The impact of polycystic ovary syndrome on placental histopathology patterns in in-vitro fertilization singleton live births.

INTRODUCTION: Pregnant polycystic ovary syndrome (PCOS) patients are at increased risk for myriad obstetric complications, with the placenta thought to play a key role in their development. We aimed to evaluate placental histopathology patterns in placentas of women with PCOS who underwent in-vitro-fertilization (IVF). METHODS: This retrospective study utilized full gross and histopathologic assessment of placentas of all women who had IVF treatment and delivered at the Royal Victoria Hospital from 2009 to 2017, regardless of complications or mode of delivery. Pathologic findings included anatomic, inflammation, villous maturation, and vascular mal-perfusion features. Placentas of PCOS women were compared to those of ovulatory controls. Multivariate logistic regression was used to adjust results for confounding factors potentially associated with significant placental and perinatal characteristics. RESULTS: Women with PCOS (n = 47) were more likely to develop gestational diabetes mellitus compared to ovulatory controls (n = 1121) (38.3% vs. 9.8%, p < 0.001). Placentas from PCOS women were more likely circumvallate placentas (aOR 8.3, 95%CI 1.9-37.3) and more likely to have a hypercoiled umbilical cord (aOR 6.8 95%CI 1.3-36.8) and villitis of unknown etiology (aOR 6.1, 95%CI 1.5-25.6). There was an increased likelihood of chorangiosis (aOR 2.7, 95% CI 1.3-5.8), evidence of fetal vascular malperfusion based on one criteria (aOR 2.7, 95%CI 1.1-7.4), or more than one criteria (aOR 6.4, 95%CI 1.6-25.9), more nucleated fetal red blood cells (aOR 5.2, 95%CI 1.1-24.5), and a higher likelihood of chorangiomas (aOR 9.4, 95%CI 1.6-55.1) in placentas from PCOS women than in controls. DISCUSSION: IVF pregnancies' placental histopathological characteristics are significantly impacted by an underlying diagnosis of PCOS, including important anatomic changes and vascular placental abnormalities.

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.

The effect of oestrogen dose and duration in programmed frozen cycles on obstetric outcomes and placental findings.

RESEARCH QUESTION: Does programmed frozen embryo transfer (FET) with high-dose oestrogen affect obstetric outcomes and placental findings? DESIGN: A retrospective cohort of live singleton deliveries at a single institution between 2009 and 2017, including deliveries attained by IVF with programmed FET; oocyte recipients were excluded. High-dose oestrogen was defined as a daily dose >6 mg throughout treatment. All placentas were evaluated regardless of complication status and the Amsterdam classification was used to analyse findings. RESULTS: A total of 57 deliveries in the high-dose oestrogen group were compared with 274 controls. The high-dose oestrogen group displayed significantly longer duration of oestrogen treatment (18.8 ± 4.9 versus 13.3 ± 2.7 days, P < 0.001), total cumulative oestrogen dose (149.7 ± 46.1 versus 80.3 ± 16.8 mg, P < 0.001) and lower endometrial thickness (8.5 ± 1.4 versus 9.8 ± 1.7 mm, P < 0.001). After adjustment for confounders, higher dose oestrogen was found to be associated with a lower average birthweight (coefficient -252.4 g, 95% confidence interval [CI] -483.5 to -21.2), a higher rate of low-birthweight neonates (adjusted odds ratio [aOR] 4.88, 95% CI 1.05 to 22.57), bilobated placentas (aOR 3.36, 95% CI 1.04 to 10.89), accessory lobes (aOR 8.74, 95% CI 1.24 to 61.5), accelerated villous maturation (aOR 2.06, 95% CI 1.09 to 3.87), retroplacental haematoma (aOR 5.39, 95% CI 1.11 to 26.13) and maternal malperfusion lesions (aOR 1.46, 95% CI 1.04 to 2.05). CONCLUSION: A higher daily oestrogen dose in programmed FET is associated with low birthweight and placental changes, although this may relate to altered endometrial properties and not to the treatment itself.

Effect of Parity on Placental Histopathology Features in Singleton Live Births Following IVF.

