Patients suffering from recurrent miscarriage form a heterogenous group, including those with well-defined underlying causes, such as rare parental translocations; those with distinct laboratory findings consistent with a specific phenotype, such as patients with primary antiphospholipid antibody syndrome; and the largest group, with apparently unexplained pregnancy losses.1,2 It has previously been reported that patients with a history of recurrent pregnancy loss also suffer a higher rate of antenatal complications in their ongoing pregnancies,3 but there are no systematic studies of placental pathologic examinations from viable pregnancies in such patients. The aim of this study was to examine the placentas from a series of consecutive deliveries from patients with a history of recurrent miscarriage with and without primary antiphospholipid antibody syndrome in relation to pregnancy outcome to determine whether there are characteristic histological features in the placenta of either group.
MATERIALS AND METHODS
The recurrent miscarriage clinic at St. Mary's Hospital, London, is a tertiary referral center for patients suffering from a history of recurrent miscarriage, defined as three or more consecutive pregnancy losses. All patients are investigated and treated according to our previously published protocol.2,4 Approval for this study was obtained from St. Mary's Hospital NHS Trust Research Ethics Committee. Screening for antiphospholipid antibodies was performed using the dilute Russell viper venom time together with a platelet neutralization procedure to detect lupus anticoagulant. Patient samples with dilute Russell viper venom time ratios of at least 1:1 were retested with a platelet neutralization procedure; a decrease of 10% or more in the ratio was considered positive for lupus anticoagulant. Anticardiolipin antibodies were identified using a standard immunosorbent assay. An immunoglobulin G (IgG) level equal to or greater than 20 IgG phospholipid units and IgM level equal to or greater than 20 IgM phospholipid units were considered positive. Primary antiphospholipid antibody syndrome–positive patients tested positive for antiphospholipid antibodies on at least two occasions, at least 6 weeks apart.3 None of the patients in this study had clinical features of lupus. Patients with a diagnosis of primary antiphospholipid antibody syndrome were treated with low-dose aspirin (75 mg daily) commencing as soon as a urinary pregnancy test was positive, and subcutaneous low molecular weight heparin, enoxaparin sodium (20 mg daily), commencing at the time that an intrauterine pregnancy was confirmed by ultrasound examination. Treatment was usually stopped at 34 completed weeks' gestation.4,5 Patients without primary antiphospholipid antibody syndrome received either no treatment (n = 31) or empirical low-dose aspirin (75 mg daily; n = 30).6,7 In three of the primary antiphospholipid antibody syndrome–negative cases treated with aspirin, other thrombophilic defects were detected, including one with protein S deficiency and two with activated protein C resistance. Pregnancy outcome and details of antenatal complications are routinely recorded in a local maternity database.
According to Royal College of Obstetricians and Gynaecologists/The Royal College of Pathologists and American College of Physicians guidelines,8,9 the placentas from all patients reaching at least 24 weeks' gestation who delivered at St. Mary's or associated hospitals were submitted for histopathologic examination. After delivery, the placenta was immersion fixed in 10% formalin solution. All gross placental pathologic examinations were carried out by a single pathologist who was not aware of the clinical details. The placentas were serially sliced and examined macroscopically and histological sections obtained according to published protocol.10 Microscopic histopathologic examination was performed by two pathologists independently, unaware of the clinical details of the case, and then a consensus report was issued. Details of the standard criteria used for the placental histological diagnoses have been described.10 For the purposes of this study, particular regard was paid to those lesions that have been suggested as possibly important in the pathophysiology of primary antiphospholipid antibody syndrome–related pregnancy complications, such as placental infarcts, intervillus thrombosis, and perivillus fibrin deposition. An infarct was defined as a well-demarcated area of ischemic villous necrosis, more than 1 cm in diameter in a nonperipheral part of the placental parenchyma,11 and intervillus thrombus was defined as an area of villi-free tissue within the placental parenchyma, more than 5 mm in diameter, containing laminated fibrin and blood components.10 Comparison of frequencies of outcomes and histological findings between the groups was performed using the Mann-Whitney U test and modified Fisher exact test as appropriate (Arcus Quickstat Biomedical 1.1 Build 137, Research Solutions Ltd., Cambridge, United Kingdom).
