Does embryo quality at transfer affect obstetric outcomes and placental findings?

STUDY QUESTION: Do obstetric outcomes and placental findings in pregnancies conceived with IVF vary according to embryo quality? SUMMARY ANSWER: Pregnancies following the transfer of lower-quality embryos were associated with a higher rate of low-lying placentas and several adverse placental lesions. WHAT IS KNOWN ALREADY: A few studies have shown reduced pregnancy and live births rates with poor-quality embryo transfer, yet with comparable obstetric outcomes. None of these studies included placental analysis. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 641 deliveries of IVF attained pregnancies between 2009 and 2017 was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: Live singleton births after IVF with a single blastocyst transfer at a university-affiliated tertiary hospital were included. Excluded were cycles of oocyte recipients and IVM. We compared pregnancies following the transfer of a poor-quality blastocyst (poor-quality group) or a good-quality blastocyst (controls, good-quality group). During the study period, all placentas from complicated and uncomplicated pregnancies were sent to pathology. Primary outcomes were placental findings, including anatomic, inflammatory, vascular malperfusion, and villous maturation lesions, categorized according to the Amsterdam Placental Workshop Group Consensus. Secondary outcomes included obstetric and perinatal outcomes, adjusted for diminished ovarian reserve, fresh versus frozen transfer, and neonatal gender (as indicated by univariable analysis). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 132 deliveries in the poor-quality group were compared to 509 controls. A diagnosis of diminished ovarian reserve was more common in the poor-quality group than in the control group (14.3% versus 5.5%, respectively, P < 0.001) and more pregnancies in the poor-quality group were following frozen embryo transfer. After adjustment for confounders, poor-quality embryos were associated with a higher rate of low-lying placentas [adjusted odds ratio (aOR) 2.35, 95% CI 1.02-5.41, P = 0.04] and placentas with a higher rate of villitis of unknown etiology (aOR 2.97, 95% CI 1.17-6.66, P = 0.02), distal villous hypoplasia (aOR 3.78, 95% CI 1.20-11.38, P = 0.02), intervillous thrombosis (aOR 2.41, 95% CI 1.39-4.16, P = 0.001), multiple maternal malperfusion lesions (aOR 1.59, 95% CI 1.06-2.37, P = 0.02), and parenchymal calcifications (aOR 2.19, 95% CI 1.07-4.46, P = 0.03). LIMITATIONS, REASONS FOR CAUTION: The study is limited by its retrospective design and the utilization of two grading systems during the study period. In addition, the sample size was limited to detect differences in outcomes of rarer occurrences. WIDER IMPLICATIONS OF THE FINDINGS: The placental lesions demonstrated in our study imply an altered immunological response to the implantation of poor-quality embryos. Yet, these findings were not associated with additional adverse obstetric outcomes and merit reaffirmation in a larger cohort. Overall, the clinical findings of our study are reassuring to clinicians and patients for whom the transfer of a poor-quality embryo is necessary. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Pregnancy complications and placental histology following embryo transfer with a thinner endometrium.

STUDY QUESTION: Are deliveries following IVF with a thinner endometrium associated with adverse perinatal outcomes and placental findings? SUMMARY ANSWER: Live births following IVF with a thinner endometrium are associated with an increased rate of placental-mediated obstetric complications and lower birthweight, while the placentas are notable for gross anatomical and histological malperfusion lesions. WHAT IS KNOWN ALREADY: Past studies have noted a higher rate of adverse outcomes on deliveries following IVF with a thinner endometrium, mainly placental-associated complications. However, no study to date has investigated placental histopathology in such cases. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study of 1057 deliveries following IVF, between 2009 and 2017. All placentas were sent to pathology irrelevant of pregnancy complication status, per protocol at our institution. PARTICIPANTS/MATERIALS, SETTING, METHODS: Live singleton births from a tertiary university hospital after IVF were compared between patients for whom embryo transfer was performed with an endometrium <9 mm (thinner endometrium group) and patients with an endometrium ≥9 mm (control group). Placental pathologic findings were categorized according to the Amsterdam Placental Workshop Group Consensus. Outcomes were placental findings, including anatomic, inflammatory, vascular malperfusion and villous maturation lesions, as well as obstetric and perinatal outcomes. Continuous and categorical variables were compared as appropriate, and multivariate regression and linear analyses were employed to control for confounders. MAIN RESULTS AND THE ROLE OF CHANCE: A total 292 cases in the thinner endometrium group, and 765 in the control group were compared. Maternal demographics were non-significant between the groups, except for main fertility indication was more commonly diminished reserve in patients with a thinner endometrium and less commonly male factor, P = 0.003. Higher rates of fresh transfers were noted in the control group, while the thinner endometrium group was notable for higher rates of blastocyte transfers. After adjustment for confounders, deliveries in the thinner endometrium group were associated with an overall higher rate of main placental-mediated complications, 22.9% versus 15.2%, P = 0.003, and significantly lower birthweight, ß -100.76 g (-184.4-(-17.0)). Placentas in the thinner endometrium group were notable for reduced thickness and a higher rate of bilobated placentas. Placental histology in the thinner endometrium group demonstrated a higher rate of maternal malperfusion lesions. LIMITATIONS, REASONS FOR CAUTION: The study was limited by its retrospective design and lack of data regarding prior uterine surgery. In addition, sample size was limited for detection of differences in outcomes of rarer occurrence and for analysis as per a stricter definition of thin endometrium. WIDER IMPLICATIONS OF THE FINDINGS: Excess obstetric risks should be taken into consideration while planning an embryo transfer with a thinner endometrium. Further studies are needed to assess the yield of cycle cancellation and the effect of potential preventive measures such as Micropirin treatment. STUDY FUNDING/COMPETING INTEREST(S): No funding was used and the authors report no conflicting interests. TRIAL REGISTRATION NUMBER: N/A.