The aim of this study was to evaluate the effect of parity (primipara vs multipara) on the histopathology of the placenta in singleton live births following in vitro fertilization. We conducted a retrospective cohort study evaluating data of all IVF resulted live births from one university affiliated hospital during 2009-2017. All patients had the placenta sent for pathological evaluation. Exclusion criteria were history of miscarriage or elective termination of pregnancy, abnormal uterine cavity findings, previous uterine surgery, in vitro maturation cycles, gestational carrier cycles, oocyte recipient cycles, preimplantation genetic diagnosis cycles, and multiple pregnancies. The outcomes measured included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. A multivariate analysis was conducted to adjust the results for factors potentially associated with placental pathology features. A total of 395 live births were included in the final analysis and were allocated to the study groups according to parity: primipara (n = 273) and multipara (n = 122). After adjustment for potential confounding factors, multiparity was found to be significantly associated with delayed villous maturation (OR 4.9; 95% CI 1.2-19.8) and primiparity was significantly associated with maternal vascular malperfusion (OR 0.6; 95% CI 0.3-0.8). We showed that parity has an impact on placental histopathological changes which in turn may affect perinatal outcome.

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.

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.

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.

Does a history of recurrent pregnancy loss affect subsequent obstetric outcomes and placental findings in in vitro fertilization?

PURPOSE: To assess perinatal outcomes and placental findings in in vitro fertilization (IVF) patients with previous recurrent pregnancy loss (RPL). METHODS: This was a retrospective cohort of live singleton births following IVF at a single university-affiliated center between 2009 and 2017. Outcomes were compared between patients with previous RPL, defined as two miscarriages (RPL group), and patients without RPL (control group). Placental examination was performed for all deliveries irrelevant of complications, and findings categorized according to the Amsterdam Placental Workshop Consensus. RESULTS: One hundred seventy-two deliveries of women with previous RPL (RPL group) were compared to 885 controls. Maternal age, 36.2 ± 4.2 vs. 35.4 ± 4.2 years, p = 0.02, and rate of uterine fibroids, 12.7% vs. 7.3%, p = 0.01, were higher in the RPL group. The rate of nulliparity was lower in the RPL group, 63.3% vs. 74.1%, p = 0.003. Unexplained infertility and diminished ovarian reserve were more common in the RPL group and male factor infertility in controls. There was a lower rate of fresh embryo transfer in the RPL group, 50.5% vs. 64.7%, p < 0.001, and reduced endometrial thickness. Similar obstetric outcomes were noted in the groups after adjustment for confounders. Placental examinations were notable for lower placental thickness, ß - 0.17 cm, 95%CI - 0.30-(- 0.0), a lower rate of velamentous cord insertion, aOR 0.44, 95%CI 0.20-0.95, and a higher rate of villous infarction, aOR 2.82, 95%CI 1.28-6.20 in the RPL group. CONCLUSION: In IVF patients with a history of RPL, subsequent deliveries were associated with a limited number of placental lesions, yet with similar obstetric outcomes.

Dual-Layer Spectral-Computed Tomography Enhances the Separability of Calcium-Based Implant Material from Bone: An Ex Vivo Quantitative Imaging Study.

Local treatment of bone loss with an injection of a resorbable, calcium-based implant material to replace bone has a long history of clinical use. The in vivo discrimination of changes in bone versus implant is challenging with standard computed tomography (CT). However, spectral-CT techniques enable the separation between tissues of similar densities but different chemical compositions. Dual-layer spectral-CT imaging and postprocessing analysis methods were applied to investigate the separability of AGN1 (a triphasic calcium-based implant) and bone after AGN1 injection in n = 10 male cadaveric femurs ex vivo. Using the area under the curve (AUC) from receiver-operating characteristic (ROC) analyses, the separability of AGN1 from bone was assessed for AGN1 (postoperatively) versus compact and versus femoral neck cancellous bone (both preoperatively). CT techniques included conventional Hounsfield (HU) and density-equivalent units (BMD, mg hydroxyapatite [HA]/cm3 ) and spectral-CT measures of effective atomic number (Zeff) and electron density (ED). The samples had a wide range of femoral neck BMD (55.66 to 241.71 mg HA/cm3 ). At the injection site average BMD, HU, Zeff, and ED increased from 69.5 mg HA/cm3 , 109 HU, 104.38 EDW, and 8.30 Zeff in the preoperative to 1233 mg HA/cm3 , 1741 HU, 181.27 EDW, and 13.55 Zeff in the postoperative CT scan, respectively. For compact bone at the femoral shaft the preoperative values were 1124.15 mg HA/cm3 , 1648 HU, 177 EDW, and 13.06 Zeff and were maintained postoperatively. Zeff showed substantially sharper distributions and significantly greater separability compared to ED, BMD, and HU (all p < 0.002, for both regions) with average AUCs for BMD, HU, ED, and Zeff of 0.670, 0.640, 0.645, and 0.753 for AGN1 versus compact and 0.996, 0.995, 0.994, and 0.998 for AGN1 versus femoral neck cancellous sites, respectively. Spectral-CT permits better discrimination of calcium-based implants like AGN1 from bone ex vivo. Our results warrant application of spectral-CT in patients undergoing procedures with similar implants. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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.

