Article

Placental pathology in egg donor pregnancies

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Abstract

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. Retrospective case-control study. Academic medical center. The study population included 20 egg donor and 33 nondonor IVF pregnancies of >24 weeks' gestation. None. 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. 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. 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 maternal-fetal interface of egg donor pregnancies could represent a host versus graft rejection-like phenomenon.

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... As noted above, placental pathology can provide information regarding the underlying mechanism and pathogenesis of these adverse pregnancy outcomes, through histopathological lesion association. Notably, studies have shown that OD-IVF placentas are associated with increased rates of inflammatory lesions compared to RD-IVF pregnancies, such as chronic deciduitis and VUE lesions, and increased prevalence of inflammatory lesions within the chorionic plate [13,[17][18][19][20]. OD-IVF placental histopathology is also associated with increased syncytial knots, compared to RD-IVF placentas [20] (i.e., a lesion that interferes with oxygenation, denotes terminal villi hyper-maturation and is seen in pregnancies complicated by PE or IUGR [21]). ...
... As noted above, placental pathology can provide information regarding the underlying mechanism and pathogenesis of these adverse pregnancy outcomes, through histopathological lesion association. Notably, studies have shown that OD-IVF placentas are associated with increased rates of inflammatory lesions compared to RD-IVF pregnancies, such as chronic deciduitis and VUE lesions, and increased prevalence of inflammatory lesions within the chorionic plate [13,[17][18][19][20]. OD-IVF placental histopathology is also associated with increased syncytial knots, compared to RD-IVF placentas [20] (i.e., a lesion that interferes with oxygenation, denotes terminal villi hyper-maturation and is seen in pregnancies complicated by PE or IUGR [21]). These studies [13,[17][18][19][20] focused primarily on placental histopathology differences between RD-IVF and OD-IVF conception and although some cases were complicated by placenta-mediated disease, the analysis did not focus on HDP and/or IUGR as a clinical covariate. ...
... Notably, studies have shown that OD-IVF placentas are associated with increased rates of inflammatory lesions compared to RD-IVF pregnancies, such as chronic deciduitis and VUE lesions, and increased prevalence of inflammatory lesions within the chorionic plate [13,[17][18][19][20]. OD-IVF placental histopathology is also associated with increased syncytial knots, compared to RD-IVF placentas [20] (i.e., a lesion that interferes with oxygenation, denotes terminal villi hyper-maturation and is seen in pregnancies complicated by PE or IUGR [21]). These studies [13,[17][18][19][20] focused primarily on placental histopathology differences between RD-IVF and OD-IVF conception and although some cases were complicated by placenta-mediated disease, the analysis did not focus on HDP and/or IUGR as a clinical covariate. ...
Article
Introduction Assisted reproductive technology including in vitro fertilization (IVF) and oocyte donation (OD) may increase risk for placenta-mediated diseases. Comprehensive analysis of histopathological placental lesions according to source of oocytes used in the IVF procedure – recipient derived (RD-IVF) vs oocyte donation (OD-IVF), has not been conducted in a population with a hypertensive disorder of pregnancy (HDP) and/or intrauterine growth restriction (IUGR). Methods A retrospective cohort study of archived placenta specimens from RD-IVF and OD-IVF pregnancies affected by HDP and/or IUGR was conducted with blinded histopathological placental examination. Three categories of lesions were differentiated and defined as main outcomes: maternal vascular malperfusion (MVM), chronic inflammatory, and fetal vascular malperfusion (FVM). To determine the relationship between conception method and placental lesions, multivariable regressions were performed with maternal age, gestational age, HDP, birth and placental weight percentiles as model covariates. Results 115 placentas were included 83(72.2%) RD-IVF, 32(27.8%) OD-IVF. Adjusted OR (aOR) for conception method was 5.05 (95%CI 0.58-43.90, p=0.142) for MVM, 1.87 (95%CI 0.68-5.15, p=0.228) for chronic inflammatory and 0.61 (95%CI 0.15-2.37, p=0.471) for FVM lesions. Multiple gestation demonstrated borderline association with MVM (aOR=0.24, 95%CI 0.04-1.51, p=0.129) and total pathology score (aRR=0.79, 95%CI 0.62-1.01, p=0.058). Subgroup analysis suggested greater odds of villitis of unknown etiology (VUE) for OD-IVF (aOR=2.98, 95%CI 1.12-7.93, p=0.029). Discussion Source of oocyte derivation demonstrated no evidence of association with main outcomes in cases of HDP and/or IUGR. Subgroup analysis demonstrated increased rates of inflammatory lesions for OD-IVF. Multiple gestation may be associated with decreased MVM and total lesions.
... All studies, except for Nakabayshi et al. [72], included vaginal deliveries and caesarean sections. Two studies [71,73] collected placentas of OD pregnancies. Martinez-Varea et al. [74]. ...
... All studies, except for Nakabayshi et al. [72], included vaginal deliveries and caesarean sections. Two studies [71,73] collected placentas of OD pregnancies. Martinez-Varea et al [74]. ...
... Gundogan et al. [73] performed research on the macroscopy and microscopy of OD placentas. More pathological lesions in placentas of OD pregnancies than in non-donor IVF were described earlier [81]. ...
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The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by acting in immunomodulation and spiral arterial remodeling. OD pregnancies represent an interesting model to study complex immunologic interactions between the fetus and the pregnant woman since the embryo is totally allogeneic compared to the mother. Here, we describe a narrative review on the role of macrophages and pregnancy and a systematic review was performed on the role of macrophages in OD pregnancies. Searches were made in different databases and the titles and abstracts were evaluated by three independent authors. In total, four articles were included on OD pregnancies and macrophages. Among these articles, some findings are conflicting between studies, indicating that more research is needed in this area. From current research, we could identify that there are multiple subtypes of macrophages, having diverse biological effects, and that the ratio between subtypes is altered during gestation and in aberrant pregnancy. The study of macrophages’ phenotypes and their functions in OD pregnancies might be beneficial to better understand the maternal-fetal tolerance system.
... One alternate hypothesis that might explain elevated AFP and inhA secretion in OD pregnancies is that the placental surface integrity is disrupted. A recent study of placenta pathology suggested that more trophoblast damage occurred in OD than in aIVF pregnancies (22). One approach to investigate this hypothesis would be to examine maternal plasma cell-free DNA concentrations in OD pregnancies to determine if increased placental apoptosis occurs, as is reported in other conditions of abnormal placentation (23). ...
... It is also likely that an immune response plays a role in altered placental function in pregnancies achieved with the use of OD. Gundogan et al. (22) reported dense fibrinoid deposition and severe deciduitis, increased in T helper cells, and increased natural killer (NK) cells in OD pregnancies but not in those achieved with the use of aIVF. In a metaanalysis finding a heightened occurrence of PE in OD pregnancies (25), the role of the immune system was explained. ...
Article
Objective: To determine whether differences exist in angiogenic placental growth factor (PlGF) and antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR-1; both being early markers of placental ischemic disease) in oocyte-donation (OD) pregnancies, compared with autologous in vitro fertilization (aIVF) and spontaneous pregnancies. Design: Case-control study of residual second-trimester serum samples from women undergoing prenatal screening. Setting: Academic medical center. Patient(s): Fifty-seven OD pregnancies were identified. Each OD pregnancy was matched to two spontaneous pregnancies (n = 114) and one aIVF pregnancy (n = 57). Interventions(s): None. Main outcome measure(s): Second-trimester serum PlGF and sVEGFR-1 levels. Result(s): sVEGFR-1, PlGF, and unconjugated E2 levels were similar among the three study groups. The ratio of sVEGFR-1 to PlGF was significantly higher in the OD group. Consistently with previous studies, alpha-fetoprotein (AFP) in the OD group was significantly elevated compared with spontaneous pregnancy. Both aIVF and OD groups had greater levels of inhibin A than the spontaneous pregnancy group, and the OD group had significantly higher levels of inhibin A than the aIVF group. hCG levels were significantly elevated in aIVF compared with spontaneous pregnancy; however, levels were not different between aIVF and OD. Conclusion(s): Second-trimester serum sVEGFR-1 and PlGF levels were not significantly altered in OD pregnancies. Our data support previous findings that OD pregnancies have uniquely increased second-trimester AFP, hCG, and inhibin A levels compared with aIVF. However, the biologic basis of these marker elevations in OD may not be related to placental angiogenesis.
... Complex immunological adaptation reactions take place to allow these pregnancies to progress. [14,18,19] Thus, specifically in the OR, there are dense deposits of fibrin on the basal plate of the placenta with chronic involvement of the decidua and site of a high level of T-helper lymphocytes and natural killer cells. This immune reaction phenomenon would result in early placentation disorder causing PE. [14,19] In addition, in a 2005 study, Kim et al. [20] discovered a decrease in the rate of PE where oocytes are donated by a relative. ...
... [14,18,19] Thus, specifically in the OR, there are dense deposits of fibrin on the basal plate of the placenta with chronic involvement of the decidua and site of a high level of T-helper lymphocytes and natural killer cells. This immune reaction phenomenon would result in early placentation disorder causing PE. [14,19] In addition, in a 2005 study, Kim et al. [20] discovered a decrease in the rate of PE where oocytes are donated by a relative. Similarly, Lashley et al. in 2015 demonstrated that there is a better human leukocyte antigen compatibility in the group of OR with no PE than in those with PE. ...
Article
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Objectives: Oocyte donation pregnancies are more frequently complicated by preeclampsia (PE), which cause significant fetal-maternal morbidity and mortality. Our objective was to determine risk factors for PE in oocyte recipients (OR). Our secondary objective was to describe the course of pregnancy and the neonatal outcome in this group. Methods: This was a historical-prospective study. One hundred and fifty OR who gave birth to children at over 22 weeks of amenorrhea between January 2010 and June 2018 were included in the study. Results: Risk factors for PE in OR found in univariate analysis were as follows: primiparity, primipaternity, body mass index (BMI), and anti-Müllerian hormone (AMH) of the OR and age and AMH of the oocyte donors (OD). In multivariate analysis, the BMI of the OR (odds ratio [OR]: 1.2, 95% confidence interval [CI]: [1.1-1.4], P = 0.0474) and the AMH of the OD (OR: 1.2, 95% CI: [1.2-1.4], P = 0.0481) were found to be statistically significant risk factors for PE. In addition, we observed an increase in the rate of prematurity in the OR that were not associated with fetal growth retardation, despite the occurrence of PE. Conclusion: In OR, the allogeneic nature of pregnancy induces an increased risk of PE, the pathophysiology of which seems different from that in other methods of conception. Thus, risk factors for PE should be reconsidered to take into account the impact of certain characteristics of OD such as age and AMH.
... [29] Parental human leukocyte antigen sharing is thought to have a role in the etiology of preeclampsia. [30] Fetus is allogenic to the gestational carrier in donor-oocyte pregnancies. [31] One study [30] has reported increased immune activity and fibrinoid deposition at the maternal-fetal interface of donor-oocyte pregnancies, representing a host versus graft rejection-like process. ...
... [30] Fetus is allogenic to the gestational carrier in donor-oocyte pregnancies. [31] One study [30] has reported increased immune activity and fibrinoid deposition at the maternal-fetal interface of donor-oocyte pregnancies, representing a host versus graft rejection-like process. ...
Article
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Aims The aim of this study is to evaluate and compare multiple obstetric and perinatal outcomes between donor-oocyte in vitro fertilization (IVF) and self-oocyte IVF group. Settings and Design This study was done in a tertiary care center with ART unit. This was a retrospective comparative cohort study. Materials and Methods The present study comprised all women between 20 and 45 years who conceived from oocyte donation (n = 78) between December 1, 2010, and December 31, 2016, and compared with all women who underwent self-oocyte IVF (n = 112). The process involved controlled ovarian stimulation and retrieval of the donor oocytes, preparation of recipient endometrium, and pregnancy management. Obstetric and perinatal outcomes were compared. Statistical Analysis Used Chi-square test was used for categorical variables. Analysis for confounding variables was performed using multivariable linear and logistic regression analysis. Results Baseline characteristics between the two groups were comparable. Miscarriage, first-trimester bleeding, pregnancy-induced hypertension (PIH), and gestational diabetes mellitus were significantly higher in donor-oocyte IVF group compared to self-oocyte cycles (P = 0.001). Using multiple logistic regression analysis, age class adjusted PIH incidence was significantly higher in donor-oocyte group as compared to self-oocyte group (P = 0.010). There was no significant variation in perinatal outcomes between the donor- and self-oocyte IVF cycles (P > 0.05). Conclusion Oocyte donation should be treated as an independent risk factor for PIH.
... Some studies have suggested that DO achieved pregnancy is allogeneic to the gestational carrier with increased antigenic dissimilarity compared to autologous oocyte achieved pregnancies. [5,6] This increased immunological activity and fibrinoid deposition were noted to play a role in the etiology of pregnancy complications such as preeclampsia. [5,6] In addition, older women are more likely to have preexisting co-morbidities further complicating their pregnancy course and outcome common obstetric and perinatal complications reported in IVF achieved pregnancies in older women include pregnancy-induced hypertension, placenta previa, preterm labor, and gestational diabetes, also a higher rate of cesarean section delivery and obstetric hemorrhage have been observed. ...
