Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients

doi:10.1016/S0029-7844(02)02385-2

Obstetrics & Gynecology

Volume 101, Issue 2, February 2003, Pages 258-263

https://doi.org/10.1016/S0029-7844(02)02385-2 Get rights and content

Abstract

Objective

To examine whether there are characteristic histological features in placentas from ongoing pregnancies of patients with a history of recurrent miscarriage, with and without primary antiphospholipid antibody syndrome, in relation to clinical pregnancy outcome.

Methods

Patients attending a recurrent miscarriage clinic were investigated and treated according to an established protocol. One hundred twenty-one consecutive patients achieving a potentially viable pregnancy (at least 24 completed weeks’ gestation), including 60 primary antiphospholipid antibody syndrome–positive cases and 61 primary antiphospholipid antibody syndrome–negative cases were included. After delivery, placental pathologic examination was carried out by a pathologist unaware of the clinical details. Histological sections were examined by two pathologists independently. Pregnancy outcome and placental findings were reviewed in relation to the maternal antiphospholipid antibody status.

Results

Pregnancy outcome was similar in primary antiphospholipid antibody syndrome–positive and primary antiphospholipid antibody syndrome–negative groups regarding gestation at delivery and antepartum obstetric complications. Several histological placental abnormalities were identified in both groups, but most pregnancies were clinically uncomplicated, with no significant placental abnormalities. In cases with pregnancy complications, the placental pathology was primarily that of uteroplacental vasculopathy, such as placental infarction and preeclampsia, but there were no specific placental lesions or patterns of abnormalities characteristic of primary antiphospholipid antibody syndrome–positive patients. A small subgroup of primary antiphospholipid antibody syndrome–positive patients may be at increased risk of development of maternal floor infarction or massive perivillus fibrin deposition.

Conclusion

There are no specific histopathologic placental abnormalities characteristic of treated patients with antiphospholipid antibody syndrome and poor reproductive history, but complications of uteroplacental disease are more common.

Section snippets

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

Results

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

Discussion

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

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Cited by (93)