There were 121 pregnancies, including 61 primary antiphospholipid antibody syndrome–negative cases and 60 primary antiphospholipid antibody syndrome–positive cases. Summary details of pregnancy outcomes and placental pathology findings are provided in Table 1. Pregnancy outcomes were similar in both primary antiphospholipid antibody syndrome–positive and primary antiphospholipid antibody syndrome–negative recurrent miscarriage patients with regard to gestational age at delivery and antepartum obstetric complication rate. There was one intrapartum death at term in a primary antiphospholipid antibody syndrome–positive patient with the histological finding of placental maternal floor infarction/massive perivillus fibrin deposition, and two stillbirths at 24 and 40 weeks in the primary antiphospholipid antibody syndrome–negative group, with no diagnostic etiological placental histopathologic findings.
A range of placental histopathologic findings were reported in both groups (Table 1), but the majority of pregnancies were clinically uncomplicated, with no significant placental pathologic abnormalities. In those cases in which placental pathology was detected, the features were primarily those described in association with recognized antepartum complications, such as placental infarction in association with preeclampsia. Furthermore, the prevalence of most histological abnormalities was similar to that expected in an unselected obstetric population (Table 1), with the exception of possible increased frequencies of uteroplacental vasculopathy resulting in villus infarction, and maternal floor infarction/massive perivillus fibrin deposition. There were no specific placental pathologic lesions or patterns of abnormalities examined in this study that were characteristic of patients with recurrent miscarriage or primary antiphospholipid antibody syndrome–positive versus primary antiphospholipid antibody syndrome–negative patients.
In the primary antiphospholipid antibody syndrome–positive group, five patients showed placental infarction, three of whom suffered from clinically determined intrauterine growth restriction and/or preeclampsia, and one other required an emergency cesarean delivery for fetal distress in labor at term. The three cases of maternal floor infarction/massive perivillus fibrin deposition all required emergency cesarean delivery delivery at 28–40 weeks; two of them were also complicated by antenatally detected intrauterine growth restriction. There were three cases of mild chorioamnionitis and three cases of plasma cell deciduitis, one of which also had an incidental placental chorioangioma present. In the primary antiphospholipid antibody syndrome–negative group, four of the six cases with placental infarction required emergency cesarean delivery for fetal distress, and one was also complicated by preeclampsia. Of the two intrauterine deaths in this group, the placenta of a stillbirth at 40 weeks did not show any diagnostic pathologic abnormalities, whereas the other case, at 24 weeks' gestation, showed marked changes consequent to fetal death only, including villus hypovascularity and marked villus fibrosis. At delivery, the fetus was macerated with overlapping of the skull bones; placental and fetal findings suggested intrauterine death of at least 1 week's duration. The underlying cause of the intrauterine death could not be determined from the placental examination. All cases from both groups in whom placental infarction was detected also showed focal areas of villus hypovascularity and increased syncytial knotting, consistent with lesser degrees of ischemia. Subtle global or patchy villus changes, such as mild abnormalities of villus maturity or cytotrophoblast hyperplasia, were not analyzed in this study, as quantitation of such lesions is difficult. The statistical power of the study was 60% to exclude a 10% difference between the groups in the prevalence of major placental pathologic findings, such as placental infarction, at α = .05.
The findings of this study have demonstrated that although several distinct placental histopathologic lesions may be detected in placentas from patients with recurrent miscarriage, with and without primary antiphospholipid antibody syndrome, the majority of placentas showed no significant histological abnormality. In most of the cases in which placental pathology was detected, the features were primarily those associated with decidual vasculopathy, and there were no specific lesions or patterns of lesions that were characteristic of patients with recurrent miscarriage or primary antiphospholipid antibody syndrome. It should of course be remembered that the primary antiphospholipid antibody syndrome–positive patients in this study were all treated with aspirin and heparin according to a standard protocol; therefore these findings may only be applicable to such treated patients.
Previous literature reporting on placental abnormalities in association with antiphospholipid antibodies primarily refers to patients with systemic lupus erythematosis, in whom the presence of antiphospholipid antibodies is also present. Early case reports suggested the association with decidual vasculopathy and placental “thrombosis,”12,13 and more recent smaller series have confirmed that the predominant placental findings in patients with antiphospholipid antibodies are those relating to chronic uteroplacental vasculopathy, particularly placental infarction.14–20 The current study is, however, the only one to specifically examine placental histopathology in patients with a history of recurrent miscarriage, both with and without primary antiphospholipid antibody syndrome. We confirm that, even in patients receiving treatment for primary antiphospholipid antibody syndrome, the major pathophysiologic mechanism is uteroplacental vasculopathy. In addition, the same placental complications also occur in patients with a similar obstetric history but without primary antiphospholipid antibody syndrome, highlighting the importance of an appropriate control group when interpreting the findings of studies reporting outcomes in selected patient groups.
