Shallow Placentation: A Distinct Category of Placental Lesions

Objective Shallow placental implantation (SPI) features placental maldistribution of extravillous trophoblasts and includes excessive amount of extravillous trophoblasts, chorionic microcysts in the membranes and chorionic disc, and decidual clusters of multinucleate trophoblasts. The histological lesions were previously and individually reported in association with various clinical and placental abnormalities. This retrospective statistical analysis of a large placental database from high-risk pregnancy statistically compares placentas with and without a composite group of features of SPI. Study Design Twenty-four independent abnormal clinical and 44 other than SPI placental phenotypes were compared between 4,930 placentas without (group 1) and 1,283 placentas with one or more histological features of SPI (composite SPI group; group 2). Placentas were received for pathology examination at a discretion of obstetricians. Placental lesion terminology was consistent with the Amsterdam criteria, with addition of other lesions described more recently. Results Cases of group 2 featured statistically and significantly (p < 0.001after Bonferroni's correction) more common than group 1 on the following measures: gestational hypertension, preeclampsia, oligohydramnios, polyhydramnios, abnormal Dopplers, induction of labor, cesarean section, perinatal mortality, fetal growth restriction, stay in neonatal intensive care unit (NICU), congenital malformation, deep meconium penetration, intravillous hemorrhage, villous infarction, membrane laminar necrosis, fetal blood erythroblastosis, decidual arteriopathy (hypertrophic and atherosis), chronic hypoxic injury (uterine and postuterine), intervillous thrombus, segmental and global fetal vascular malperfusion, various umbilical cord abnormalities, and basal plate myometrial fibers. Conclusion SPI placentas were statistically and significantly associated with 48% abnormal independent clinical and 51% independent abnormal placental phenotypes such as acute and chronic hypoxic lesions, fetal vascular malperfusion, umbilical cord abnormalities, and basal plate myometrial fibers among others. Therefore, SPI should be regarded as a category of placental lesions related to maternal vascular malperfusion and the “Great Obstetrical Syndromes.” Key Points

P–406 Placental histopathology is different in specific subsets of ICSI singleton pregnancies with programmed cycles : a prospective study