The effect of endometriosis on placental histopathology and perinatal outcome in singleton live births resulting from IVF.

RESEARCH QUESTION: Does endometriosis have an effect on the placental histopathology pattern and perinatal outcome in singleton live births resulting from IVF treatment? DESIGN: Retrospective cohort study evaluating the data on all live births following IVF treatment between 2009 and 2017 at one university-affiliated tertiary hospital. All patients had placentas sent for full gross and histopathology assessment, irrespective of complication status or delivery mode. The primary outcomes of the study included anatomical, inflammation, vascular malperfusion and villous maturation placental disorders. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate logistic model was used to adjust the results for confounding factors potentially associated with significant placental characteristics. RESULTS: A total of 1057 live births were included in the final analysis and were allocated to the group of women with endometriosis (n = 75) and those without (n = 982). After adjustment for confounding factors, endometriosis was found to be significantly associated with acute chorioamnionitis with moderate to severe maternal (odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.1-4.6) and fetal (OR 4.9, 95% CI 1.8-13.1) inflammatory response, placenta previa (OR 3.1, 95% CI 1.2-7.8), subchorionic fibrin deposition (OR 3.4, 95% CI 1.2-9.1), intervillous thrombosis (OR 3.4, 95% CI 1.5-8.1), and fetal vascular malperfusion (OR 5.1, 95% CI 1.4-18.1), as well as with preterm birth (OR 2.5, 95% CI 1.4-4.7). CONCLUSIONS: Endometriosis has a significant impact on the placental histopathology and is associated with a higher incidence of preterm birth.

Placental histology following assisted hatching in fresh transfer cycles.

PURPOSE: To assess placental histological findings following assisted hatching in fresh transfer in vitro fertilization cycles. METHODS: Evaluation of a historic cohort of live singleton deliveries after fresh embryo transfer (ET) at a single university medical center between 2009 and 2017. We compared perinatal outcomes and placental histology in cases where assisted hatching was performed prior to ET (AH group) and cases with no AH (no AH group). RESULTS: Overall, 166 deliveries following AH were compared to 494 deliveries with no AH. Patients' demographics were similar between the groups. Median antral follicle count was significantly lower in the AH group, median 11 (range 1-50) vs. 16 (range 1-80), p < 0.001, and the primary indication for infertility treatment significantly more often diminished ovarian reserve (p < 0.001). Cycle characteristics in the AH group included a higher gonadotropin dose employed, and a lower rate of single and blastocyte transfer. Pregnancies following AH were associated with less low-lying placentas, 0.6% vs. 6.2%, p = 0.001, and comparable for other perinatal outcomes. After adjusting for confounders, the rate of bilobated placentas was higher following AH, aOR 7.10, 95% CI 1.50-33.51. The rate of perivillous depositions was higher with AH, aOR, 95% CI 3.18, 1.46-6.93, and the rate of chorangiosis lower in this group, aOR, 95% CI 0.32, 0.11-0.93. The overall rate of vascular lesions was similar between the groups. CONCLUSION: Pregnancies following AH are notable for a lower rate of placenta previa, yet a higher rate of bilobated placentas and perivillous depositions and less chorangiosis, warranting further investigation.