... [5,6] This increased immunological activity and fibrinoid deposition were noted to play a role in the etiology of pregnancy complications such as preeclampsia. [5,6] In addition, older women are more likely to have preexisting co-morbidities further complicating their pregnancy course and outcome common obstetric and perinatal complications reported in IVF achieved pregnancies in older women include pregnancy-induced hypertension, placenta previa, preterm labor, and gestational diabetes, also a higher rate of cesarean section delivery and obstetric hemorrhage have been observed. [4,7] Researchers have shown that use of DO IVF treatment with improved oocyte quality resulted in higher pregnancies and live birth rates compared to autologous oocyte treatment cycle. ...
Article
Background: As the number of older women attempting to conceive through donor oocyte-in vitro fertilization (DO-IVF) rises, their safety in pregnancy needs to be judiciously considered. Aims: This study aims to review the obstetric and perinatal outcomes of pregnancies achieved by DO-IVF. Study setting and design: A retrospective study design conducted at a private health facility with services for assisted reproduction and gynecologic endoscopy. Methods: A retrospective comparative study of all pregnancies achieved using DO-IVF and that using Self oocyte In-vitro fertilization (SO-IVF) treatment over a 3 years' period was performed. Statistical analysis: Comparative analysis of demographic variables, major obstetric, and perinatal complications was done with Chi-square test and Student's t-test as appropriate. Regression analysis was done to determine a significant predictor variable for pregnancy and delivery outcome. The significance level was set at P < 0.05. Results: A total of 343 completed IVF treatment cycles was reviewed; there were 238 DO-IVF and 105 SO-IVF cycles, with clinical pregnancy rate of 41.6% and 37.1%, respectively. The DO-IVF group was significantly older than the SO-IVF group (46.1 years vs. 34.1 years, P < 0.001). Major obstetric complications identified, were hypertensive disorders in pregnancy (23.9%), preterm labor (16.7%), antepartum hemorrhage (11.6%). There was no statistically significant difference between the two groups in terms of obstetric complications and adverse maternal or perinatal outcomes. There were 97 (77.6%) singleton and 28 (22.4%) multiple pregnancies. Pregnancy complications were significantly associated with fetal plurality, P < 0.001. Multiple pregnancy had higher odds of experiencing adverse perinatal 4.96 (1.95-12.58) and maternal 7.16 (2.05-25.03) outcomes compared to singleton pregnancies, P < 0.001. Conclusion: Key obstetric outcomes did not differ between DO or SO IVF achieved pregnancy. Even for older women, satisfactory outcomes can be expected for pregnancies achieved by DO-IVF. It is, however, instructive that for multiple pregnancies, obstetricians should institute appropriate surveillance strategies during pregnancy and delivery period and also to develop institutional capacity for quality neonatal care.
... Chronic endometritis (CE) is a localized inflammatory disease of the uterine lining, which is characterized by unusual plasmacyte infiltration in the endometrial stromal compartment and is asymptomatic/oligosymptomatic nature [1]. A growing body of evidence demonstrates that CE is identified in a substantial population of infertile women with repeated implantation failure (RIF), unknown etiology, and recurrent pregnancy loss, as well as some obstetric/neonatal complications such as preterm labor and periventricular leukomalacia/cerebral palsy in premature infants [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. The mucosal expression of multiple genes such as ovarian steroid receptors, adhesion molecules, immunomodulators, and apoptosis are dysregulated in CE, suggesting the impaired endometrial receptivity, decidualization, and uterine contractility in this pathologic condition [11,14,15,21]. ...
Article
Full-text available
Purpose To evaluate the yearly prevalence and annual transition of multi-drug-resistant-chronic endometritis (MDR-CE) in infertile women with a history of repeated implantation failure (RIF) and to establish the third-line antibiotic treatment regimen against MDR-CE. Methods This retrospective/prospective cohort and pilot study included 3473 RIF women between April 2010 and September 2021. The endometrial stromal plasmacyte density index (ESPDI) was calculated in 3449 CD138-immunostained endometrial sections to evaluate CE. The microbiota in the vaginal secretions and endometrial fluid was compared between 17 patients with MDR-CE and 16 patients with antibiotics-sensitive CE. In a pilot study, oral moxifloxacin (400 mg/day, 10 days, n = 24) or azithromycin (500 mg/day, 3 days, n = 24) was administered to eligible patients with MDR-CE. Results From April 2010 to March 2020, CE was detected in 31.4% of RIF women and MDR was detected in 7.8% of CE. While the prevalence of CE was stable for a decade, MDR in CE increased steadily (OR 8.27, 95% CI 2.58–26.43, p trend < 0.001). The bacterial species/communities unique to MDR-CE were not found. The histopathologic cure rate of MDR-CE was similar between the moxifloxacin and azithromycin groups (79.2% vs 75.0%, OR 1.27, 95% CI 0.32–4.89, p value 0.73), as well as reproductive outcomes in subsequent embryo transfer cycles. Conclusion In RIF women, MDR in CE increased over the decade. As a third-line treatment for MDR-CE, azithromycin may have a clinical advantage due to its shorter time administration periods. Clinical trial number ClinicalTrials.gov Identifier: UMIN-CTR 000029449/000031909.
... However, the use of a donor oocyte may not be completely benign and can influence the immune response, thereby driving the increase in perinatal complications. Placentas examined from donor oocyte cycles were significantly more likely to demonstrate pathologic findings such as chronic villitis and deciduitis, increased perivillous fibrin, ischemic changes/infarction, increased proinflammatory immune expression, and intervillous thrombi [40,41]. These significant histological and immunohistochemical changes in the placentas of donor oocyte cycles can potentially lead to adverse pregnancy outcomes. ...
Article
Full-text available
Purpose To determine whether gestational carrier (GC) in vitro fertilization (IVF) cycles (commissioned cycles) for same-sex or single male intended parents have an increased incidence of adverse perinatal outcomes compared with spontaneous cycles in the same GCs. Design GC singleton pregnancies were identified from a database of 895 commissioned cycles from a large fertility center. Of these, 78 commissioned cycles met inclusion and exclusion criteria and were compared with 71 spontaneous cycles by the same GCs. The primary outcome was the composite score for adverse perinatal outcomes. Secondary outcomes included mode of delivery, birthweight, and gestational age. Chi-square test of association and Mann-Whitney U tests were used to compare categorical and continuous variables between the cohorts, respectively. Logistic and linear regressions controlling for GC age were constructed to determine the influence of GC cycle type on adverse perinatal outcomes. Results Commissioned cycles were significantly associated with adverse perinatal outcomes (25.6% vs. 9.9%; p = 0.02) and lower average gestational age (38.7 ± 1.5 vs. 39.4 ± 0.9; p < 0.001) compared with spontaneous cycles. Commissioned cycle increased the likelihood of adverse perinatal outcomes (OR 3.3; p = 0.03) and was a significant independent predictor of a lower average gestational age (β = 0.897; p < 0.001). There were no significant differences in the incidence of vaginal deliveries or cesarean sections between commissioned and spontaneous cycles. Conclusions Commissioned cycles confer a greater incidence of composite perinatal complications and were independently associated with a lower average gestational age when compared with spontaneous pregnancies carried by the same GC despite a confirmed healthy uterine environment, sperm samples, and donor oocytes.
... It has been suggested that the increase in risk of preeclampsia in IVF-OD pregnancies is secondary to an immune rejection phenomenon in the placental-endometrial interface [45,77]. One study on placental biopsies has found significant histological and immunohistological differences between the placenta in IVF-OD and IVF-AO pregnancies, specifically an increase in immunological activation, villitis, chronic deciduitis, ischemic changes, and fibrin deposition, which is similar to the graft versus host disease after solid organ transplant and further supports the immunological hypothesis of preeclampsia [59,78]. ...
Article
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... It has been suggested that the increase in risk of preeclampsia in IVF-OD pregnancies is secondary to an immune rejection phenomenon in the placental-endometrial interface [45,77]. One study on placental biopsies has found significant histological and immunohistological differences between the placenta in IVF-OD and IVF-AO pregnancies, specifically an increase in immunological activation, villitis, chronic deciduitis, ischemic changes, and fibrin deposition, which is similar to the graft versus host disease after solid organ transplant and further supports the immunological hypothesis of preeclampsia [59,78]. ...
Article
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Research question In women with singleton pregnancies conceived after assisted reproductive technologies, does the in vitro fertilization with oocyte donation (IVF-OD) affect the perinatal and maternal outcomes compared to autologous in vitro fertilization (IVF-AO)? Design Systematic review and meta-analysis of studies comparing perinatal and maternal outcomes in singleton pregnancies resulting from IVF-OD versus IVF-AO. An electronic literature search in Pubmed, MEDLINE, and Cochrane database was performed. The main outcome measures were hypertensive disorders in pregnancy, preeclampsia, severe preeclampsia, pregnancy-induced hypertension, preterm birth, early preterm birth, low birth weight, and very low birth weight. Results Twenty-three studies were included. IVF-OD is associated with a higher risk of hypertensive disorders in pregnancy (OR 2.63, 2.17–3.18), preeclampsia (OR 2.64; 2.29–3.04), severe preeclampsia (OR 3.22; 2.30–4.49), pregnancy-induced hypertension (OR 2.16; 1.79–2.62), preterm birth (OR 1.57; 1.33–1.86), early preterm birth (OR 1.80; 1.51–2.15), low birth weight (OR 1.25, 1.20–1.30), very low birth weight (OR 1.37, 1.22–1.54), gestational diabetes (OR 1.27; 1.03–1.56), and cesarean section (OR 2.28; 2.14–2.42). There was no significant difference in the risk of preterm birth or low birth weight when adjusted for preeclampsia. Conclusions IVF-OD patients should be considered an independent risk factor for some adverse perinatal outcomes, mainly hypertensive disorders in pregnancy, preeclampsia, and severe preeclampsia. Immunological and hormonal aspects may be involved in these results, and further research focusing in the etiopathogenesis of these pathologies are needed.
... This places an additional burden on the maternal immune system to effectively regulate the extent of reactivity to antigens from two exogenous sources. As a result, immune-mediated placental pathology, has been shown to occur more frequently after pregnancy with oocyte donors [3,4] and there is evidence of an increase in both pro-and anti-inflammatory immune activity [5]. The most definitive study to date on maternal immune responses to donor oocytes identified several differences from conventional pregnancies [6]. ...
Article
Full-text available
Background and Objectives: To investigate if pregnancies conceived using an oocyte donor necessitate an alteration in immune regulation, we compared concentrations of insulin-like growth factor binding protein (IGFBP)-1, insulin-like growth factor (IGF)-1 and T cell immunoglobulin mucin-3 (Tim-3) in women with ongoing successful twin pregnancies conceived spontaneously, using assisted reproductive technologies that utilized homologous oocytes or with donor oocytes. Differences in levels of these immune modulatory proteins may be magnified and easier to detect in twin as compared to singleton pregnancies. Methods: In this prospective study IGFBP-1 and IGF-1 were measured in sera and Tim-3 in lysates of peripheral blood mononuclear cells (PBMCs) by ELISA. Results: Median IGFBP-1 levels were lower in women with donor oocytes (41.4 ng/ml) as compared to those with a spontaneous conception (51.2 ng/mL) or who conceived with various assisted reproduction protocols using homologous oocytes (52.4 ng/mL) (p < 0.001). IGF-1 and Tim-3 levels were comparable in each group. The IGFBP-1 level was inversely correlated to the IGF-1 concentration only in women with donor oocytes (p = 0.032). IGFBP-1 and Tim-3 levels were similarly negatively correlated in the donor oocyte group (p = 0. 012). Women in the assisted reproduction group who conceived following intracytoplasmic sperm injection were the only other group in which IGFBP-1 and Tim-3 were negatively correlated (p = 0.018). Conclusions: Down-regulation of IGFBP-1 production in pregnancies conceived with donor oocytes may reduce the extent of pro-inflammatory immunity and contribute to successful outcome in totally allogeneic pregnancies.
... This is probably not the only explanation because young oocyte recipients have similar rates of HDP to women of more advanced age (Keegan et al., 2007). One hypothesis is that in these HDP pregnancies the genetically foreign fetus induces immunological reactions and placental pathology, such as villitis, chronic deciduitis and ischemic changes, in the oocyte recipient (Gundogan et al., 2010;van der Hoorn et al., 2010;Savasi et al., 2016). Lashley et al. (2015) suggested that HLA matching between donor and recipient might prevent the immunologic mismatch between mother and fetus thereby decreasing the risk of HDP and other obstetric and perinatal complications. ...