Study question Does embryo vitrification or donor oocytes (DO) alter the histopathology of the placenta in ICSI singleton pregnancies with similar endometrial preparation? Summary answer Placentas from programmed cycles had significantly more immune/idiopathic-inflammation with vitrified-thawed embryos versus fresh transfer and significantly more maternal vascular-malperfusion(MVM) in DO versus autologous oocyte(AO) pregnancies. What is known already DO pregnancies and frozen embryo transfer(FET) pregnancies with programmed cycles are associated with hypertensive complications. As these complications are linked with abnormal placentation, comparing the placental histopathology in these pregnancies may point to a causative association. Studies of placental histopathology in DO in comparison to AO pregnancies show a dysregulated immune process and vasculopathy. The hormonal milieu during implantation remains an important confounder. Placental histopathology in fresh/ frozen cycles has recently shown variable results. To isolate the effect of embryo vitrification on placental histopathology, the donor oocyte model can provide valuable data, which till now is scarcely available. Study design, size, duration A prospective cohort study conducted in a tertiary center from 2018–2020. Placental histopathology, pregnancy-outcomes were studied in 116 ICSI singleton pregnancies≥28 weeks. Group1-Pregnancies with DO, by FET(n = 32) and freshET(n = 34) were compared to study the effect of embryo-vitrification. Group2-Pregnancies by DO FET(n = 32) were compared to AO FET(n = 50) to study the effect of DO. All patients had ICSI, cleavage embryo-transfer, programmed cycles and delivered at the same institute. The placentas were examined by pathologists (blinded to the ET type). Participants/materials, setting, methods 116 singleton pregnancies were followed for hypertensive disorders of pregnancy (HDP), preterm delivery(PTD&lt;37weeks) and low birth-weight (LBW&lt;2.5kg). Placentas were examined for cord mal-insertions Placental histopathology lesions were classified into 4 groups according to ‘Amsterdam criteria’ infectious-inflammatory, immune/ idiopathic-inflammatory, MVM, fetal vascular malperfusion (FVM). Chi-square and t-tests were used to compare outcomes across groups. Adjusted odds ratio were calculated using logistic regression. Statistical significance set at P &lt;.05, two-tailed. Main results and the role of chance No patient had a history of chronic hypertension/smoking. Group 1 Patients conceived by DO, with FET and freshET were comparable with regards to age (34.1 vs 36.4years, P=.07),BMI(26.7 vs 27.1 kg/m2,P=.6),nulliparity(81%vs82%,P=.9) HDP(25%vs29.4%,P=0.69),birth-weight(2.48 vs 2.47kg,P=.93) LBW(31.3%vs41.2%,P=.41)respectively PTD was significantly less in donor FET versus donor freshET (6.3%vs47.1%P=.0002) Placental weight and cord mal-insertions were comparable for FET vs freshET (466 vs 486gms P=.03 12.5%vs23.5% P=.25)respectively. Amongst the placental histopathology lesions, immune/ idiopathic-inflammatory lesions were significantly more in the FET vs freshET group (37.5% vs 11.8%,P=.02)The other lesions were comparable infectious-inflammatory(6.3%vs17.6%,P=.16), MVM(75%vs58.8%, P=.16),FVM(18.8%vs17.6%,P=.9) Group 2 Patients conceived by DO compared to AO by FET were significantly older and had a higher BMI (34.1vs31.7years,P=.02 ,26.7vs25.5 kg/m2,P=.002) respectively. Nulliparity was comparable(81%vs92%,P=.15) Birth weight was significantly less in DO vs AO(2.4vs2.7kg,P=.02) HDP and LBW were significantly more in DO vs AO(25%vs8% ,P=.03, 31.3%vs 8%,P=.007),respectively. PTD was comparable(6.3%vs8.0%,P=.77). Placental weight was significantly less in DO vs AO (466 vs 513gms,P=.03) cord mal-insertions were comparable(12.5% vs 24%,P=.2) The MVM lesions were significantly more in the DO group compared to AO(75% vs 40%,P=.002) The difference remained after adjusting for age/BMI/HDP (AOR 4.31;95% CI 1.24–14.8;P=.02). The rest of placental lesions were comparable in DO vs AO, infectious-inflammatory lesions(6.3%vs16%,P=.19) immune/idiopathic-inflammatory lesions(37.5%vs28%,P=.37) FVM(18.8% vs 12%,P=.4)respectively. Limitations, reasons for caution These findings are based on a small number of patients. The results observed need to be confirmed using a larger study sample. Wider implications of the findings: Placentas in pregnancies by embryo-vitrification, in a DO-model, had significantly more immune/idiopathic-inflammation, the cause/significance of this needs to be explored. Placentas in DO-pregnancies had significantly more MVM-lesions and increased risk of HDP, emphasizing the clinical/histopathological link of DO with HDP and the need for counselling/preventive strategies for HDP in DO-pregnancie. Trial registration number Not applicable

Placental Complement Activation in Fetal and Neonatal Alloimmune Thrombocytopenia: An Observational Study