An Unconventional Regimen of Carboplatin and Paclitaxel in Metastatic Colorectal Carcinosarcoma: A Case Report and Review of Literature.

Colorectal carcinosarcoma is an exceedingly rare subtype of colorectal cancer that displays the histological and molecular features of both mesenchymal and epithelial tumors. Due to its rarity, there are no guidelines regarding the systemic treatment of this disease. This report describes a case of a 76-year-old woman with colorectal carcinosarcoma with extensive metastatic burden treated with carboplatin and paclitaxel. After four cycles of chemotherapy, the patient had an excellent clinical and radiographical response to treatment. To the best of our knowledge, this is the first report addressing the use of carboplatin and paclitaxel in this disease. We reviewed seven published case reports of metastatic colorectal carcinosarcoma where various systemic treatments were offered. Remarkably, there are no previously published reports where even a partial response was noted, which underscores the aggressiveness of this disease. While further studies are required to validate our experience and assess long-term outcomes, this case suggests an alternative treatment regimen for metastatic colorectal carcinosarcoma.

Maternal hypothyroidism and its effect on placental histopathology in singleton live births resulting from in vitro fertilization treatment.

We aimed to examine the impact of maternal hypothyroidism on placental pathology and perinatal outcomes in singleton live births resulting from IVF, using medical records of IVF births between 2009 and 2017 at a tertiary hospital. The primary outcomes included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. Secondary outcomes included foetal, maternal, perinatal, and delivery complications. There were 1,057 live births, of which 103 (9.7%) and 954 (90.3%) were in the study and control groups, respectively. Patients in the study group were more likely to have diabetes mellitus, polycystic ovarian syndrome, gestational diabetes mellitus, and non-reassuring foetal heart rate (NRFHR) tracing during delivery. After adjustment for potential confounding factors, hypothyroidism was significantly associated with the bilobed placenta (aOR 4.1; 95% CI 1.2-14.3), retroplacental haematoma (aOR 2.4; 95% CI 1.2-4.9), decidual arteriopathy (aOR 2.0; 95% CI 1.2-4.1) and subchorionic thrombi (aOR 2.4; 95% CI 1.3-5.0). Additionally, there was a statistically significant relationship with NRFHR tracing. The incidence of acute chorioamnionitis and severe foetal inflammatory response was higher in the study group. In conclusion, the placental histopathology patterns of singleton IVF live births show that maternal hypothyroidism has a significant impact on adverse perinatal outcomes.

Diminished ovarian reserve is a risk factor for preeclampsia and placental malperfusion lesions.

OBJECTIVE: To assess obstetric outcomes and placental findings in pregnancies attained by in vitro fertilization (IVF) in patients with diminished ovarian reserve (DOR). DESIGN: Retrospective cohort study. SETTING: University-affiliated tertiary hospital. INTERVENTIONS: DOR, defined as an antral follicle count (AFC) of 6 or less (DOR group), compared with patients with no DOR and an antral count above 6 (control group). PATIENTS: Live singleton births after IVF between 2009 and 2017. MAIN OUTCOME MEASURES: Primary outcomes were placental findings, including anatomic, inflammatory, vascular malperfusion, and villous maturation lesions, as categorized according to the Amsterdam Placental Workshop Group Consensus. Secondary outcomes included obstetric and perinatal outcomes. RESULTS: A total of 110 deliveries of patients with DOR were compared with 772 controls. Maternal age was higher in the DOR group than in the control group (36.3 ± 4.4 years vs. 35.3 ± 4.1 years, P=.02). Patients with DOR were more likely to have a diagnosis of endometriosis (P=.02) and less likely to have a diagnosis of male factor (P<.001), ovulation disorder (P<.001), or tubal factor (P=.04), or a transfer of a blastocyte (P=.007). After adjustment for confounders, pregnancies in the DOR group were notable for a significantly higher rate of preeclampsia (8.1% vs. 2.7%, adjusted odds ratio: 3.05, 95% confidence interval: 1.33-6.97). On placental examination, DOR was associated with a higher rate of fetal vasculopathy (P=.01) and multiple fetal vascular malperfusion lesions (P=.03), and a lower rate of circummarginate insertion (P=.01) and intervillous thrombosis (P=.02). CONCLUSION: DOR, specifically defined as an AFC of 6 or less, is associated with a higher incidence of preeclampsia and multiple placental fetal vascular lesions.

The effect of higher estradiol levels during stimulation on pregnancy complications and placental histology.