Article
Worldwide, more than 7 million children have now been born after ART: these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and overall improved health for the ART progeny. In this review we summarize the risks for short- and long-term health in ART singletons and discuss if the increased health risks are associated with intrinsic maternal or paternal factors related to subfertility or to the ART treatments per se. Although the risks are modest, singletons born after ART are more likely to have adverse perinatal outcomes compared to spontaneously conceived (SC) singletons dependent on the ART method. Fresh embryo transfer is associated with a higher risk of small for gestational age babies (SGA), low birthweight and preterm birth (PTB), while frozen embryo transfer is associated with large-for-gestational age babies and pre-eclampsia. ICSI may be associated with a higher risk of birth defects and transferral of the poor semen quality to male progeny, while oocyte donation is associated with increased risk of SGA and pre-eclampsia. Concerning long-term health risks, the current evidence is limited but suggests an increased risk of altered blood pressure and cardiovascular function in ART children. The data that are available for malignancies seem reassuring, while results on neurodevelopmental health are more equivocal with a possible association between ART and cerebral palsy. The laboratory techniques used in ART may also play a role, as different embryo culture media give rise to different birthweights and growth patterns in children, while culture to blastocyst stage is associated with PTB. In addition, children born after ART have altered epigenetic profiles, and these alterations may be one of the key areas to explore to improve our understanding of adverse child outcomes after ART. A major challenge for research into adverse perinatal outcomes is the difficulty in separating the contribution of infertility per se from the ART treatment (i.e. 'the chicken or the egg'?). Choosing and having access to the appropriate control groups for the ART children in order to eliminate the influence of subfertility per se (thereby exploring the pure association between ART and child outcomes) is in itself challenging. However, studies including children of subfertile couples or of couples treated with milder fertility treatments, such as IUI, as controls show that perinatal risks in these cohorts are lower than for ART children but still higher than for SC indicating that both subfertility and ART influence the future outcome. Sibling studies, where a mother gave birth to both an ART and a SC child, support this theory as ART singletons had slightly poorer outcomes. The conclusion we can reach from the well designed studies aimed at disentangling the influence on child health of parental and ART factors is that both the chicken and the egg matter.
... Placentas in cluster 2 demonstrated classic preeclampsia-associated findings (small for gestational age, distal villous hypoplasia, with syncytial knots and infarcts) and were significantly more likely to be associated with infants that were small for gestational age (SGA) and/or had a clinical diagnosis of intrauterine growth restriction. Genes involved with hormone secretion, response to nutrient, redox activity and response to hypoxia/angiogenesis were over-represented in cluster 2. Preeclampsia placentas in cluster 3 showed increased rates of massive perivillous fibrin deposition, a placental lesion associated with maternal anti-fetal rejection (Romero, et al., 2013;Gundogan, et al., 2010), and increased expression of genes associated with allograft rejection, immune and inflammatory responses. ...
Article
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Preeclampsia is a pregnancy-induced hypertensive disorder, the pathophysiology of which includes underlying maternal cardiovascular disease, deficient spiral artery remodeling during placenta development, and inflammatory immune responses at the maternal-fetal interface. Human leukocyte antigens (HLA) are major histocompatibility complex molecules essential for the recognition of foreign antigens that is central to immune defense against pathogens and critical determinants for the immune system discriminating between self and non-self tissues, such as in transplantation. Pregnancy represents a naturally existing “transplantation”, where the maternal immune system must be immunologically tolerant to the developing fetus which is 50% allogeneic. It is then unsurprising that HLA also influence normal pregnancy and pregnancy complications including preeclampsia. Here we review the role of classical and non-classical HLA molecules in influencing normal physiologic function during pregnancy and describe the association of HLA with pathophysiology in preeclampsia.
... Already back in the 90s, especially pre-eclampsia has been associated with AMA, nulliparity and ovarian failure (101). Moreover, aging per se (>40 year) is an independent risk for gestational diabetes, thrombophlebitis (102)(103)(104), proteinuria, premature rupture of the membranes, hemorrhage, pre-term birth and low birth-weight, intrauterine growth restriction and abnormal placentation (105)(106)(107). Indeed, despite the high success rate of OD, recent evidences from reviews and meta-analyses suggest that pregnancies achieved by this strategy showed a significant increase in the likelihood of several obstetrics and maternal complications with respect to pregnancies achieved through IVF with own eggs (108,109). ...
Article
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Advanced maternal age (AMA; >35 year) is associated with a decline in both ovarian reserve and oocyte competence. At present, no remedies are available to counteract the aging-related fertility decay, however different therapeutic approaches can be offered to women older than 35 year undergoing IVF. This review summarizes the main current strategies proposed for the treatment of AMA: (i) oocyte cryopreservation to conduct fertility preservation for medical reasons or “social freezing” for non-medical reasons, (ii) personalized controlled ovarian stimulation to maximize the exploitation of the ovarian reserve in each patient, (iii) enhancement of embryo selection via blastocyst-stage preimplantation genetic testing for aneuploidies and frozen single embryo transfer, or (iv) oocyte donation in case of minimal/null residual chance of pregnancy. Future strategies and tools are in the pipeline that might minimize the risks of AMA through non-invasive approaches for embryo selection (e.g., molecular analyses of leftover products of IVF, such as spent culture media). These are yet challenging but potentially ground-breaking perspectives promising a lower clinical workload with a higher cost-effectiveness. We also reviewed emerging experimental therapeutic approaches to attempt at restoring maternal reproductive potential, e.g., spindle-chromosomal complex, pronuclear or mitochondrial transfer, and chromosome therapy. In vitro generation of gametes is also an intriguing challenge for the future. Lastly, since infertility is a social issue, social campaigns, and education among future generations are desirable to promote the awareness of the impact of age and lifestyle habits upon fertility. This should be a duty of the clinical operators in this field.
... This supports the idea of a connection between nulliparity and hypertensive disorders. In the placenta of oocyte donor pregnancies, histological and immunohistochemical reactions have been described, which could represent a host-versus-graftrejection-like phenomenon (Gundogan et al., 2010). For gestational carriers in a surrogacy procedure, it has been speculated that 'a healthy carrier with a normal reproductive background might somehow compensate for atypical immunological reactions related to a foreign embryo' (Soderstrom-Anttila et al., 2016). ...
Article
Research question: What are the reproductive and obstetric outcomes of the gestational surrogacy treatment in the Netherlands? Design: This retrospective cohort study reports all data of gestational surrogacy treatment in the VU University Medical Centre over a period of 10 years. Data was collected from 60 intended parents and 63 gestational carriers, including reproductive and obstetric outcomes. Results: All intended mothers had a medical indication for gestational surrogacy and used autologous oocytes, and semen of the intended father. Ninety-three IVF cycles were initiated in 60 intended mothers, with subsequent 184 single embryo transfers in 63 gestational carriers. This resulted in 35 ongoing singleton pregnancies. At least one live birth was achieved for 55.0% of intended couples. Pregnancy was complicated in 20.6% by a hypertensive disorder. Labour was induced in 52.9%, and the Caesarean section rate was 8.8%. None of the pregnancies was complicated by preterm birth. Postpartum haemorrhage (>500 ml) occurred in 23.5%. Conclusions: This study shows the effective results of the non-commercial gestational surrogacy programme in the Netherlands, in a multidisciplinary team setting. An increased risk for adverse obstetric outcomes in surrogate mothers is noted for hypertensive disorders and post-partum haemorrhage compared with the incidence in non-surrogacy pregnancies.
... Intriguingly, chronic deciduitis is seen more frequently in IVF-ET pregnancies resulting from donor eggs (2.8%-42%) compared with those from autologous eggs (1.6%-1.8%), suggesting that chronic deciduitis may represent chronic semiallograft rejection by the maternal immune system of the conceptus (75)(76)(77). The expression level of several proinflammatory genes (IGJ, IGLL1, CXCL13, CD27, CXCL9, CXCL10, ICOS, and KLRC1) is increased in the placenta with chronic deciduitis compared with in the placenta without inflammation (72,78,79). ...
Article
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Endometritis is subdivided into two categories. Acute endometritis is symptomatic and characterized by microabscess formation and neutrophil invasion in the endometrial superficial epithelium, gland lumina, and uterine cavity. Chronic endometritis is rather silent and recognized as unusual plasmacyte infiltration in the endometrial stromal areas. Over the last decade, studies have disclosed the potential association between poor reproductive outcomes and endometritis, particularly chronic endometritis. The aim of this review is to address the current literature surrounding chronic endometritis and highlight recent advances in the research of this long-neglected gynecologic disease.
... Recent studies investigating outcomes with donor oocyte IVF treatment have consistently found a higher risk of pre-eclampsia, preterm birth (PTB) and low birthweight (LBW) (Dude et al., 2016;Kamath et al., 2017;Masoudian et al., 2016). It is speculated that the allogenicity of the donor oocyte is possibly contributing to the risk of adverse pregnancy outcomes (Gundogan et al., 2010). ...
Article
It is a matter of interest whether pregnancies with the use of donor sperm are associated with a higher risk of adverse perinatal outcomes compared with partner sperm. Anonymized data were obtained from the Human Fertilization & Embryology Authority. Data from 1991 to 2011 involving a total of 95,787 singleton births (4523 with donor sperm and 91,264 with partner sperm) following fresh IVF/intracytoplasmic sperm injection (ICSI) were analysed to compare perinatal outcomes of preterm birth (PTB), low birthweight (LBW) and high birthweight (HBW). The risk of LBW was significantly lower (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI]: 0.79-0.99) following donor sperm versus partner sperm IVF/ICSI. There was no significant difference in the risk of PTB (aOR 0.93, 95% CI: 0.83-1.04), early PTB (aOR 0.86, 95% CI: 0.67-1.11), very LBW (aOR 0.95, 95% CI: 0.75-1.20), HBW (aOR 1.09, 95% CI: 0.98-1.21) and very HBW (aOR 1.15, 95% CI: 0.90-1.45) following donor sperm versus partner sperm IVF/ICSI. The current study did not demonstrate an increased risk of adverse perinatal outcomes following donor sperm compared with partner sperm IVF/ICSI treatment.
... The higher risk of hypertensive disorders and adverse perinatal outcomes after oocyte donation has been attributed to immunological maladaptation to foreign antigen from the fetus (Gundogan et al., 2010;Savasi et al., 2016). Gestational surrogacy entails carrying a pregnancy resulting from gametes either from the intended parent, parents or donor gametes. ...
Article
Anonymized data were obtained from the Human Fertilization and Embryology Authority to determine whether gestational surrogacy influences perinatal outcomes compared with pregnancies after autologous IVF. A total of 103,160 singleton live births, including 244 after gestational surrogacy, 87,571 after autologous fresh IVF and intractyoplasmic sperm injection (ICSI) and 15,345 after autologous frozen embryo transfers were analysed. Perinatal outcomes of pretern birth (PTB), low birth weight (LBW) and high birth weight (HBW) were compared. No difference was found in the risk of PTB and LBW after gestational surrogacy compared with autologous fresh IVF-ICSI: PTB (adjusted OR 0.90, 95% CI 0.56 to 1.42), LBW (adjusted OR 0.90, 95% CI 0.57 to 1.43) and gestational surrogacy compared with autologous frozen embryo transfers: PTB (adjusted OR 0.96, 95% CI 0.58 to 1.60), LBW (adjusted OR 1.16, 95% CI 0.69 to 1.96). The incidence of HBW was significantly higher after gestational surrogacy compared with fresh IVF-ICSI (adjusted OR 1.94, 95% CI 1.38 to 2.75); no difference was found in HBW between gestational surrogacy and autologous frozen embryo transfers. The dataset is limited by lack of information on confounders, i.e. ethnicity, body mass index, underlying medical history, which could result in residual confounding.
... During invasion, it is important that the mother (gestational carrier) is not rejecting the allogeneic foetus; this is obtained by complex mechanisms of immunoregulation [58]. When compared to non-donor IVF pregnancies, placental analysis after oocyte donation showed an increased immunological activity at the maternal-foetal interface that could either represent a host versus graft rejection-like phenomenon or an effort to suppress rejection [39]. The fact that adverse outcomes decrease when the oocyte donor is related to the recipient suggests a lower HLA mismatch between relatives. ...
Article
As the oocyte is the starting point for a new life, artificial reproductive technology (ART) techniques should not affect the (ultra) structural and functional integrity, or the developmental competence. Oocyte vitrification -one of the most significant achievements in human ART during the past decade-should therefore be a safe and efficient technique. This review discusses the principles and developments of the existing and future techniques, applications possibilities and safety concerns. The broad range of vitrification media and devices that are currently available, show differences in their effects on the oocyte ultrastructure and preimplantation development. It is not yet fully decided whether this has an influence on the obstetric and neonatal outcome, since only limited information is available with different media and devices. For autologous oocytes, the obstetric and neonatal outcomes appear promising and comparable to pregnancies obtained with fresh oocytes. This however, is not the case for heterologous fresh or vitrified oocytes, where the immunological foreign foetus induces adverse obstetric and neonatal outcomes. Besides the oocyte vitrification process itself, the effect of multiple stimulations (for oocyte banking or for oocyte donors), seems to influence the possibility to develop gynaecological cancers further in life. Automated vitrification/warming should offer a consistent, cross-contamination free process that offers the highest safety level for the users. They should also produce more consistent results in survival, development and clinical pregnancies between different IVF clinics.
... The situation is more dramatic after embryo transfer (ET), where approximately 70% of the embryos transferred to recipient females die in their reproductive tract [5,6]. Likewise, results from human, using allogeneic embryos from egg donation (ED) indicated maternal alterations compared to pregnancies after in vitro fertilization (IVF) of the mother's own eggs (semi-allogeneic embryos), alterations related to an increased immune activity, comparable to the immunological rejection of a graft [7,8]. Although embryo mortality after pig ET has been a topic of increased interest, the contributing causes are still not well understood, particularly regarding the response of the maternal uterus to the stimuli produced by allogeneic embryos. ...