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

658 An Audit of Frequency of Cancer Genetics Referral in Patients with a Family History of Colorectal Cancer

Introduction Guidelines on the management of hereditary colorectal cancers were updated in 2019. In this study, data from patients within the colonoscopy surveillance programme for hereditary cancer at York Teaching Hospitals Trust were analysed to assess category of risk and appropriateness of referrals to regional geneticists. Method After examination of electronic records and clinical notes, patients were assigned a risk category of average, moderate or high according to the Amsterdam criteria and latest BSG/ACPGBI/UKCGG guidelines. Patients were then assessed to see if a concurrent referral had been made to the regional cancer genetic services. Results There were 228 patients. 72(31.6%) patients were in the average, 81(35.5%) in the moderate and 41(18%) were in the high-risk category. 34 (14.9%) patients with insufficient data and/or assessments were in the indeterminate category. 18 of 72 (25%) patients with average risk were unnecessarily referred to the regional genetics team, while 5/41(12%) of high-risk patients were not. A large proportion of patients with insufficient data (19/34, 55.8%) were rightly or wrongly, referred to the regional genetics team. Conclusions Assessment of hereditary cancer risk is difficult in the absence of good quality information. Risk assessment may be improved with use of a dedicated family history questionnaire/template - this facilitates identification of high-risk patients that benefit most from referral to geneticists.

Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan

Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

A Novel Stop-Gain Mutation in MSH2 Gene Among a Persian Family Fulfilling Classic Amsterdam Criteria for Lynch Syndrome

Purpose Lynch syndrome is the most common hereditary cancer syndromes due to a germline mutation in one of the mismatch-repair (MMR) genes. It results in early-onset colorectal cancer (CRC) and other Lynch-associated cancers in an autosomal dominant pattern. In this article, a new pathogenic variant in a Persian family with familial CRCs and positive Amsterdam II criteria has been described. Methods IHC-MMRs was done on tissue sections from tumor and its adjacent healthy tissue of the proband. Microsatellite instability (MSI) testing was also performed on DNA extracted from tumor and healthy tissue using Promega kit. Next Generation Sequencing (NGS) was finally done on genomic DNA of the proband using a 12-gene-panel including MMR genes. Variant filtering and prioritization were done using bioinformatics tools. Co-segregation analysis was used to evaluate the explored pathogenic variant. Results The proband was a 38-year woman at-diagnosis affected with CRC located in the sigmoid colon. The family history of cancer was observed in three successive generations. IHC was absent for MSH2 and MSH6, and MSI-High was reported from MSI testing. NGS analysis explored a new stop gained codon mutation on the first exon of MSH2 gene as a substitution of A to G MSH2: c.364A > T which was pathogenic according to the variant interpretation guidelines of American College of Medical Genetics and Genomics. Conclusion Revealing of a more obvious molecular feature of Lynch-syndrome among Iranian populations could lead to identification of at-risk people for early care and prevention of cancer.

Identification and management of Lynch syndrome in the Middle East and North African countries: outcome of a survey in 12 countries

Background Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient’s prognosis. Recently, a network of physicians in Middle Eastern and North African (ME/NA) countries was established to improve the identification and management of LS families. The aim of the present survey was to evaluate current healthcare for families with LS in this region. Methods A questionnaire was developed that addressed the following issues: availability of clinical management guidelines for LS; attention paid to family history of cancer; availability of genetic services for identification and diagnosis of LS; and assessment of knowledge of LS surveillance. Members of the network and authors of recent papers on LS from ME/NA and neighbouring countries were invited to participate in the survey and complete the online questionnaire. Results A total of 55 individuals were invited and 19 respondents from twelve countries including Algeria, Azerbaijan, Cyprus, Egypt, Iran, Jordan, Kuwait, Lebanon, Morocco, Palestine, Tunisia, and Turkey completed the questionnaire. The results showed that family history of CRC is considered in less than half of the surveyed countries. Guidelines for the management of LS are available in three out of twelve countries. The identification and selection of families for genetic testing were based on clinical criteria (Amsterdam criteria II or Revised Bethesda criteria) in most countries, and only one country performed universal screening. In most of the surveyed countries genetic services were available in few hospitals or only in a research setting. However, surveillance of LS families was offered in the majority of countries and most frequently consisted of regular colonoscopy. Conclusion The identification and management of LS in ME/NA countries are suboptimal and as a result most LS families in the region remain undetected. Future efforts should focus on increasing awareness of LS amongst both the general population and doctors, and on the improvement of the infrastructure in these countries.