INTRODUCTION: We aimed to assess obstetric outcomes and placental histology in stimulated in vitro fertilization (IVF) cycles with a high serum estradiol level. METHODS: This was a historic cohort of live singleton deliveries after IVF, at a single university affiliated medical center between 2009 and 2017. Included were pregnancies following controlled ovarian stimulation with fresh embryo transfer. Excluded were IVF cycles with oocyte recipients and with a diagnosis of diminished ovarian reserve. High estradiol was defined as peak value above the upper quartile for the cohort, corresponding to 8700 pg/mL. RESULTS: A total 147 deliveries in the higher estradiol group were compared to 427 deliveries in the control group. No differences were demonstrated in patient demographics and infertility workup, except for a significantly higher antral follicle count in the high estradiol group, 21.5 ± 13.1 vs. 17.3 ± 10.7 follicles, p < 0.001 and lower rate of single embryo transfer, 51.7% vs. 73.5%, p < 0.001. No differences were demonstrated between the groups in pregnancy and obstetric outcomes investigated, including gestational age, preterm delivery, preeclampsia, cesarean delivery, birthweight and low birth weight. Placental histological examination was notable for a higher rate of velamentous cord insertion in the higher estradiol group - 12.2% vs. 6.7%, p = 0.03, more so in a sub analysis of cases of very high estradiol - 15.7% vs. 7.3%, p = 0.02. DISCUSSION: Placental histology following IVF with high estradiol level was notable for a higher rate of velamentous cord insertion.

Pregnancy complications and placental histology in in vitro fertilization pregnancies with initial low serum ß-hCG levels.

OBJECTIVE: To assess perinatal outcomes and placental findings after in vitro fertilization (IVF) with an initial low serum ß-human chorionic gonadotropin (hCG). DESIGN: A retrospective cohort study. SETTING: University-affiliated tertiary hospital. INTERVENTION(S): Low serum ß-hCG after transfer, defined as the low 10th percentile for the cohort on day 16 embryo age (low ß-hCG group), compared with an initial serum ß-hCG at or above the low 10th percentile (control group). PATIENT(S): Live singleton births after IVF between 2009 and 2017. MAIN OUTCOME MEASURE(S): Primary outcomes were placental findings, including anatomic, inflammatory, vascular malperfusion, and villous maturation lesions, as categorized according to the Amsterdam Placental Workshop Group Consensus. Secondary outcomes included obstetric and perinatal outcomes. RESULT(S): The low 10th percentile of ß-hCG results corresponded to 149 mUI/mL. There were 103 cases in the low ß-hCG group, and 928 in the control group. Maternal demographics were similar between the groups, whereas blastocyte transfer was more common in the control group. Deliveries in the low ß-hCG group were associated with an increased rate of preterm births, 15.5% vs. 8.1%, which maintained significance after adjustment for confounders. Placentas in the low ß-hCG group were notable for a high rate of velamentous cord insertion, 19.4% vs. 7.7%, single umbilical artery 3.8% vs. 0.6%, and histological maternal vasculopathy, 10.6% vs. 4.8%. CONCLUSION: Live births after IVF with an initial low ß-hCG level are associated with a twofold increase in preterm births and placental gross and histological changes. It may thus be considered to observe such cases in a high-risk pregnancy setting.

Interobserver Reliability for Identifying Specific Patterns of Placental Injury as Defined by the Amsterdam Classification.

CONTEXT.­: Placental pathology is an essential tool for understanding neonatal illness. The recent Amsterdam international consensus has standardized criteria and terminology, providing harmonized data for research and clinical care. OBJECTIVE.­: To evaluate the interobserver reliability of these criteria between pathologists at different levels of experience using digitally scanned slides from placentas in a birth population including a large proportion of normal deliveries. DESIGN.­: This was a secondary analysis of selected placentas from a large case-control study of placental lesions associated with neonatal encephalopathy. Histologic slides from 80 placentas were digitally scanned and blindly evaluated by 6 pathologists. Interobserver reliability was assessed by positive and negative agreement, Fleiss κ, and interrater correlation coefficients. RESULTS.­: Overall agreement on the diagnosis, grading, and staging of acute chorioamnionitis and villitis of unknown etiology was moderate to good for all observers and good to excellent for a subset of 4 observers. Agreement on the diagnosis and subtyping of fetal vascular malperfusion was poor to fair for all observers and fair to moderate for the subset of 4 pathologists. Agreement on accelerated villous maturation was poor. CONCLUSIONS.­: This study critically evaluates interobserver reliability for lesions defined by the Amsterdam consensus using scanned images with a low frequency of pathologic lesions. Although reliability was good to excellent for inflammatory lesions, lower reliability for vascular lesions emphasizes the need to more explicitly define the specific histologic features and boundaries for these patterns.

