the environment of the intervillus space, as in the present series. The majority of ongoing pregnancies in patients with PAPS do not, however, develop MPVFD and therefore further investigation of the specific antibodies present in such cases, including epitope specificity, may allow more accurate prediction of the likelihood of complications in such pregnancies following treatment. Furthermore, since fetal growth restriction, oligohydramnios and increased placental echogenicity may allow prenatal diagnosis of MPVFD/MFI14, particularly in cases at high risk due to previous obstetric history, antenatal surveillance in such cases may allow delivery prior to the development of critical fetal distress.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 570 – 573
573
References 1. Naeye RL. Maternal floor infarction. Hum Pathol 1985;16:823 – 828. 2. Fox H. Macroscopic abnormalities of the placenta. In: Fox H, editor. Pathology of the Placenta. London: WB Saunders, 1997:102 – 150. 3. Benirschke K, Kaufmann P. Nonvillous parts of the placenta. In: Benirschke K, Kaufmann P, editors. Pathology of the Human Placenta. New York: Springer-Verlag, 1995:182 – 267. 4. Rushton DI. Pathology of placenta. In: Wigglesworth JS, Singer DB, editors. Textbook of Fetal and Perinatal Pathology. London: Blackwell Science, 1998:145 – 199. 5. Andres RL, Kuyper W, Resnik R, Piacquadio KM, Benirschke K. The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol 1990;163:935 – 938. 6. Clewell WH, Manchester DK. Recurrent maternal floor infarction: a preventable cause of fetal death. Am J Obstet Gynecol 1983;147: 346 – 347. 7. Salafia CM, Pijnenborg R. Diseases of the decidua and maternal vasculature. In: Lewis SH, Perrin E, editors. Pathology of the Placenta. Philadephilia: Churchill Livingstone, 1999:185 – 212. 8. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin versus aspirin plus heparin in pregnant women with recurrent miscarriage associated with antiphospholipid antibodies. BMJ 1997;314:253 – 257. 9. Backos M, Rai R, Chilcott I, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin. Br J Obstet Gynaecol 1999;106:102 – 107. 10. Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome — a possible thrombogenic mechanism. N Engl J Med 1997;337:154 – 160. 11. Benirschke K, Kaufmann P. Maternal diseases complicating pregnancy: diabetes, tumors, preeclampsia, lupus anticoagulant. In: Benirschke K, Kaufmann P, editors. Pathology of the Human Placenta. New York: Springer-Verlag, 1995:476 – 536. 12. Bendon RW, Hommel AB. Maternal floor infarction in autoimmune disease: two cases. Pediatr Pathol 1996;16:293 – 297. 13. Fox H. The placenta in abortion. In: Fox H, editor. Pathology of the Placenta. London: WB Saunders, 1997:270 – 293. 14. Mandsager NT, Bendon R, Mostello D, Rosenn B, Miodovnik M, Siddiqi TA. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol 1994;83:750 – 754. Accepted 5 February 2002