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.

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.

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.

Placental histology and pregnancy complications following intracytoplasmic sperm injection for non-male factor infertility.

PURPOSE: To assess obstetric outcomes and placental histology following intracytoplasmic sperm injection (ICSI), for non-male infertility. METHODS: This was a retrospective cohort of live born singleton deliveries after in vitro fertilization (IVF) at a single university affiliated medical center between 2009 and 2017. Excluded were IVF cycles with male infertility and oocyte recipients. We compared obstetric outcomes and placental histology in cases ICSI was performed (ICSI group) and cases with no ICSI (IVF group). RESULTS: A total of 400 deliveries following ICSI were compared to 218 in the IVF group. Maternal age was similar between the groups, while diminished ovarian reserve was more common among ICSI patients and tubal disease less common (p < 0.001). The rate of blastocyte transfer was also significantly lower in the ICSI group-67.5% vs. 77%, p = 0.01. Pregnancies following ICSI were characterized by similar rates of preeclampsia, preterm birth, and small for gestational age neonates. Although cesarean delivery rate was significantly higher in the group, this did no attain significance after adjustment for confounders. Placentas in the ICSI group were notable for a lower rate of villitis of unknown etiology (1% vs. 4.5%, p = 0.007) and a higher rate of maternal surface calcifications (33% vs. 23.8%, p = 0.01) after adjustment for confounders. CONCLUSION: The employment of ICSI with no male indication is associated with similar obstetric outcomes. Despite isolated placental differences among many investigated, placental histology seems overall comparable as well. These results are reassuring to clinicians and patients.

AGN1 implant material to treat bone loss: Resorbable implant forms normal bone with and without alendronate in a canine critical size humeral defect model.

BACKGROUND: Fractures secondary to osteoporosis, particularly those of the hip and spine, are a major public health concern with high social and economic costs. The Local Osteo-Enhancement Procedure (LOEP) is an approach intended to strengthen skeletal areas that are at the highest risk for fracture due to osteoporosis. LOEP involves the implantation of AGN1, a triphasic, calcium-based, osteoconductive material which is then resorbed and replaced by bone. Since alendronate is the most prescribed osteoporotic treatment, the purpose of this canine study is to determine if the newly formed bone has the same properties as normal bone and whether alendronate treatment impacts AGN1 resorption and replacement with bone. METHODS: Sixty skeletally mature male hounds (24-38 kg) were evenly divided between alendronate (0.2 mg/kg/day) and non-alendronate treatment groups. A critical-size core bone defect created in one proximal humerus was implanted with AGN1 while the contralateral non-operated humerus served as a paired control in each animal. Animals were sacrificed 13, 26, and 52 weeks post-operatively (10 per treatment per timepoint). The control and treatment site bone specimens from each animal were examined using radiographic, histomorphometric, and biomechanical techniques. Results between alendronate-treated and non-alendronate-treated animals were compared as groups. RESULTS: AGN1 implant material was consistently resorbed and replaced by bone in all animals. At 52 weeks, only minimal residual implant material could be detected (0.9 ± 2.3% non-alendronate group; 2.2 ± 3.1% alendronate group), and new bone filled the defects in both the non-alendronate and alendronate groups. At 13 and 26 weeks, microCT revealed the newly formed bone in the defects had significantly higher trabecular bone volume and number connectivity than control bone in both groups. Mechanical testing demonstrated that the new bone had ultimate compressive strength and modulus equivalent to control bone as early as 13 weeks post-surgery which was maintained to 52 weeks in both groups. CONCLUSIONS: In this canine critical-sized humeral core defect model, AGN1 was progressively replaced by normal bone as evaluated by all outcome measures. Concurrent alendronate therapy did not significantly impact AGN1 resorption or new bone formation. These results demonstrate that AGN1 can be used in conjunction with alendronate in non-osteoporotic animals. CLINICAL RELEVANCE: This study suggests that the AGN1 implant material demonstrates potential for local restoration of bone in critical-size core defects, and that the material is compatible with alendronate drug therapy. Further studies will be required to determine if these results apply to other osteoporosis medications.

Triphasic calcium-based implant material resorbs and is replaced with bone in ovariectomized rats with or without bisphosphonate treatment.