Massive perivillous fibrin deposition: Diagnosis, obstetrical features, and treatment
2024, European Journal of Obstetrics and Gynecology and Reproductive Biology
MPVFD (Massive perivillous fibrin deposition) is placental lesion characterized by extensive massive deposits of fibrin in the intervillous space, extending over at least 25 % of the placental volume. Currently, this pathology can only be detected through histopathological examination of the placenta after a pregnancy has ended. The underlying mechanisms are poorly studied, there is no biomarker available for the diagnosis of MPVFD and treatment protocols are experimental and still lacking. The objective of this study is to systematically review the literature on the associated clinicopathologic features, treatment, and prognosis of MPVFD.
We ended up with 17 studies, of these 12 studies were considered relevant for this article and included in the final analysis. All studies reporting MPVFD are retrospective. MPVFD is associated with recurrent miscarriage, intra uterine fetal death (IUFD), intra uterine growth restriction (IUGR) and preterm delivery. The prevalence in pregnancies with a delivery after 22 weeks of gestation was at 1.1 % and even higher to 2.7 % in recurrent early miscarriages.
The reported risk of fetal death in MPVFD ranges mainly from 15 to 80 %. Preterm delivery is spontaneous in 50 to 70 % of cases and induced by of a severe intrauterine growth restriction (IUGR) in 30 to 50 % of cases depending on the study. Its causes and treatment are still poorly understood, although several avenues have been explored.
This review summarizes current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology, and potential prophylaxis against recurrence in this chronic inflammatory placental syndrome.
Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology
2022, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Therefore, it is not surprising that vascular pathology is the most frequent mechanism of disease in obstetrics. Lesions of vascular pathology are most frequently found in cases of fetal death,97,175–177 preeclampsia,73,84,178,179 SGA/fetal growth restriction,180–183 and abruptio placentae,184,185 yet they have also been recognized in other obstetrical syndromes conventionally not considered to be predominantly of vascular origin (PTL,60,186,187 PPROM,59,186,188 and spontaneous abortion175,189,190). Biomarkers for placental vascular lesions can be expected to predict obstetrical syndromes caused by this pathologic process but not by other mechanisms of disease such as infection, sterile intra-amniotic inflammation, and maternal anti-fetal rejection.
The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known.
To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion.
This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion.
1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions.
Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.
Clinicopathological characteristics of miscarriages featuring placental massive perivillous fibrin deposition
2019, Placenta
Massive perivillous fibrin deposition (MPFD) is frequently associated with detrimental pregnancy outcomes, and extensive perivillous fibrin deposition results in severe placental dysfunction and loss of maternofetal interface. Unfortunately, the fundamental pathogenesis of MPFD remains unknown, and systematic analyses of MPFD in miscarriage is lacking. We analyzed the frequency and clinicopathological characteristics of MPFD in first trimester miscarriages.
We analyzed a consecutive series of miscarriages (n = 582) gathered between March 2012 and June 2016. MPFD was classified as fibrin-type (f-MPFD) and matrix-type (m-MPFD) by immunostaining for fibrin and collagen type IV. The control group consisted of miscarriage cases (MC, n = 18) that were matched to f-MPFD with normal chromosome (f-MPFD-nc) for number of previous miscarriages and placental chromosomal status.
MPFD was identified in 2.7% of miscarriages. f-MPFD was associated with recurrent abortions. Compared with miscarriages without fibrin deposition, MPFD cases had higher proportion of those with normal placental chromosome (69.2% vs. 27.4%, P < 0.005) and higher frequency of villous syncytiotrophoblast C4d deposition (73.3% vs. 33.9%, P < 0.005). All C4d(+) f-MPFD patients had more than three recurrent miscarriages, whereas C4d(−) f-MPFD patients had no history of recurrent miscarriage (P < 0.05). Patients with f-MPFD-nc had significantly higher HLA PRA immunopositivity rate than did MC patients (P = 0.005).
MPFD was more common in miscarriages than in preterm and term pregnancies. Placental massive fibrin-type fibrinoid deposition and villous C4d immunoreactivity were associated with recurrent miscarriage.
Gene expression profiling identifies distinct molecular signatures in thrombotic and obstetric antiphospholipid syndrome
2018, Journal of Autoimmunity
Antiphospholipid antibodies (aPL) cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Differential mechanisms however, underlying the pathogenesis of these different manifestations of antiphospholipid syndrome (APS) are not fully understood. Therefore, we compared the effects of aPL from patients with thrombotic or obstetric APS on monocytes to identify different molecular pathways involved in the pathogenesis of APS subtypes. VT or PM IgG induced similar numbers of differentially expressed (DE) genes in monocytes. However, gene ontology (GO) analysis of DE genes revealed disease-specific genome signatures. Compared to PM, VT-IgG showed specific up regulation of genes associated with cell response to stress, regulation of MAPK signalling pathway and cell communication. In contrast, PM-IgG regulated genes involved in cell adhesion, extracellular matrix and embryonic and skeletal development. A novel gene expression analysis based on differential variability (DV) was also applied. This analysis identified similar GO categories compared to DE analysis but also uncovered novel pathways modulated solely by PM or VT-IgG. Gene expression analysis distinguished a differential effect of VT or PM-IgG upon monocytes supporting the hypothesis that they trigger distinctive physiological mechanisms. This finding contributes to our understanding of the pathology of APS and may lead to the development of different targeted therapies for VT or PM APS.