Prevalences of placental infarction, as defined in the present study according to previously published criteria,11 in the primary antiphospholipid antibody syndrome–positive and primary antiphospholipid antibody syndrome–negative groups were similar (8–10%), which is greater than that reported in an unselected obstetric population when similar criteria are used (about 1%),11 indicating that an increased proportion of these pregnancies are complicated by uteroplacental vascular pathology. This is further supported by the increased prevalence of clinical complications such as preeclampsia and intrauterine growth restriction, which were present in 18% of primary antiphospholipid antibody syndrome–positive cases and 15% of primary antiphospholipid antibody syndrome–negative cases, compared with a reported frequency of about 6% in a geographically similar unselected population.21 Further evidence for the increased frequency of placental compromise is the finding that delivery was by emergency cesarean delivery in 18% and 25% of the primary antiphospholipid antibody syndrome–positive and primary antiphospholipid antibody syndrome–negative cases, respectively, which is much greater than that observed in an unselected population (about 8%).22 In the primary antiphospholipid antibody syndrome–positive group there were three cases of maternal floor infarction/massive perivillus fibrin deposition, all requiring delivery by emergency cesarean delivery and one resulting in fetal death. The underlying cause of this entity is unknown but may be related to both abnormal intervillus flow characteristics and/or abnormalities of the trophoblast surface predisposing to coagulation.10 Recently, it has been demonstrated that antiphospholipid antibodies may bind to term trophoblast as a potential initiator of massive perivillus fibrin deposition,23 and hence it is possible that a subgroup of patients with primary antiphospholipid antibody syndrome may be predisposed to the development of this rare complication, which is usually reported in less than 0.5% of pregnancies.10
Because antiphospholipid antibodies may predispose to vascular thrombosis in nonpregnant patients, it is often assumed that adverse pregnancy outcomes in women with primary antiphospholipid antibody syndrome may be a consequence of intervillus space thrombosis. Prevalences of intervillus thrombosis were similar in both groups in this study, and no greater than previously reported in uncomplicated pregnancies without a history of recurrent miscarriage (up to 30%).10 In addition, in this study there was only one case in which fetoplacental vascular thrombosis was identified; this occurred in a clinically uncomplicated primary antiphospholipid antibody syndrome–positive pregnancy delivered at 38 weeks, and the observed frequency does not differ from that previously reported in an unselected population (4%).10 The present findings therefore do not support the hypothesis that most pregnancy complications in primary antiphospholipid antibody syndrome are related to intraplacental “thromboses,” although it is acknowledged that this could occur in failed pregnancies as opposed to those successfully treated and resulting in live birth.
In this study, patients with primary antiphospholipid antibody syndrome were treated with low-dose aspirin and heparin, which may significantly modify any pathologic findings in the placenta because pregnancy outcome is significantly improved with this regime.5 The precise mode of action of this regime remains unknown, but the findings of the present study support a role in modification of uteroplacental blood flow because many treated primary antiphospholipid antibody syndrome–positive cases continue to demonstrate some degree of uteroplacental compromise. It would be optimal to examine a cohort of cases with and without primary antiphospholipid antibody syndrome, suffering from pregnancy complications, before the diagnosis is made and treatment is offered, but unfortunately, submission of placentas for specialist placental pathology is still not routinely carried out in the United Kingdom according to the Royal College of Obstetricians and Gynaecologists and College of American Pathologists guidelines, making collection of such data impractical at the present time.9,24 Nevertheless, the findings of this study have demonstrated that, in patients with successful pregnancies after a history of recurrent miscarriage, placental pathology related to uteroplacental vascular disease is the most common finding in both primary antiphospholipid antibody syndrome–positive and primary antiphospholipid antibody syndrome–negative placentas. However, in the majority of cases there are no significant placental histopathologic abnormalities detected and there are no lesions or patterns of features that appear specific either for patients with recurrent miscarriage or for primary antiphospholipid antibody syndrome–positive as compared with primary antiphospholipid antibody syndrome–negative women. A minority of primary antiphospholipid antibody syndrome–positive women may be at increased risk for maternal floor infarction/massive perivillus fibrin deposition. Routine histopathologic examination of the placenta in all cases of women with a history of recurrent miscarriage is unlikely to provide additional clinical information when there is an unremarkable clinical course because these cases almost all also demonstrate unremarkable placental pathology. There is, however, a definite need to further investigate the mechanisms of antenatal and peripartum complications in such pregnancies, and future studies should concentrate on thorough pathologic examination of placentas from cases with any pregnancy complications, in accordance with recently published guidelines for cases to be submitted for pathologic placental examination.23
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