Article
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Pig embryo transfer (ET) is burdened by high embryo mortality, with cytokines playing a significant role in recruitment of immune cells during embryo attachment and placentation. We hereby tested if their levels in endometrium and placenta from sows carrying hemi-allogeneic (artificially inseminated sows; C+ positive control) or allogeneic embryos (sows subjected to ET; ET) during peri-implantation (D18) or post-implantation (D24) are suitable mirrors of embryo rejection or tolerance after ET. Non-pregnant sows (C-) were used as negative controls. A set of cytokines was assayed in the tissues through multiplexed microsphere-based flow cytometry (Luminex xMAP, Millipore. USA). Fewer (58.7%. p < 0.003) conceptuses were recovered at D24 after ET compared to C+ (80.9%); with more than 20% of the ET conceptuses being developmentally delayed. Cytokine levels shifted during implantation. Anti-inflammatory IL-10 levels were significantly (p < 0.05) lower in ET sows compared to C+ at D24 of pregnancy. The C+ controls (carrying hemi-allogeneic embryos) consistently showed higher levels of pro-inflammatory TNF-α, IFN-γ, and IL-2 cytokines at D18 and IL-1α at D24, compared to the ET group. This clear dysregulation of pro- and anti-inflammatory cytokine levels in sows subjected to ET could be associated with an impaired maternal immune tolerance, explaining the high embryonic mortality of ET programs.
... The present study focused on chronic deciduitis (CD) for the purpose of histologically examining the effects of CE on the decidua. CD is defined as a type of long-term and slight inflammation of the decidua found during pregnancy [19][20][21][22][23]. Chronic microbial infection and immune mechanisms have been implicated as the etiology of CD [19,24,25]. The diagnosis of CD is similar to that of CE, depending histologically on the presence of plasma cells in the decidua [19,20]. ...
Preprint
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Background: The presence of chronic deciduitis (CD) was determined in patients diagnosed with or without chronic endometritis (CE) before pregnancy to study the effect of CE on decidua in cases of miscarriage. Methods: Decidual tissue was obtained from the patients who miscarried at the first pregnancy within a year after the diagnosis of the presence or absence of CE. The number and distribution pattern of plasma cells stained with CD138 in decidual tissue in 10 high-power fields (HPFs) was examined. The prevalence of CD diagnosed with four different grade; grade 0, no plasma cell in 10 HPFs, thus Non-CD ;grade 1, rare single plasma cells; grade 2, rare clusters or more than 5 single cells total; and grade 3, many plasma cells with more than 5 clusters, were examined and compared between Non-CE and CE. Results: The incidence rate of CD of grade2+3 was significantly higher in CE than Non-CE (53.8%; 7/13 vs. 0%; 0/13, P<0.01). Presence of clusters or a number of plasma cells in 10 HPFs of decidua showed a sensitivity of 53.8%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 68.4% for the diagnosis of CE. Conclusion: Presence of clusters of plasma cells or five or more of plasma cells in decidua was found in more than half of CE, but not found in Non-CE. When CD with cluster or five or more of plasma cells is confirmed histologically in miscarriage decidual tissue, the presence of CE before the pregnancy should be suspected.
... The present study focused on chronic deciduitis (CD) for the purpose of histologically examining the effects of CE on the decidua. CD is de ned as a type of long-term and slight in ammation of the decidua found during pregnancy [19][20][21][22][23]. Chronic microbial infection and immune mechanisms have been implicated as the etiology of CD [19,24,25]. The diagnosis of CD is similar to that of CE, depending histologically on the presence of plasma cells in the decidua [19,20]. ...
Preprint
Full-text available
Background: The presence of chronic deciduitis (CD) was determined in patients diagnosed with or without chronic endometritis (CE) before pregnancy. Objective: To study the effect of CE on decidua in cases of miscarriage. Methods: Decidual tissue was obtained from the patients who miscarried at the first pregnancy within a year after the diagnosis of the presence or absence of CE. The number and distribution pattern of plasma cells stained with CD138 in decidual tissue in 10 high-power fields (HPFs) was examined. The prevalence of CD diagnosed with four different grade; grade 0, no plasma cell in 10 HPFs, thus Non-CD ;grade 1, rare single plasma cells; grade 2, rare clusters or more than 5 single cells total; and grade 3, many plasma cells with more than 5 clusters, were examined and compared between Non-CE and CE. Results: The incidence rate of CD of grade2+3 was significantly higher in CE than Non-CE (53.8%; 7/13 vs. 0%; 0/13, P<0.01). Presence of clusters or a number of plasma cells in 10 HPFs of decidua showed a sensitivity of 53.8%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 68.4% for the diagnosis of CE. Conclusion: Presence of clusters of plasma cells or five or more of plasma cells in decidua was found in more than half of CE, but not found in Non-CE. When CD with cluster or five or more of plasma cells is confirmed histologically in miscarriage decidual tissue, the presence of CE before the pregnancy should be suspected.
... Differences in placental hormonal production were shown both in autologous and heterologous IVF/ICSI pregnancies mainly with lower pregnancy-associated plasma protein-A and higher free Beta-hCG, respectively (Savasi et al., 2015;Cavoretto et al., 2017). Moreover, studies on placental histology in OD pregnancies show increased risk of chronic deciduitis; syncytial nodes; plasma cells and fibrin; and intervillar trombi as compared to autologous IVF (Perni et al., 2005;Gundogan et al., 2010;Schonkeren et al., 2012). Embryonic cryopreservation, common in OD, may alter trophoblast gene expression and expose the trophoblast to specific noxae due to in vitro manipulation (e.g. ...
Article
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Study question: Do uterine arteries Doppler studies show different pulsatility index (UtA-PI) measurements in IVF/ICSI pregnancies with oocyte donation (OD) as compared to natural conceptions? Summary answer: In IVF/ICSI pregnancies with OD, UtA-PI is reduced by an average of about 40% as compared to pregnancies with natural conception. What is known already: OD pregnancies present worse pregnancy outcomes as compared to natural conception, particularly for increased incidence of pre-eclampsia (PE). Recent evidence shows that IVF/ICSI pregnancies with frozen blastocyst transfer also present higher prevalence of PE and 15% lower UtA-PI as compared to pregnancies after fresh blastocyst transfers. Study design, size, duration: Prospective, longitudinal matched cohort study performed in the Fetal Medicine and Obstetric Departments of San Raffaele Hospital in Milan, between 2013 and 2018. The analysis is based on 584 Doppler observations collected from 296 women with different method of conception (OD n = 122; natural conception n = 174). Participants/materials, setting, methods: IVF/ICSI viable singleton pregnancies with OD and natural conception control pregnancies matched for BMI and smoking, performing repeated UtA-PI measurements at 11-34 weeks. Miscarriages, abnormalities, twins, significant maternal diseases and other types of ARTs were excluded. Log mean left-right UtA-PI was used for analysis with linear mixed model (LMM) and correction for significant confounders. Pregnancy outcome was also analyzed. Main results and the role of chance: Participants after OD were older and more frequently nulliparous (mean age: OD 43.4, 95% CI from 42.3 to 44.6; natural conception 35.1, 95% CI from 34.5 to 35.7; P-value < 0.001; nulliparous: OD 96.6%; natural conception 56.2%; P-value < 0.001). Mean pulsatility index was lower in OD (UtA-PI: natural conception 1.22; 95% CI from 1.11 to 1.28; OD 1.04; 95% CI from 0.96 to 1.12; P-value < 0.001). A significant effect of parity, gestational age (GA) modeled with a cubic polynomial and BMI was described in the LMM. The mean Log UtA-PI was on average 37% lower in OD as compared to natural conception pregnancies at LMM (P-value < 0.001). We also found a significant interaction between longitudinal UtA-PI Doppler and GA. Therefore, at 11 weeks' gestation the Log UtA-PI was 42% lower and, at 34 weeks, the differences reduced to 32%. GA at delivery and birth weight were statistically lower in OD group; however, birthweight centile was not statistically different. Preeclampsia was 11-fold more common in the OD group (0.6% and 6.6%, P-value = 0.003). No other significant difference in pregnancy outcome was shown in the study groups (gestational diabetes mellitus, small or large for GA). Limitations, reasons for caution: It was not possible to properly match for maternal age and to blind the assessment given the major differences between cohorts; however, we did not find significant within-groups effects related to maternal age. Future research is needed to reassess outcomes and correct them for maternal characteristics (e.g. cardiovascular function). Wider implications of the findings: This finding reproduces our previous discovery of lower UtA-PI in frozen as compared to fresh blastocyst transfer. The vast majority of OD is obtained by the use of cryopreservation. We speculate that increased uterine perfusion may be the physiological response to compensate dysfunctions both in the mother and in the placenta. Study funding/competing interest(s): This is a non-funded study. The authors do not declare competing interest. Trial registration number: N/A.
... The expression of multiple genes such as ovarian steroid receptors, adhesion molecules, cytokines, chemokines, and apoptosis are dysregulated in the secretory phase endometrium with CE, indicating the impaired endometrial receptivity in this pathology [12][13][14]. Furthermore, persistent CE is considered to lead to chronic deciduitis, a pathologic condition associated with preterm labor and neonatal periventricular leukomalacia/cerebral palsy [15][16][17][18][19][20][21][22]. Thus, CE is thought to have a negative impact on entire period of human reproduction. ...
Article
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Purpose: Chronic endometritis (CE) is an infectious and inflammatory disorder associated with infertility of unknown etiology, repeated implantation failure, and recurrent pregnancy loss. In the current clinical practice, intrauterine interventions such as endometrial biopsy/histopathologic examinations and/or hysteroscopy are required for the diagnosis of CE. In this study, we analyzed the microbiota in vaginal secretions (VS) as a potential prediction tool for CE in infertile women. Methods: Using next-generation sequencing analysis, we compared the VS and endometrial fluid (EF) microbiota in infertile women with (n = 20) or without CE (n = 103). Results: The detection rate of Streptococcus and Enterococcus as well as the bacterial abundance of Atopobium and Bifidobacterium in the VS microbiota was significantly lower in the CE group than in the non-CE group. Meanwhile, the detection rate and bacterial abundance of Lactobacillus in the EF and VS microbiota were at similar levels between the two groups. Conclusion: These findings suggest that VS microbiota in infertile women with CE is characterized by the reduction in Bifidobacterium and lactic-acid-producing bacteria other than Lactobacillus. Our results hold promise for the prediction of CE, not by somewhat interventional intrauterine procedures, but by less invasive VS sampling. Trial registration number: UMIN000029449 (registration date 6 October 2017).
... Increased immune activity at the maternal-fetal interface and significant histological and immunohistochemical differences were observed in placentas from pregnancies obtained by IVF of heterologous oocytes, compared to those obtained using homologous oocytes [112], and may be the consequence of a host versus graft rejection-like condition. This aspect was further investigated using 3D ultrasound analysis. ...
Article
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Obstetric and newborn outcomes of assisted reproductive technology (ART) pregnancies are associated with significative prevalence of maternal and neonatal adverse health conditions, such as cardiovascular and metabolic diseases. These data are interpreted as anomalies in placentation involving a dysregulation of several molecular factors and pathways. It is not clear which extent of the observed placental alterations are the result of ART and which originate from infertility itself. These two aspects probably act synergically for the final obstetric risk. Data show that mechanisms of inappropriate trophoblast invasion and consequent altered vascular remodeling sustain several clinical conditions, leading to obstetric and perinatal risks often found in ART pregnancies, such as preeclampsia, fetal growth restriction and placenta previa or accreta. The roles of factors such as VEGF, GATA3, PIGF, sFLT-1, sEndoglin, EGFL7, melatonin and of ART conditions, such as short or long embryo cultures, trophectoderm biopsy, embryo cryopreservation, and supraphysiologic endometrium preparation, are discussed. Inflammatory local conditions and epigenetic influence on embryos of ART procedures are important research topics since they may have important consequences on obstetric risk. Prevention and treatment of these conditions represent new frontiers for clinicians and biologists involved in ART, and synergic actions with researchers at molecular levels are advocated.
... Chronic deciduitis was the most frequently detected entity (n = 95) and was observed in all trimesters, often in combination with other inflammatory lesions. This connection with other, most probably autoimmunological, lesions and the reported detection of CD in cases with in vitro fertilization-in this cohort three cases were observed-point to a pathologic immune reaction rather than a chronic infection as etiology of this lesion [51,52]. In this study and as confirmed by Edmondson and colleagues preterm birth was often associated with CD [20]. ...