Pathogenesis of antiphospholipid antibody syndrome
2018, Dubois' Lupus Erythematosus and Related Syndromes
Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia characterized by venous or arterial thrombosis, and/or pregnancy loss or complications in the presence of persistently positive antiphospholipid antibodies (aPLs). These aPLs are a heterogeneous family of autoantibodies that bind various phospholipids (PLs) (principally cardiolipin) and PL-binding serum proteins, with the most important of these being β₂-glycoprotein I (β₂-GPI). The aPLs that are currently used in clinical practice to identify patients with APS tests include the detection of anticardiolipin antibodies and/or anti–β₂-GPI antibodies by enzyme-linked immunosorbent assay (ELISA) and/or positive lupus anticoagulant (LA) assay by prolongation of in vitro PL-dependent clotting assays, which can be corrected by the addition of excess PL. The development of various aPL tests and evidence that aPLs have wide-ranging proinflammatory and procoagulant effects on target cells, complement factors, and regulators of the coagulation cascade to promote vascular thrombosis and/or pregnancy morbidity will be reviewed in this chapter.
Antiphospholipid syndrome and pregnancy: Obstetrical prognosis according to the type of APS
2015, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Le but de notre étude est de comparer les résultats obstétricaux des femmes atteintes d’un syndrome des anticorps antiphospholipides selon le traitement instauré en distinguant les formes thrombotiques et obstétricales.
Il s’agissait d’une étude de cohorte historique réalisée entre 1998 et 2009 portant sur 23 patientes ayant eu 83 grossesses. Le syndrome était diagnostiqué selon les critères de Sapporo de 2006.
Parmi ces grossesses, trente et une se sont déroulées avant le diagnostic, donnant naissance à 22 % d’enfants vivants, dont 26 % étaient hypotrophes. Dans 26 % des cas, une mort fœtale est survenue. Les grossesses ont été divisées en 2 groupes selon l’accident à l’origine de sa découverte : obstétrical ou thrombotique. Cette classification a permis d’adapter le traitement : aspirine et héparine à dose curative lors d’accident thrombotique, à dose préventive lors d’accident obstétrical. Aucune mort fœtale n’a été constatée lorsque le traitement était bien conduit. Malgré celui-ci, 20 % des grossesses de la forme obstétricale se sont compliquées de retard de croissance et seulement 38 % des enfants sont nés vivants. Parmi les formes thrombotiques traitées, plus de 87 % des grossesses ne se sont pas compliquées, aboutissant à la naissance d’un enfant vivant.
Le traitement adapté semble permettre d’améliorer le pronostic des grossesses de ces patientes. Malgré celui-ci, ces patientes ont un risque accru de présenter un accident obstétrical, et nécessitent un suivi rapproché, plus encore dans les formes « obstétricales » qui semblent avoir un pronostic péjoratif. Un suivi multidisciplinaire par une équipe expérimentée est indispensable.
The objective of our study was to compare treatment-based obstetrical outcomes in women with either thrombotic or obstetrical antiphospholipid syndrome (APS).
This was a historical cohort study conducted between 1998 and 2009 in 23 patients who had a total of 83 pregnancies. The syndrome was diagnosed using the 2006 Sapporo criteria.
Thirty-one of these 83 pregnancies were valid before the diagnosis was made. A live infant was born in 22% of them, the infant being small for gestational age in 26% of cases. The fetus died in utero in a further 26% of cases. Pregnancies were subdivided into 2 groups depending on whether the initial event leading to APS diagnosis was obstetrical or thrombotic. Treatment (aspirin and low molecular weight heparin) was based on this classification: the latter was given in a curative dose for thrombotic events, in a preventive dose for obstetrical events. No fetal loss was observed when treatment was administered according to the protocol. Nevertheless, 20% of the pregnancies with obstetrical APS were complicated by smallness for gestational age and only 38% of the infants were live births. More than 87% of the thrombotic forms treated were free of complications and led to birth of a living child.
Appropriate treatment appears to improve the prognosis for pregnancies in patients with APS. These patients are nevertheless at increased risk of an obstetrical event and require close monitoring, especially in obstetrical manifestations, which appear to have a poorer prognosis. Multidisciplinary follow-up by an experienced team is essential.

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Original researchPlacental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Materials and methods

Results

Discussion

Am J Obstet Gynecol

Rheum Dis Clin North Am

Am J Obstet Gynecol

Recurrent miscarriage

BMJ

An informative protocol for the investigation of recurrent miscarriagePreliminary experience of 500 consecutive cases

Hum Reprod

International consensus statement on preliminary classification criteria for definite antiphospholipid syndromeReport of an international workshop

Arthritis Rheum

Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin

Br J Obstet Gynaecol

Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)

BMJ

The modern preventative treatment of recurrent miscarriage

Br J Obstet Gynaecol

Recurrent miscarriage—an aspirin a day?

Hum Reprod

The Royal College of Pathologists. Fetal and perinatal pathologyReport of a joint working party

Practice guideline for examination of the placentaDeveloped by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists

Arch Pathol Lab Med

Original research
Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients