Placental pathology in egg donor pregnancies Fusun Gundogan, M.D.,a Diana W. Bianchi, M.D.,b Sicco A. Scherjon, M.D., Ph.D.,c and Drucilla J. Roberts, M.D.d a Department of Pathology, Women and Infants Hospital, Providence, Rhode Island; b Department of Pediatrics, Tufts Medical Center, Boston, Massachusetts; c Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands; and d Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
Objective: To determine placental pathology and immune response at the maternal-fetal interface in pregnancies conceived by IVF via egg donation compared with nondonor IVF pregnancies. Design: Retrospective case-control study. Setting: Academic medical center. Patient(s): The study population included 20 egg donor and 33 nondonor IVF pregnancies of >24 weeks’ gestation. Intervention(s): None. Main Outcome Measure(s): Perinatal complications (gestational hypertension, abruption, preterm delivery, cesarean section), microscopic features indicating an immune response and trophoblast damage, and characterization of inflammatory cells using immunohistochemistry. Result(s): There was an increase in gestational hypertension and preterm delivery in egg donor pregnancies. Dense fibrinoid deposition in the basal plate with severe chronic deciduitis containing significantly increased numbers of T helper and natural killer cells were demonstrated in egg donor placentas. Trophoblast damage was also increased in the preterm egg donor group. Conclusion(s): There are significant histological and immunohistochemical differences between the placentas of egg donor and nondonor IVF pregnancies. The increased immune activity and fibrinoid deposition at the maternalfetal interface of egg donor pregnancies could represent a host versus graft rejection-like phenomenon. (Fertil Steril 2010;93:397–404. 2010 by American Society for Reproductive Medicine.) Key Words: Egg donation, placenta, pathology, immunology
As the blastocyst reaches the uterine cavity and the implantation process begins, trophoblastic cells that are fetal in origin start to invade the maternal decidua and myometrium (1–3). Despite this close interaction, through complex mechanisms of immunoregulation, the maternal immune system does not reject the fetal allograft (4). Several mechanisms, including expression of nonpolymorphic major histocompatibility class I antigens like human leukocyte antigen (HLA)-G and HLA-C on these invasive fetal cells and the presence of regulatory T cells, have been demonstrated to protect the fetus from maternal rejection (3, 5–8). While the question of maternal tolerance to paternal antigens is under study, advances in the field of assisted reproductive technology create iatrogenic perturbations in maternal-fetal immunology. IVF via egg donation makes it possible for women with premature ovarian failure, diminished ovarian reserve, and multiple failed IVF attempts to become pregnant (9, 10). In
Received September 24, 2008; revised December 30, 2008; accepted December 31, 2008; published online February 26, 2009. F.G. has nothing to disclose. D.W.B. has nothing to disclose. S.A.S. has nothing to disclose. D.J.R. has nothing to disclose. Presented at the 14th International Federation of Placenta Associations Conference, which was held in Seggau Castle, Austria, on September 10–13, 2008. Reprint requests: Fusun Gundogan, Women and Infants Hospital, Department of Pathology, 101 Dudley St. Providence, Rhode Island 02905 (FAX: 401-453-7681; E-mail:
[email protected]).
0015-0282/10/$36.00 doi:10.1016/j.fertnstert.2008.12.144
contrast to spontaneously conceived or nondonor IVF pregnancies, in egg donor pregnancies the embryo is immunogenetically completely unrelated to mother unless the egg is donated by a relative. Previous studies have demonstrated that egg donor pregnancies are at increased risk of hypertensive complications (9, 11, 12). In both nondonor and egg donor pregnancies, the pathogenesis of preeclampsia is still poorly understood. Some of the mechanisms under debate include the relationship between maternal and fetal HLA-DR allotypes (13) and interaction of two polymorphic gene systems, maternal killer cell immunoglobulin-like receptors and fetal HLA-C molecules, altering uterine natural killer (NK)-cell function (14). Defective trophoblast invasion leading to shallow implantation is a key pathological feature in maternal hypertensive disorders (15). Intrauterine growth restriction (IUGR) is associated with the occurrence of preeclampsia. Interestingly, despite the increased incidence of preeclampsia in egg donor pregnancies, there appears to be no effect on neonatal birth weight (12, 16). This observation suggests that the underlying mechanism of preeclampsia in egg donor pregnancies might be different than that in spontaneously conceived pregnancies. Placental tissues from pregnancies that are conceived after egg donation provide a good model to study the immunologic reactions occurring at the maternal-fetal interface. The placental pathologies that are thought to be immune mediated include villitis of unknown etiology (VUE) (17), chronic
Fertility and Sterility Vol. 93, No. 2, January 15, 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
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deciduitis (CD; with or without plasma cell deciduitis) (18, 19), massive chronic intervillositis (20, 21), maternal floor infarction (22, 23), and the placental pathology associated with preeclampsia (severe and chronic placental ischemia) (24). Some of these lesions were shown to be increased in small studies of placentas from egg donor pregnancies (25, 26). In this study, we aimed to investigate the immune-mediated placental pathology by light microscopy and immunohistochemistry in egg donor IVF pregnancies. The control group consisted of placentas from nondonor IVF pregnancies, so the IVF process was not a variable.
or intervillous thrombus) was microscopically characterized. All the cases were initially examined by one pathologist (FG), who was not blinded to the clinical histories. During this first review, CD with or without increased fibrinoid deposition in the basal plate was identified as the most significant finding. A second pathologist (DJR) was asked to blindly evaluate and score all the cases for evidence of CD. A consensus diagnosis for CD was obtained between the two pathologists in 90/93 placentas. After the diagnostic criteria for CD were reviewed, both pathologists, who were now both blinded, reanalyzed the three cases in which there were discordant results, and a final consensus was reached.
MATERIALS AND METHODS Clinical Data We retrospectively searched the perinatal pathology case files of Women and Infants Hospital (WIH) for placentas derived from pregnancies conceived by IVF between January 2004 and December 2006. In our institution, IVF-conceived pregnancy is one of the clinical criteria for required placental examination. Cases