Article
Full-text available
Purpose Chronic inflammatory disorders of the placenta, in particular villitis of unknown etiology (VUE), chronic deciduitis (CD), chronic chorioamnionitis (CC), chronic histiocytic intervillositis (CHI), and eosinophilic/T-cell chorionic vasculitis (ETCV) can exclusively be diagnosed histologically. Using a standardized procedure for submission and pathological–anatomical examination of placentas in a single perinatal care center, we analyzed the association of chronic placental lesions to perinatal complications. Methods We reviewed all singleton placentas and miscarriages that were examined histologically over a period of ten years after having implemented a standardized protocol for placental submission in our hospital. Cases with chronic inflammatory lesions were identified, and clinical data were analyzed and compared with a focus on preterm birth, hypertensive disorders, and fetal growth restriction and/or fetal demise. Results In 174 placentas, at least one of the chronic inflammatory entities was diagnosed. CD was the most frequent disorder (n = 95), and had strong associations with preterm birth (47.3% of all cases with CD) and intrauterine fetal demise. VUE (n = 74) was exclusively diagnosed in the third trimester. This disorder was associated with a birth weight below the 10th percentile (45% of the cases) and hypertensive disease in pregnancy. Miscarriage and intrauterine fetal demise were associated with CHI (in 66.7% of cases, n = 18). Conclusions Chronic inflammatory disorders are frequently observed and contribute to major obstetric and perinatal complications. Further studies are needed to get a better picture of the connection between adverse obstetric outcomes and chronic inflammation to aid in the better counseling of patients.
... Many studies have demonstrated that compared to the general population, patients who conceive through assisted reproductive technologies experience significantly higher rates of pre-term births, which may be associated with multiple gestations, higher average maternal age, suboptimal implantation environment due to supra-physiologic estrogen levels during IVF stimulation, and donor egg usage [10][11][12][13]. Increased prevalence of pre-term birth and low birth weights have also been found among singletons conceived through IVF [13,14]. ...
Article
Full-text available
Purpose To study the effects of frozen embryo transfer (FET) and FET post-PGT on pre-term and very pre-term births in patients undergoing in vitro fertilization (IVF). Materials and methods A study was conducted using the SART National Summary Report from 2014 to 2017. Cycle inclusion criteria were eSET, fresh embryo transfers (ET), frozen embryo transfers without PGT (FET), and frozen embryo transfers with PGT (FET/PGT). Exclusion criteria were use of gestational carriers and donor eggs. Pregnancy outcomes included live births and gestational age at birth. Results A total of 161,550 eSETs were analyzed for the effect of FET and FET/PGT on IVF outcome and pre-term births including 43,618 ET, 58,812 FET, and 59,120 FET/PGT cycles. Live birth rates in patients with FET/PGT were significantly higher than those in ET (52.9% vs 46.4%, P < 0.0001) and FET (52.9% vs 43.1%, P < 0.0001). Patients with FET had a significantly lower live birth rate compared with that of ET (43.1% vs 46.4%, P < 0.0001). Both FET and FET/PGT significantly decreased total pre-term births compared with ET (10.8% and 10.5% vs 11.5%, P < 0.05 and < 0.001). FET/PGT significantly reduced very pre-term births when compared with ET and FET (1.5% vs 2.0%, P < 0.0001 and 1.5% vs 1.9%, P = 0.0002). Conclusion This study demonstrates that PGT significantly improves IVF outcome. Moreover, patients undergoing FET/PGT had significantly decreased total pre-term births. More importantly, patients with FET/PGT had significantly lower very pre-term births.
... Chronic deciduitis is associated with basal villitis and more frequently observed in the basal plate of the placenta of pregnancies resulting from donated eggs (i.e. immunogenetically distinct from the mother) compared to non-egg donor pregnancies (semi-allograft) [69,70]. ...
Article
Chronic placental inflammatory lesions lead to poor obstetric outcomes. These lesions often proceed undetected until examination of placental tissues after delivery and are mediated by CXCR3, a seven-transmembrane G protein-coupled receptor, and its chemokine ligands – CXCL9, CXCL10 and CXCL11. CXCR3-chemokine ligand interaction disrupts feto-maternal immune tolerance and activate obnoxious immunological responses similar to transplant rejection and graft-versus-host disease. The resultant chronic inflammatory responses manifest in different parts of the placenta characterised by the presence of incompatible immunocompetent cells from the feto-maternal unit i.e. maternal CD8⁺ T cells in the chorionic membrane or plate (chronic chorioamnionitis); foetal Hofbauer cells and maternal CD8⁺ T cells in the chorionic villous tree (villitis of unknown aetiology); maternal CD8⁺ T and plasma cells in the basal plate (chronic deciduitis); and maternal CD8⁺ T cells, histiocytes and T regulatory cells in the intervillous space (chronic intervillositis). This review critically examines how the CXCR3-chemokine ligand interaction disrupts feto-maternal immune tolerance, initiates a series of chronic placental inflammatory lesions, and consequently activates the pathways to intrauterine growth restriction, stillbirth, spontaneous abortion, preterm prelabour rupture of membranes, preterm labour and birth. The possibility of interrupting these signalling pathways through the use of CXCR3 chemokine inhibitors to prevent adverse reproductive sequelae as well as the potential clinical utility of CXCR3 chemokines as non-invasive predictive clinical biomarkers are also highlighted.
... These results are also supported by the high rates of HDP reported in oocyte donation pregnancies (Blazquez et al., 2018;Storgaard et al., 2017), which were mostly obtained after HRT-cycles. In addition to the often promoted immunological theory (Gundogan et al., 2010;Levron et al., 2014), the absence of the CL could be another mechanism explaining the increased risk of pregnancy complications in egg-donor recipients. ...
Article
The freeze-all strategy is gaining popularity worldwide as an alternative to the conventional fresh embryo transfer (ET) approach. The freeze-all strategy consists of cryopreservation of the entire embryo cohort, and performance of the ET in a subsequent cycle that takes place separately from the ovarian stimulation. Initially performed as a “rescue” strategy, in case of a high risk of ovarian hyperstimulation syndrome, this approach has been extended to other indications as a scheduled strategy in an effort to improve implantation rates. This is based on the assumption that ovarian stimulation can alter endometrial receptivity in fresh cycles due to the impact of supraphysiological levels of steroids on endometrial maturation. However, the procedure has not been associated with increased live birth rates in all infertile couples, and concerns have been raised regarding the occurrence of a number of adverse perinatal outcomes. It is, therefore, crucial to identify in which subgroups of patients a freeze-all strategy could be beneficial. Our aim in this review was to provide a summary of the current scientific background in this field, in order to highlight potential indications for this strategy and to guide clinicians in their daily practice.
... 6 There is mounting evidence, however, that maternal alloimmune or autoimmune mechanisms are involved, in at least a subset of cases. MFD/MFI occurs more commonly in women with autoimmune disorders with or without thrombophilia 1,12,17 and pregnancies achieved by egg donation (eg, total allograft) 18,19 ; has high recurrence risks of 12% to 78%; may exhibit coexistent massive chronic histiocytic (monocytic) intervillositis 1 ; and may be associated with earlier and more rapid progression when it does recur. 13 Although it did not eradicate the recurrence of MFD/MFI, IUGR, or preterm birth, a few cases of women with a history of prior MFI/MFD and primary anticardiolipin autoantibody (3 patients) 20 and one without evidence of autoimmune disease or preeclampsia, 21 who were treated with aspirin and low-dose heparin, and 1 patient treated with intravenous immunoglobulin, 22 have been observed to have improved outcomes in subsequent pregnancies and generally less extensive MFD. ...
Article
Massive perivillous fibrinoid deposition (MFD) and maternal floor infarction (MFI) are lesions of unknown etiology associated with poor perinatal outcomes, including fetal intrauterine growth restriction and neurodevelopmental injury, high risks of pregnancy loss, and recurrence in subsequent gestations. MFI comprises massive intervillous fibrinoid deposition concentrated at the maternal floor. MFD is a similar lesion but is diffuse within the parenchyma. MFD/MFI lesions represent a spectrum of severity of cloak-like perivillous fibrinoid deposition, and there is mounting evidence that, often, they represent sequelae of immune-mediated phenomena and/or an imbalance in factors that normally maintain the fluidity of blood in the maternal space. There are only a handful of reported instances of discordant MFD/MFI occurrence in twin placentas. We present a fourth such occurrence in a fused, dichorionic diamniotic twin placenta and submit that our dizygotic twin gestation case provides additional supportive evidence that immune-mediated mechanisms are involved in the formation of pathological accumulations of fibrinoid, at least in some cases.
... Two competing theories have arisen to explain these cases 1) That CPI results from failure of maternal tolerance to fetal antigens or 2) That unknown or untested-for infectious agents in the placenta induce a maternal response, akin to transplant rejection (111). Evidence for the alloimmune theory includes the increased frequency of CPI in egg donor pregnancies, where the fetus is fully allogeneic, rather than ½ self and ½ allogeneic (112,113). Conversely, interbreeding of inbred mouse strains is associated with immune activation and resorption, the degree of which is strain dependent (114). Activation of the maternal immune system by lipopolysaccharide (LPS), a Gram negative bacterial component, or polyinosine:cytosine (poly-IC), a viral mimetic, increases the rate of resorption, prompting a model of immune activation in an allogeneic background (115,116). ...
Article
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Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and is the site of juxtaposition between the maternal and fetal circulations. Most diseases of pregnancy are caused by, impact, or are reflected in the placenta. The purpose of this review is to describe the main inflammatory processes in the placenta, discuss their immunology, and relate their short- and long-term disease associations. Acute placental inflammation (API), including maternal and fetal inflammatory responses corresponds to the clinical diagnosis of chorioamnionitis and is associated with respiratory and neurodevelopmental diseases. The chronic placental inflammatory pathologies (CPI), include chronic villitis of unknown etiology, chronic deciduitis, chronic chorionitis, eosinophilic T-cell vasculitis, and chronic histiocytic intervillositis. These diseases are less-well studied, but have complex immunology and show mechanistic impacts on the fetal immune system. Overall, much work remains to be done in describing the long-term impacts of placental inflammation on offspring health.
... These findings suggest some questions about the cure criteria or if necessary, to adopt other strategies in obstetrical manage. On the other hand, a higher frequency of premature births in oocyte donation has been published, suggesting a different modulated immune activity at the maternal-fetal interface of egg-donor pregnancies (Gundogan et al., 2010). Probably the advent of the endometrium regenerative cell therapy appears to be an efficient tool in endometrial immunology therapy (Tersoglio et al., 2020). ...
Article
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Objective: The primary objective was to establish the endometrial predictors of clinical pregnancy in a population of repeated implantation failure with oocyte donation after specific endometrial treatment. The secondary one was to evaluate reproduction outcomes in terms of Implantation rate (IR), Clinical pregnancy (CP), Live birth delivery rate (LBDR) and Prematurity, in relation to normalization or no-normalization of the predictors. Methods: 66 patients were assigned to the study. We ran a Pipelle endometrial biopsy to investigate the endometrium lymphocyte population by Flow Cytometry and abnormal/normal patterns by histopathology in pre/post-treatment. We employed the binary logistic regression model to identify the predictors for CP. For the secondary objective, we assessed the clinical outcomes in function to the normalization or no normalization in post-treatment. Results: Endometrial histopathology and endometrial NK cell counts resulted in CP predictors (Wald chi2 test (p=0.044 and 0.001)), respectively. We had a higher IR, CP and LBDR when both predictors were normalized in comparison with no normalization (p<0.001). There was a high percentage of prematurity in both normalized vs. non-normalized groups (34.4% (11/32) and 71.43% (5/7), respectively) without significant differences. Conclusion: Endometrial histopathology and endometrial NK cell counts showed that they are valid predictors of pregnancy outcome in repeated implantation failure after treatment. In post-treatment, the pregnancy outcomes were significantly higher in the presence of both normalized predictors. Pregnancy rates were zero in the no-normalization of both predictors. There was a high percentage of prematurity in both groups.
... Interesting findings suggest the hypothesis of a differential pathophysiological mechanism of preeclampsia in OD compared to NC pregnancies. (Gundogan et al., 2010;Lashley et al., 2015; van der Hoorn Fig. 3. A). Correlation between CD200 protein expression and total amount of HLA mismatches in uncomplicated OD pregnancies (rho = 0.636*). ...
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Oocyte donation (OD) pregnancies are characterized by a complete immunogenetic dissimilarity between mother and fetus, which requires enhanced immunoregulation compared to naturally conceived (NC) pregnancies. The trophoblast expresses co-inhibitory ligands crucial for regulation of the maternal T cell response. Therefore, we studied the role of placental immune checkpoint inhibitors for the establishment of fetal tolerance and their relation to the development of preeclampsia in OD compared to NC pregnancies. Placental tissue from uncomplicated OD (n = 21) and NC (n = 21) pregnancies, and OD (n = 9) and NC (n = 15) pregnancies complicated with preeclampsia were studied. Protein expression of co-inhibitory ligands PD-L1 and CD200 was double blind semi-quantitatively determined by immunohistochemistry. Messenger RNA expression of PD-L1, CD200 and indoleamine 2,3-dioxygenase (IDO) was determined using qPCR. Decreased PD-L1 and CD200 protein expression and increased IDO mRNA expression was observed in uncomplicated OD versus NC pregnancies (all p < 0.05). CD200 protein expression was positively correlated with PD-L1 expression in all groups, with the number of HLA total mismatches and with HLA class I mismatches in uncomplicated OD cases (all p < 0.05). Preeclamptic cases showed lower PD-L1 protein and CD200 protein and mRNA expression in OD compared to NC pregnancies (all p < 0.05). This study shows that signaling by co-inhibitory PD-L1 and CD200 and by immunosuppressive IDO is altered in the placenta of OD pregnancies, suggesting a contribution to the higher risk for preeclampsia. These insights provide future prospects in unraveling the immune paradox of oocyte pregnancy, which are applicable for better risk management and treatment of uncomplicated and preeclamptic pregnancies.