Effect of embryo stage at transfer on placental histopathology features in singleton live births resulting from fresh embryo transfers.

OBJECTIVE: To evaluate the effect of embryo stage at transfer on placental histopathology and perinatal outcome in singleton live births resulting from fresh embryo transfers (ETs). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): The study population included all live births after fresh ETs during the period from 2009 to 2017. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcomes included anatomic, inflammatory, vascular malperfusion, and villous maturation placental features. Secondary outcomes included fetal, maternal, and perinatal complications. RESULT(S): A total of 677 live births were included in the final analysis and were allocated to the cleavage-stage (n = 252) and blastocyst (n = 425) ET groups. After the adjustment for confounding factors, the blastocyst group was found to be associated with a higher incidence of circummarginate membranes insertion (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.2-3.4), delayed villous maturation (OR 8.5, 95% CI 1.2-69.3), chorangiosis (OR 2.0, 95% CI 1.2-3.8), parenchymal calcifications (OR 10.6, 95% CI 1.4-80.2), and intrapartum nonreassuring fetal heart rate tracing (OR 2.4, 95% CI 1.3-4.5). Compared with cleavage-stage ETs, live births resulting from the blastocysts were associated with a lower incidence of velamentous cord insertion (OR 0.5, 95% CI 0.3-0.9), retroplacental hematoma (OR 0.3, 95% CI 0.1-0.8), subchorionic thrombi (OR 0.3, 95% CI 0.1-0.8), and avascular villi (OR 0.2, 95% CI 0.03-0.7). CONCLUSION(S): Live births resulting from fresh cleavage-stage and blastocyst ETs have different placental histopathology features, with a higher rate of intrapartum nonreassuring fetal heart rate tracing in the blastocyst group.

Modeling High-Grade Serous Ovarian Carcinoma Using a Combination of In Vivo Fallopian Tube Electroporation and CRISPR-Cas9-Mediated Genome Editing.

Ovarian cancer is the most lethal gynecologic cancer to date. High-grade serous ovarian carcinoma (HGSOC) accounts for most ovarian cancer cases, and it is most frequently diagnosed at advanced stages. Here, we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR-Cas9-mediated genome editing. Mutation of tumor suppressor genes associated with HGSOC in two different combinations (Brca1, Tp53, Pten with and without Lkb1) resulted in successfully generation of HGSOC, albeit with different latencies and pathophysiology. Implementing Cre lineage tracing in this system enabled visualization of peritoneal micrometastases in an immune-competent environment. In addition, these models displayed copy number alterations and phenotypes similar to human HGSOC. Because this strategy is flexible in selecting mutation combinations and targeting areas, it could prove highly useful for generating mouse models to advance the understanding and treatment of ovarian cancer. SIGNIFICANCE: This study unveils a new strategy to generate genetic mouse models of ovarian cancer with high flexibility in selecting mutation combinations and targeting areas.

The value of the "suspicious for urothelial carcinoma" cytology category: a correlative study of 4 years including 337 patients.

BACKGROUND: The terminology used in reporting urine cytology lacks uniformity and the significance of the "atypical" and "suspicious" categories is still not well established. This results in variable clinical follow-up and management of those cases. The authors sought to investigate the prognostic value of a diagnosis of "suspicious for high-grade urothelial carcinoma" (HGUCA). METHODS: All cases with a "suspicious" or "positive" cytological diagnosis spanning 4 years were included and correlated with the subsequent biopsies obtained within 6 months of urine collection. RESULTS: A total of 447 correlative events (57% positive and 43% suspicious) corresponding to 773 cytology specimens and 337 patients were included. The morphology of the "suspicious" cells was similar to what has recently been reported in the literature as "atypical urothelial cells, cannot exclude HGUCA." A "suspicious" diagnosis was more often rendered than a "positive" one in voided specimens (80% vs 65%, respectively). The mean interval between cytology and biopsy was 31 days. On follow-up, 92% of "suspicious" diagnoses (176 of 191 diagnoses) and 90% of "positive" diagnoses (230 of 256 diagnoses) were found to have a biopsy with a diagnosis of carcinoma (low grade or high grade). A diagnosis of HGUCA followed a "suspicious" and a "positive" diagnosis in 79% and 86% of cases, respectively. CONCLUSIONS: A "suspicious" diagnosis as defined in the current study warrants close investigations and repeat biopsy to rule out HGUCA. In addition, the findings of the current study raise the question of the need for quantitative criteria for diagnosing HGUCA on cytology.