... The present study focused on chronic deciduitis (CD) for the purpose of histologically examining the effects of CE on the decidua. CD is defined as a type of long-term and slight inflammation of the decidua found during pregnancy [19][20][21][22][23]. Chronic microbial infection and immune mechanisms have been implicated as the etiology of CD [19,24,25]. The diagnosis of CD is similar to that of CE, depending histologically on the presence of plasma cells in the decidua [19,20]. ...
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Background: The presence of chronic deciduitis (CD) was determined in patients diagnosed with or without chronic endometritis (CE) before pregnancy. Objective: To study the effect of CE on decidua in cases of miscarriage. Methods: Decidual tissue was obtained from the patients who miscarried at the first pregnancy within a year after the diagnosis of the presence or absence of CE. The number and distribution pattern of plasma cells stained with CD138 in decidual tissue in 10 high-power fields (HPFs) was examined. The prevalence of CD diagnosed with four different grade; grade 0, no plasma cell in 10 HPFs, thus Non-CD;grade 1, rare single plasma cells; grade 2, rare clusters or more than 5 single cells total; and grade 3, many plasma cells with more than 5 clusters, were examined and compared between Non-CE and CE. Results: The incidence rate of CD of grade2 + 3 was significantly higher in CE than Non-CE (53.8%; 7/13 vs. 0%; 0/13, P < 0.01). Presence of clusters or a number of plasma cells in 10 HPFs of decidua showed a sensitivity of 53.8%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 68.4% for the diagnosis of CE. Conclusion: Presence of clusters of plasma cells or five or more of plasma cells in decidua was found in more than half of CE, but not found in Non-CE. When CD with cluster or five or more of plasma cells is confirmed histologically in miscarriage decidual tissue, the presence of CE before the pregnancy should be suspected.
Article
Background: Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown. Objective: To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception. Study design: A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders. Results: A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43-2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22-2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20-3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29-2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27-2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47-2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26-2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03-1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies. Conclusion: No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes.
Article
Research question We aimed to assess the clinical characteristics of pregnancies complicated by fetal growth restriction (FGR) and preeclampsia (PE) in in vitro fertilization (IVF) patients, and the correlation to histopathological placental findings in such pregnancies. Design This was a retrospective cohort of deliveries at our institution, of patients’ files with a diagnosis of FGR and/or PE. We included deliveries in which the placenta was sent to histopathological examination. Computerized files and pathological reports were reviewed, and maternal, obstetric, neonatal outcomes and placental histopathological reports were compared between pregnancies conceived by IVF and controls. Placental lesions were classified according to the "Amsterdam" criteria. Results During the study period between 12/08 and 12/18, 1114 singleton deliveries with the diagnosis of FGR and/or PE occurred, for which placental examination was performed, 105 conceived with IVF (IVF group) and 1009 non-IVF conceived (control group). The IVF group was older, of lower parity, had a higher rate of diabetes and chronic hypertension, and smoked less. Deliveries occurred at an earlier gestational age, although birth weight was non-significant between the groups. There was a significantly lower rate of neonatal adverse composite outcome among IVF deliveries (59.0% vs. 76.6%, p<0.001). On placental examination, placental weight, maternal and fetal vascular malperfusion lesions were similar between the groups, while villitis of unknown etiology was significantly more common among the IVF group (16.1% vs. 8.3%, p=0.007). Conclusion Neonatal outcome is relatively favorable in placental related diseases in IVF patients. Placental chronic villitis is more common in IVF patients, pointing to an additive immunological etiology.
Article
Research Question To evaluate pre-existing comorbidities, obstetric risks factors and adverse obstetric and neonatal outcomes in pregnancies conceived by oocyte donation (OD), as compared to spontaneously conceived (SC) pregnancies or by conventional in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Design In a retrospective single-centre cohort study, data from singleton deliveries occurring at the University Hospital of Careggi, Florence, from 2009 to 2017 were reviewed. Maternal and perinatal outcomes were analysed. Results The study included 25851 pregnancies and new-borns: 276 (1.1%) children were conceived after OD, 925 (3,6%) after IVF-ICSI and 24650 (95.4%) after SC. The OD groups included patients who were significantly older and with a higher prevalence of chronic hypertension. They were administered anticoagulant medications more frequently in their pregnancies. The incidence of gestational hypertension was significantly higher than in SC (aOR 3.6) and IVF/ICSI pregnancies (aOR 2.7). The incidence of caesarean section (CS) in OD pregnancies was higher than in both SC and IVF/ICSI groups (aOR 3.4 and aOR 2.3 respectively). An elevenfold increased risk of postpartum haemorrhage (PPH) was found in OD versus SC and a threefold increased risk was found in OD versus IVF/ICSI; prematurity and low birth weight (LBW) were more frequent after OD versus SC (aOR 2.4 for preterm birth and aOR 1.8 for LBW). Conclusions Patients undergoing OD represent a group with increased comorbidities and risk factors for adverse obstetric outcomes. OD seems to be independently associated with gestational hypertension and PPH. Pregnancies after OD warrant clinical surveillance with proper screening and, possibly, preventive strategies.
Article
Objectives: To perform a systematic review and meta-analysis of the known literature to assess whether the perinatal outcomes are different after oocyte donation (OD) compared to autologous oocyte (AO) in vitro fertilization (IVF) pregnancies. Study design: A systematic literature search was done for studies published in English from 1980 to 2016. Studies comparing perinatal outcomes of pregnancies following fresh or frozen OD and AO IVF were included. Meta-analysis was performed using the Rev Man 5.3 software (Cochrane Collaboration) for the perinatal outcomes of PTB (<37 weeks), early PTB (<32 weeks), LBW (<2500g), very LBW (<1500g), and SGA (<10th centile). Six studies provided data on PTB, three studies on early PTB, five studies on LBW, four studies on very LBW and three studies on SGA after fresh embryo transfer. Two studies provided data on PTB, early PTB, LBW and very LBW after frozen embryo transfer. Results: There is an increased risk of PTB following fresh embryo transfer in OD pregnancies than in AO IVF pregnancies (OR 1.45, 95% CI 1.20-1.77). If the PTB risk is assumed to be to 9% for pregnancies following AO IVF, then OD pregnancies will have a PTB risk between 10.8% and 15.9%. Similarly, the risk of LBW is higher after fresh embryo transfer in OD pregnancies than AO IVF pregnancies (OR 1.34, 95% CI 1.12-1.60). If the assumed LBW risk is 9% for AO IVF pregnancies, then OD pregnancies have a LBW risk between 10.1% and 14.4%. There is an increased risk of early PTB (OR 2.14, 95% CI 1.40-3.25) and very LBW (OR 1.51, 95% CI 1.17-1.95) in a fresh embryo transfer after OD as compared to AO IVF pregnancies. Conclusions: There appears to be a higher risk of adverse perinatal outcomes following fresh OD compared to AO IVF pregnancies.
Chapter
The placenta is a unique mammalian organ required for in utero life but disposable at birth. The placenta acts as a conduit and impediment to environmental toxins, infections, and other pathologies but is prone to damage. Studying the ex vivo placenta can offer insights into the in utero environment and clues to pathologies that might affect the fetus/infant.
Chapter
Since the birth of Louise Brown, the first “test tube baby,” in 1978, assisted reproductive technology (ART) has been widely implemented as a standard treatment for couples with subfertility problems. An estimated 8 million children have been born via ART worldwide and up to 6% of newborns in Europe and 1.5% in United States are conceived via this technique [2]. ART pregnancies are at an increased risk for neonatal complications such as preterm birth and low birth weight as well as maternal complications such as gestational diabetes and preeclampsia. The exact mechanism behind the adverse outcomes is not known, but a role for the placenta is likely. In this chapter we will summarize current knowledge on human placenta development and functioning in relation to ART treatments. We will focus on morphology, vascularization, immunology, placental biomarkers, and aneuploidies.
Article
Chronic deciduitis (CD) is slight inflammation of the decidua found during pregnancy. The cause of preeclampsia is thought to be placental hypoplasia, and various theories have been proposed to explain the detailed mechanism; however, its association with decidual inflammation is unclear. A retrospective case control study was conducted in a single university. Subjects were cases who delivered by cesarean section between January 1, 2013 and June 30, 2020 and whose placentas were pathological assessed. CD was diagnosed by CD138 immunostaining of placental decidua tissue, and the perinatal prognosis and incidences of hypertensive disorder of pregnancy and preeclmpsia were examined according to the presence or absence of CD. A logistic regression analysis was performed to evaluate the association between preeclampsia and 11 explanatory variables (10 patient or perinatal background factors and CD). The study population included 76 patients (non-CD, n = 54; CD, n = 22). The rate of preeclampsia was significantly higher in the CD group (P = 0.0006). Patients with CD gave birth at a significantly earlier gestational age (P=0.040) with a lower birth weight (P = 0.001), and a higher rate of LFD (P = 0.005). The Apgar scores at 1 and 5 minutes and umbilical artery pH were lower (P = 0.0003, 0.021 and 0.002, respectively) in the CD group. The logistic regression analysis revealed that CD was positively associated with preeclampsia. A retrospective examination of the placenta found that patients with CD had a significantly higher incidence of preeclampsia and CD is considered to be a factor that is associated with poor perinatal outcomes.
Chapter
Chronic deciduitis is characterized by the presence of lymphoplasmacytic inflammation or, in the absence of plasma cells, diffuse and intense (>50/HPF) non-perivascular lymphocytes in the decidua. Chronic deciduitis is one of a group of chronic placental inflammatory lesions, which include VUE and chronic chorioamnionitis. While the exact cause is not known, it is suggested that immune mechanisms related to maternal anti-fetal rejection, or alternatively, chronic microbial infection, may be involved in causation. Chronic deciduitis is an association with preterm labour. Chronic deciduitis is more frequent in chromosomally normal and abnormal spontaneous miscarriage, when compared to elective terminations, suggesting a role in first trimester pregnancy loss.
Article
We sought to assess chronic inflammatory responses in patients who achieved pregnancy by oocyte donation and non-oocyte donation-assisted reproductive technology and delivered at The Ottawa Hospital. Data describing maternal health, obstetrical outcomes, neonatal outcomes, and placental pathology were collected and analyzed from electronic medical records. An increased frequency of adverse obstetrical outcomes was observed. In the oocyte donation-assisted reproductive technology group, placental pathology data demonstrated increased frequency of fetal vascular malperfusion (p = 0.02) and placenta accreta (p < 0.001), representing a chronic inflammatory response. Placental pathology reflecting dysregulated immune processes and vasculopathy is associated with oocyte donation.
Article
Introduction Chronic villitis of unknown etiology (VUE) is a chronic inflammatory lesion of third trimester placenta, which contributes to major adverse obstetric outcomes. However, the inciting factors and mechanisms by which VUE contributes to adverse outcomes are poorly understood. This limits our ability to develop preventions or interventions. Our goals were to determine whether viruses can be detected in placental tissues with VUE and to determine whether gene expression profiles support an antiviral response. Methods We extracted RNA and DNA from 20 placentas with high-grade chronic villitis and 20 control placentas without inflammation. Viruses were assessed using ViroCap viral nucleic acid enrichment coupled with metagenomic sequencing. RNA sequencing was used to evaluate the inflammatory gene expression profiles in each placenta. Results We detected at least 1 virus in 50% of the samples tested. We found that herpesviruses, were found more frequently in cases compared with controls (P = 0.01). Antiviral pathways, including defense response to virus, interferon gamma response, and IFN alpha/beta response, were upregulated in cases. We observed two clusters of gene expression profiles in the VUE cases, suggesting multiple inflammatory profiles are associated with VUE. Discussion These data support a viral etiology for some cases of VUE. Furthermore, gene expression profiles suggest the possibility of more than one cause or manifestation of VUE. Viral mechanisms should be explored as potential targets for prevention or intervention in VUE.
Article
Background: The aim of the study is to compare the obstetric outcome between single pregnancies obtained by medically-assisted procreation using oocyte donors (MAP-E) versus homologous gametes (MAP-O) and single spontaneous conception pregnancies (SC). Methods: This is a retrospective case-control study on pregnancy outcome of consecutive singleton live birth pregnancies from MAP-E between January 2011 and August 2017 referred to Careggi University Hospital, Florence. The control group includes singleton pregnancies from MAP-O and pregnancies from spontaneous conceptions in the same period. The pregnancy outcomes considered were: postpartum hemorrhage (PPH), cesarean section (CS), gestational diabetes mellitus (GDM), hypertensive disorders including preeclampsia (HDP), preterm birth ≤34 weeks (PTB), and small-for-gestational-age (SGA) fetuses. Results: The study group included 290 MAP-E pregnancies that were compared with 290 MAP-O and 870 singleton spontaneous conception pregnancies. The three groups did not show significant differences in maternal traits except for mean age (43.4±2.9 vs. 37.7±2.4 vs. 33.6±5.5, P<0.001), including a higher percentage of patients over 45 years (41.3% vs. 5% vs. 0.8%, P<0.001) and higher incidence of obesity (7.2% vs. 1.7%, P=0.02) in MAP-E than in MAP-O. The risk of HDP is increased in singleton pregnancies by oocyte donation with a significantly increased risk if compared to MAP-O (12% vs. 1%, P<0.001, OR=12.6). The risk of PPH in singleton pregnancies from oocyte donation is higher than in MAP-O (22% vs. 9% P<0.0001, OR=2.87). When we considered severe PPH (blood loss >1000 mL) the risk for MAP-E was higher if compared to MAP-O (OR=2.1, P=0.2) and mostly to SC (OR=14, P<0.005). Compared to SC, MAP-E pregnancies showed increased OR for all the outcomes: CS (78% vs. 30.8%, P<0.001, OR=7.91); GDM (26.1% vs. 10.8%, P<0.001, OR=2.92); HDP (12% vs. 2.2%, P<0.001, OR=5.99); PPH (22% vs. 8.5%, P<0.0001, OR=3.0); SGA (16% vs. 11%, P<0.05, OR=1.16); PTB ≤34 weeks (9.4% vs. 1%, P<0.001, OR=7.94). Conclusions: Most women who undergo MAP-E are in advanced age, representing a high-risk population for obstetric complications, like HPD and PPH, which stands as the main worldwide cause of maternal mortality.
Article
Objective: To study the structural and immunohistochemical features of placentas in women after assisted reproductive technology (ART) with allogeneic eggs (oocyte donation and surrogate motherhood). Study design: The study involved 89 women whose pregnancy occurred as a result of in vitro fertilization (IVF) with a donor egg in a surrogate motherhood program (IVF-SM, n = 47 patients) or oocyte donation (IVF-DO, n = 42). The comparison group consisted of 21 patients in whom pregnancy occurred as a result of IVF with their own egg (IVF-OE). A clinical and anamnestic analysis of the pregnant women was carried out. Morphological and immunohistochemical studies were performed on placental material. Immunohistochemical analysis of CD8, CD56, CD138, and CD25/CD4 markers indicating the processes of impaired tolerance in placenta was carried out. -Results: We observed a predominance of women aged >40 (range 42.7-3.91) years with a burdened somatic and obstetric-gynecological history and a high incidence of hypertensive pregnancy complications, such as gestational arterial hypertension (27.4%) and preeclampsia (28.5%), in the IVF-DO group. The IVF-SM group included mainly somatically healthy women aged <30 (29.4-3.19) years with a high risk of termination of pregnancy in the third trimester (49.6%) and premature birth (21.6%). Placentas taken from women after allogeneic pregnancy had pronounced signs of immune alteration, such as chronic histiocytic intervillositis, lymphoplasmacytic deciduitis, chronic chorioamnionitis, chronic villitis, and perivillous fibrinoid with lymphocytes (p [F] < 0.05). Immunohistochemical study of the placentas showed accumulation of CD138+ plasma cells, CD8+ T lymphocytes, and uterine natural killer cells, and a decrease in the number of CD25/CD4+ regulatory T cells (Tregs) in the structures of the uteroplacental region (Kruskal-Wallis test, p < 0.05). Conclusion: Placentas after IVF with oocyte donation and surrogate motherhood programs are characterized by similar changes, associated with the development of chronic inflammation in the structures of the placenta and immunohistochemical signs of impaired immunological tolerance at the maternal-fetal interface. The data we obtained allow us to classify pregnancies under surrogate motherhood programs as a risk factor for the development of pregnancy complications with immune pathogenesis.
Article
Research question: To study gestational hypertensive disorders in oocyte donation pregnancies compared with other modes of conception at very advanced maternal age. Design: A historical cohort study of all women aged 45-47 years who gave birth to singletons at a tertiary medical centre between March 2011 and May 2018, at 24 weeks' gestation or later. Pregnancy outcomes were compared between donor oocyte (IVF-OD), IVF using autologous oocytes (IVF-A) and naturally conceived pregnancies. A multivariate logistic regression was used to evaluate the association between the mode of conception and gestational hypertensive disorders. Results: The final analysis included 159, 68 and 73 patients in the IVF-OD, IVF-A and natural conception groups, respectively. The rate of gestational hypertensive disorders was significantly higher among those who conceived by IVF compared with those who conceived naturally but did not differ between the two IVF groups (27.0% for IVF-OD, 19.1% for IVF-A, P = 0.204; 5.5% for natural conception, P < 0.001 and P = 0.013 compared with IVF-OD and IVF-A, respectively). The results remained similar in a multivariate logistic regression analysis. The rate of Caesarean deliveries was significantly higher in the IVF-OD and IVF-A groups compared with the natural conception group (83.6%, 70.6% and 37.0%, respectively, P < 0.001), but other pregnancy outcomes did not differ between the groups. Conclusions: IVF pregnancies in the late fifth decade of life were associated with significantly higher rates of gestational hypertensive disorders compared with naturally conceived pregnancies. No difference existed between the two IVF groups. These results may highlight the impact of IVF itself on gestational hypertensive disorders at very advanced maternal age.
Article
Cardiovascular function is impaired and preeclampsia risk elevated in women conceiving by in vitro fertilization (IVF) in the absence of a corpus luteum (CL). Here, we report the serial evaluation of hormones and other circulating factors in women who conceived with (or without) IVF. After a pre-pregnancy baseline, the study participants (n=19-24/cohort) were evaluated six times during pregnancy, and once postpartum (~1.6 yr). IVF pregnancies were stratified by protocol and CL number, i.e., ovarian stimulation (>1 CL) or hypothalamic-pituitary suppression (0 CL) vs spontaneous conceptions (1 CL). Results: (1) relaxin was undetectable throughout pregnancy (including late gestation) in the 0 CL cohort, but markedly elevated in ~50% of women in the >1 CL cohort; (2) progesterone, plasma renin activity, and aldosterone transiently surged at 5-6 gestational weeks in the >1 CL group; (3) soluble vascular endothelial growth factor-1 (sFLT-1) abruptly increased between 5-6 and 7-9 gestational weeks in all 3 participant cohorts producing a marked elevation in sFLT-1/PLGF (placental growth factor) ratio exceeding any other time-point during pregnancy; (4) sFLT-1 was higher throughout most of gestation in both IVF cohorts with or without abnormal obstetrical outcomes; (5) during pregnancy, C-reactive protein (CRP) increased in 0 and 1 CL, but not >1 CL cohorts; and (6) plasma protein, but not hemoglobin was lower in the >1 CL group throughout gestation. The findings highlight that, when compared to spontaneously conceived pregnancy, the maternal milieu of IVF pregnancy is not physiologic, and the specific perturbations vary according to IVF protocol and CL status.
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The largest series of normal singleton placental weights was collected in the Collaborative Perinatal Study between the years 1959 and 1966 but values for normal twin placental weights were not published. In our study we examined 787 singleton and 514 twin normal placentas. Placentas with associated conditions known to affect the weights of placentas were excluded. After establishing the normal values for singleton and twin placental weights, we concluded that weight gain of twin placentas appears to accelerate between 24 and 36 weeks but reaches a plateau after 37 weeks, whereas singleton placentas appear to gain weight more uniformly throughout gestation. The mean values of twin placental weights for each gestational age are less than double those of singleton placental weights for the same duration of gestation. Our singleton and twin placentas are heavier than those from previously published data and may reflect a generational or nutritional change over the 30 years since the original numbers were compiled.
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The Placental Pathology Practice Guideline Development Task Force, a multidisciplinary group, has prepared this guideline to assist those involved with placental examination. It provides recommendations related to indications and methods for placental examination as well as sample worksheets. An algorithm for the handling of placentas summarizes the recommendations of the guideline. A summary of specific findings of placental examination together with their pathogenesis and clinical associations is also provided. Recommendations related to reporting with sample reporting formats are included. The guideline is intended as an educational tool, and its use should be guided by the individual circumstances and care setting of specific cases.
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The obstetric and perinatal outcome in 51 oocyte donation pregnancies (61 infants) was compared with that of a control group of standard in-vitro fertilization (IVF) patients (97 pregnancies, 126 infants). The oocyte recipients (mean ± SD age 33.5 ± 4.7 years) included 39 women with ovarian failure and 12 women with functioning ovaries. In oocyte recipients, first trimester bleeding (53 %) occurred significantly more often than in IVF mothers (31%, P < 0.01). pregnancy-induced hypertension was observed in 31% of oocyte recipients compared with 14% in IVF mothers (P < 0.05). There was no difference in the duration of pregnancies or in the preterm delivery rate between the two groups. When restricting analysis to singleton pregnancies, 63 % of oocyte recipients were hospitalized in the antenatal period compared with 29% in the IVF group (P < 0.001). The Caesarean section rate was 57 % in the oocyte donation group and 37 % in the IVF group (P < 0.05). Birthweight in singleton pregnancies was similar in both groups. The perinatal mortality rate was 3.3% in the oocyte donation group and 0% in the IVF group. In conclusion, oocyte donation pregnancies are associated with an increased risk compared with IVF pregnancies, but the complications are usually manageable and most oocyte recipients experience a good pregnancy outcome.
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The health, growth and development of a cohort of children (n = 59) aged 6 months to 4 years and born after oocyte donation (OD) was compared with that from a group of children born after in-vitro fertilization (IVF) (n = 126). The study was performed by questionnaire, and the response rate was 100% in the OD group and 95% in the IVF group. All OD children were healthy. Three IVF children had a neurological disorder. Surgical intervention had been carried out in 8% of the OD and 13% of the IVF children. Height and weight development were normal, and eating and sleeping disorders were uncommon in both groups of children. The IVF mothers more often expressed concern about the child's behaviour than did the OD mothers. Thirty-eight percent of the OD parents and 60% of the IVF parents intended to tell the child about the nature of its conception (P < 0.01). Although oocyte recipients appear to have more complications during their pregnancies than conventional IVF patients, the general health status of OD children aged <5 years is at least as good as that of IVF children. Growth and development in both groups of children is similar to that of the general population.
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The occurrence of twins, triplets, and other multiple births increased significantly between 1970 and 2000 in the United States and other industrialized countries. The number of triplet placentas submitted for examination as pathologic specimens has also markedly increased, but no reference values are published for triplet weights. We examined 196 normal triplet placentas. Specimens with associated conditions known to affect the weights of the placentas were excluded. The gestational ages ranged between 20 and 38 weeks. Mean weights for different gestational ages are summarized as follows: 253 g for 20 weeks, 319 g for 22 weeks, 406 g for 24 weeks, 509 g for 26 weeks, 621 g for 28 weeks, 738 g for 30 weeks, 855 g for 32 weeks, 965 g for 34 weeks, 1,065 g for 36 weeks, and 1,147 g for 38 weeks. Weight gain of triplet placentas appears to parallel that of twin placentas. The mean values of placental weights for triplets at each gestational age are less than triple those of singleton weights for the same duration of gestation. The placental weights in multiple gestations do not increase proportionately with the number of fetuses.
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The human placenta represents an abundant; easily accessible and unlimited study material (at birth a human placenta provides about 500 g of trophoblast). Cytotrophoblastic cells (CTB) are one constituent of the human placenta and represent epithelial cells with fascinating properties: They are able to fuse to form syncytia, can behave like immotile polarized epithelial cells, can phenocopy stromal fibroblasts or endothelial cells or undergo a mesenchymal-like transformation that converts them into non proliferative and highly invasive cells. Like a chameleon, CTB are thus able to adapt to their immediate environment by phenocopying their neighbor cells. This review describes the different routes that CTB follow during their differentiation pathways, the regulation of these at the molecular level, it gives also an overview of the pathologies associated with faulty pathways and describes the usual phenotypic markers used to identify the different CTB subsets. This review is intended to stimulate investigators not acquainted with the field of placental biology to use CTB as a model to study important biological functions in vitro, such as cell fusion, cell invasion and cell transformation.
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Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.
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The placenta and fetus present a substantial challenge to the maternal immune system (Lu et al. 1991). Vigorous local immune responses can potentially activate maternal anti-fetal allograft immunity but a less than adequate local immune response would allow pathogens to enter the placenta and gain access to an immature fetal immune system that is ill-prepared to respond to them. Clearly, the balance between reactivity and suppression is most sorely tested when strong antigens such as microorganisms, alloantigens, novel placental antigens, or maternal autoantigens are expressed in the placental environment and become targets for maternal immunity. Irrespective of their etiology, the resulting immune responses can lead to adverse outcomes such as intrauterine fetal demise, premature delivery, fetal growth restriction, and organ-specific damage to the developing conceptus.
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Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology included massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alphafetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.
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Acute atherosis is a maternal vascular lesion observed regularly in cases of pre-eclampsia and idiopathic intrauterine growth retardation. This vasculopathy is characterized by fibrinoid necrosis of the vessel wall, an accumulation of lipid-laden macrophages, and a mononuclear perivascular infiltrate. Similar vascular lesions are seen in the decidual vessels of patients with autoimmune diseases, and in renal, cardiac and hepatic homograft rejection. Immunohistochemical studies often reveal extensive vascular deposition of IgM and complement in acute atherosis-like lesions. Granular deposition of immunoglobulins and complement within the vessel walls and mononuclear perivascular infiltrate may be a histopathological hallmark of a maternal immunological aggression against fetal tissues.
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Oocyte and embryo donation has become increasingly common over the past 10 years. Today, it is successfully used to treat women with a variety of disorders, including ovarian failure, avoidance of genetic disease transmission, declining ovarian function, poor oocyte quality following conventional assisted reproduction, and age-related infertility. Success rates do not appear to vary with the recipient's age or diagnosis, with live birth rates in the 25-35% range. Oocyte and embryo donation represent the most efficacious method of assisted reproduction.
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A total of 199 patients participated in the oocyte donation programme in 336 replacement cycles in whom 69 clinical pregnancies were achieved, of which 53 reached term and delivery. Data concerning the evolution and outcome of pregnancies were retrieved in 52 cases, which involved 39 women with ovarian failure and 18 with functional ovaries. The most frequent complications of pregnancy were uterine bleeding in the first trimester in 18 cases (34.6%), hypertension in 17 (32.7%) and intra-uterine growth retardation (IUGR: 11.5%). These complications were more prominent in twin pregnancies. The Caesarean section rate was 63.5% and a high percentage of elective sections (54.5%) was observed. Of singleton pregnancies, 54.6% had a birth weight of > 3000 g at full term (> 37 weeks), while 62.5% of twins weighed between 2000 and 3000 g. One intra-uterine death occurred, so that the perinatal mortality was 1.7% and one newborn was operated on for stenosis of the pulmonary artery, while the incidence of premature labour was low (1.9%). A comparison of complications between pregnancies associated with ovarian failure and with functional ovaries revealed a higher frequency of bleeding in the first trimester (38.2% and 27.8% respectively) and of hypertension (38.2% and 22.2% respectively) in those with ovarian failure, although the differences were not statistically significant. In conclusion, women who become pregnant after oocyte donation and especially those with ovarian failure should be considered as high-risk obstetric patients.
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To determine whether maternal floor infarction can be diagnosed prenatally. We reviewed the charts of 13 patients with maternal floor infarction confirmed histopathologically to determine the frequency of increased placental echogenicity, fetal growth restriction (FGR), and oligohydramnios. Subsequently, we applied these criteria prospectively to diagnose maternal floor infarction in three cases. Twelve of the 13 pregnancies reviewed retrospectively resulted in small for gestational age infants, of which eight were stillbirths. Fetal growth restriction and oligohydramnios were evident on ultrasound in five pregnancies and a placental abnormality was noted in four; two patients exhibited this complete triad of sonographic abnormalities. Three patients were identified prospectively with maternal floor infarction based on sonographic findings and electively delivered live preterm infants. Maternal floor infarction is a placental condition with profound risk for FGR and stillbirth. Antenatal diagnosis may improve the perinatal outcome with this condition.
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This study tested whether concordance could be achieved for abnormal inflammation in the basal decidua of placental specimens among 6 pathologists experienced in placental pathology. Thirty microscope slides were evaluated by the pathologists for chronic deciduitis. They also scored the severity and extent of inflammation and the presence of plasma cells. No definition of chronic deciduitis was provided. Concordance (5/6 or 6/6 agreement) was achieved in 23 cases (76%). Spearman's rank correlation showed that the diagnosis of chronic deciduitis was almost identical to the assessment of the severity of the inflammation. A regression analysis showed that the perception of severity (and hence chronic deciduitis) was influenced by the other 2 variables, extent and plasma cells. The results were shared with the pathologists, and 25 cases (excluding those with previous 6/6 consensus) were reevaluated. Concordance was now achieved in the 83% of those remaining cases. Using a threshold based on the severity and the extent of lymphocytes, and the presence of plasma cells, pathologists are able to diagnose chronic deciduitis with sufficient concordance to be of value in clinical correlation studies.
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To determine whether preeclampsia is associated with an increase in placental apoptosis and differential expression of mediators of apoptosis. Placental samples from 31 preeclamptic women and 31 normotensive controls were analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Expression of Fas, Fas ligand, Bcl-2, and Bax was assessed using immunohistochemistry. The median percent apoptotic nuclei was significantly higher for the study group than for the controls (0.49 versus 0.19; P =.001), as was the median percent apoptotic nuclei in the trophoblast nuclei (0.33 versus 0.09; P <.01). Fas ligand expression was significantly less and Fas expression significantly greater in the villus trophoblast among the study subjects compared with controls. There was no difference in the expression of Bax or Bcl-2 between groups. Placental apoptosis and altered expression of Fas and Fas ligand in trophoblast might influence pathogenesis or sequelae of preeclampsia.
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Chronic (histiocytic) intervillositis (CHIV), defined for the purposes of this study as diffuse histiocytic infiltration of the intervillous space without villitis, is an idiopathic lesion seen in the chorionic sacs of some spontaneous abortion specimens and placentas. In this retrospective study, we evaluated all patients diagnosed with CHIV from 2 hospitals between 1993 and 2000, plus 1 additional patient from 1977. Histopathology, phenotype of the leukocytic infiltrate, perinatal outcome, and other associated clinical features were assessed by review of clinical records and all available pathology specimens plus immunohistochemical staining. CHIV was found in 31 of 45 specimens examined from 21 patients (23 of 31 first trimester, 3 of 5 second trimester, and 5 of 9 third trimester). Recurrence rate was 67% for patients with more than one specimen reviewed. Overall perinatal mortality rate was 77%, and only 18% of pregnancies reached 37 weeks. Eight of 19 patients with 3 or more pregnancies had recurrent spontaneous abortion (RSA); 5 with primary RSA (> or = 3 consecutive spontaneous abortions (SAB) with no living children) and 3 with secondary RSA (> or = 3 consecutive SAB with 1 or more living children). Severe intrauterine growth restriction was seen in 5 of 8 second- and third-trimester placentas with CHIV. Patients were generally not of advanced maternal age (mean, 29.8 +/- 6.2 years), and there was no obvious racial predisposition. Autoimmune or allergic phenomena were identified in 11 patients. Immunohistochemical staining of the intervillous infiltrate showed a near uniform population of monocyte-macrophages at varying stages of maturity and activation: more than 90% CD45Rb and CD68 positive, 30% to 40% MAC387 positive, less than 5% CD3 positive, and CD1a, CD20, CD30, and CD56 negative. We conclude that CHIV is an uncommon but important cause of recurrent spontaneous abortion and, in some cases, loss at later gestational ages. HUM PATHOL 31:1389-1396.
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This study was undertaken to determine whether preeclampsia and intrauterine growth retardation are associated with an increase in placental apoptosis. Tissue specimens from 7 normal term placentas and each of 7 term placentas complicated by severe preeclampsia or intrauterine growth retardation were analyzed. Fas antigen and Bcl-2 protein expression were examined by the avidin/biotin immunoperoxidase method, whereas apoptosis was assessed by the terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) method and transmission electron microscopy. Fas antigen was immunolocalized in syncytiotrophoblasts in all placentas examined. No changes in the intensity of Fas antigen immunostaining in syncytiotrophoblasts were apparent among those placentas. Bcl-2 protein was abundantly immunolocalized in syncytiotrophoblasts in normal term placentas, but least abundant in term placentas complicated by severe preeclampsia or intrauterine growth retardation. Apoptosis was apparent in the nuclei of both cytotrophoblasts and syncytiotrophoblasts. The apoptosis positive rate of syncytiotrophoblast nuclei in severe preeclamptic and intrauterine growth retardation term placentas was significantly higher than that in normal term placentas (severe preeclampsia, P <.001; intrauterine growth retardation, P <.01). Transmission electron microscopy revealed the appearance of apoptotic nuclei in trophoblasts in severe preeclamptic term placenta. Decreased expression of Bcl-2 protein in syncytiotrophoblasts in severe preeclamptic and intrauterine growth retardation placentas may result in the increase in apoptosis in syncytiotrophoblasts in those placentas.
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Maternal floor infarction (MFI) is a poorly understood placental lesion reportedly associated with intrauterine growth restriction (IUGR) and recurrence. In this study of MFI and the related placental disorder, massive perivillous fibrin deposition (MFD), semiquantitative histologic criteria for these diagnoses are defined and rates of IUGR and recurrence are assessed. Pathologic slides of 80 placentas diagnosed as MFI or MFD at the Brigham and Women's Hospital (1989-99) were reviewed and reclassified as classic MFI, transmural MFD, borderline MFD, or neither MFI or MFD. The prevalence of IUGR was determined, and placental slides from additional pregnancies were reviewed to evaluate recurrence. Among 25 cases originally diagnosed as MFI, 5 (20%) were reclassified by study criteria as classic MFI, 9 (36%) as transmural or borderline MFD, and 11 (44%) as neither lesion. Among 55 cases originally diagnosed as MFD, 27 (49%) were reclassified as transmural or borderline MFD, 4 (7%) as classic MFI, and 24 (44%) as neither lesion. IUGR was identified in no case with classic MFI, in 31% of cases with transmural or borderline MFD (P = 0.02), and in 11% of cases with neither lesion. Recurrence was documented in 1 of 7 (14%) second- or third-trimester placentas. Possible recurrence was suggested in 3 of 6 (50%) first-trimester spontaneous abortion specimens. Classification of intraplacental fibrin is subjective and problematic; almost half of potential cases of MFI or MFD did not fulfill our study's diagnostic criteria. MFD may be more common and more strongly associated with IUGR than classic MFI. Recurrence of these lesions appears to be infrequent among second- and third-trimester placentas, but may be relatively common in first-trimester spontaneous abortions.
Article
Preliminary observations by a single pathologist at our institution revealed a 75% incidence of villitis of unexplained etiology in ovum donor in vitro fertilization pregnancies. Because the incidence of villitis of unexplained etiology in the general population is approximately 10%, we conducted a controlled study to compare the incidence of villitis of unexplained etiology in ovum donor in vitro fertilization pregnancies to that in in vitro fertilization pregnancies that do not use donated ova. Placental specimens of ovum donor in vitro fertilization pregnancies were matched randomly with pregnancies that resulted from both fresh and frozen/thawed native oocyte in vitro fertilization from March 5, 1995, to October 10, 2001, and examined in a blinded fashion by a single pathologist (D. J. R.) for villitis of unexplained cause. The incidence of villitis of unexplained etiology was analyzed in 27 patients who underwent ovum donor in vitro fertilization versus 37 patients who underwent native oocyte in vitro fertilization. Villitis of unexplained cause occurred in 22.2% of ovum donor in vitro fertilization pregnancies, 10.8% of native oocyte in vitro fertilization pregnancies (fresh and frozen/thawed combined), and 14.3% of frozen/thawed cycles (P=.21). Although the incidence was not statistically different than in in vitro fertilization that used native maternal oocytes, there was a 2-fold increase in villitis of unexplained cause in the ovum donor in vitro fertilization placentas, which suggests that immune-related disorders may be increased in ovum donor pregnancies.
Article
Placental inflammatory disorders represent a diverse and important category of pathological processes leading to fetal and neonatal morbidity and mortality. These processes can be divided into two broad subcategories, those caused by micro-organisms and those caused by host immune responses to non-replicating antigens. The mechanisms by which these inflammatory processes cause death and disability are diverse and can be separated into four distinct classes: placental damage with loss of function, induction of premature labour and subsequent preterm birth, release of inflammatory mediators leading to fetal organ damage and transplacental infection of the fetus. Each specific inflammatory process can be modulated by properties of the specific organism, the route and timing of infection and variations in the host's genetic background and immune responsiveness. All of these factors combine to produce specific patterns of placental pathology that can be used to guide treatment, predict complications and explain adverse outcome.
Article
Two standardized gross sampling protocols were compared with the intention of maximizing the histologic detection rate of atherosis in at-risk (i.e., preeclamptic) placentas. The first, 4-block, protocol was designed to be broadly representative of good current practice (central, edge, en face shave, and membrane roll blocks). A second, 5-block, protocol incorporated all of protocol 1 with the addition of a block composed of multiple flat membrane leaves stacked and sectioned 5 times at 200-mum intervals. Data were available on the first protocol from 80 consecutive accessioned cases of singleton preeclamptic placentas and on the second protocol from 40 cases. Criteria for diagnosis for atherosis were relatively rigorous and excluded "burnt-out" fibrinoid lesions in which foam cells were not positively identified. With the first protocol, atherosis was detected in 30 of 80 (37.5%) of placentas studied. With the second protocol, atherosis was detected in 25 of 40 (62.5%) of placentas studied. This increase was related to a high detection rate of 50% in the flat membrane stack block. Evaluation of the more traditional forms of block produced atherosis detection rates of 2.5% for central full-thickness blocks, 14% for edge blocks, 10% for en face shave blocks, and 25% for membrane rolls. The flat membrane stack was found to be the single most sensitive block for detection of atherosis. When used in conjunction with traditional blocking techniques, it offers significantly increased reliability for detection of atherosis in placentas when maternal vascular compromise is suspected.