This study evaluated the effects of AGN1, a triphasic calcium-based material, and alendronate (A) on distal femoral defect bone repair in ovariectomized (OVX) rats. Of 106 rats, 92 were OVX'ed at 12 weeks old and underwent a 12-week induction period. Animals were randomized into five groups: OVX Control, OVX Alendronate Control, Normal Control, OVX Implantation, OVX Alendronate + Implantation. OVX Alendronate Control and OVX Alendronate + Implantation groups received alendronate injection twice weekly (0.015 mg/kg) from 6 weeks until sacrifice. Twelve weeks after OVX, 2.5 mm diameter by 4.0 mm long cylindrical, bilateral distal femoral defects were created in experimental animals. One defect was left empty, and one filled with AGN1. Dual-energy X-ray absorptiometry, microcomputed tomography, and histomorphometry were performed 0-, 6-, 12-, and 18-week postdefect/implantation surgery (N = 6-8/group). Results showed OVX induced significant and progressive bone loss which alendronate prevented. Histomorphometry demonstrated rapid AGN1 resorption: AGN1 resorbed from 95.1 ± 0.7% filling of the implant site (week 0) to 1.3 ± 1.0% (18 weeks) with no significant alendronate effect (1.6 ± 1.1%, 18 weeks). Bone formation in empty defects consisted primarily of cortical wall healing, whereas AGN1 implants demonstrated cortical wall healing with new trabecular bone filling the subcortical space. Alendronate dramatically increased bone formation in empty and AGN1 defects. We conclude AGN1 is resorbed and replaced by new cortical and trabecular bone in this OVX model, and alendronate did not compromise these effects.

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.

Effect of newborn gender on placental histopathology and perinatal outcome in singleton live births following IVF.

RESEARCH QUESTION: Does newborn gender affect placental histopathology pattern and perinatal outcome in singleton live births following IVF treatment? DESIGN: Retrospective cohort study evaluating data of all live births from one academic tertiary hospital following IVF treatment during 2009-2017. All patients had placentas sent for pathological evaluation irrelevant of maternal and fetal complications status. Exclusion criteria were abnormal uterine cavity findings, previous uterine surgery, in-vitro maturation cycles, gestational carrier cycles, oocyte recipient cycles, preimplantation genetic diagnosis cycles and multiple pregnancies. The primary outcomes included anatomical, inflammation, vascular malperfusion and villous maturation placental features. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate analysis was conducted to adjust the results for factors potentially associated with placental pathology features. RESULTS: A total of 1057 live births were included in the final analysis and were allocated to the study groups according to fetal gender: males (n = 527) and females (n = 530). After adjustment for potential confounding factors, male gender was significantly associated with villous agglutination (odds ratio [OR] 9.8; 95% confidence interval [CI] 1.4-78.2), avascular villi (OR 4.1; 95% CI 1.3-12.6) and maternal vascular malperfusion (OR 1.8; 95% CI 1.2-2.7). Female gender was significantly associated with bilobed placenta (OR 0.2; 95% CI 0.06-0.8) and subchorionic thrombi (OR 0.5; 95% CI 0.3-0.9). The prevalence of adverse fetal, maternal and delivery outcomes was similar between the groups. CONCLUSIONS: Newborn gender has a significant impact on the placental histopathology pattern, which can contribute to the development of adverse perinatal outcomes.

Impact of intramural non-cavity-distorting leiomyoma on placental histopathology and perinatal outcome in singleton live births resulting from in vitro fertilization treatment.

PURPOSE: To evaluate the effect of non-cavity-distorting intramural leiomyomas on the placental histopathology pattern and perinatal outcome in singleton live births resulting from in vitro fertilization treatment. METHODS: The study population included all singleton live births following in vitro fertilization treatment with autologous oocytes during the period from 2009 to 2017. Primary outcomes included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. Secondary outcomes included fetal, maternal, delivery, and perinatal complications. RESULTS: A total of 1119 live births were included in the final analysis and were allocated to the group of pregnancies with non-cavity-distorting intramural myomas (n = 101) and without myomas (n = 1018). After the adjustment for confounding factors, the non-cavity-distorting intramural myomas were found to be significantly associated with assisted placental delivery (OR 2.4; 95% CI 1.5-3.9), furcate cord insertion (OR 3.6; 95% CI 1.4-9.3), circumvallate membranes insertion (OR 5.2; 95% CI 1.4-19.3), chronic deciduitis (OR 8.2; 95% CI 1.6-42.2), focal intramural fibrin deposition (OR 25.1; 95% CI 2.1-306.2), subchorionic thrombi (OR 3.6; 95% CI 1.7-7.6), maternal vasculopathy (OR 2.5; 95% CI 1.2-5.5), and chorangioma (OR 5.9; 95% CI 1.4-25.2) as well as with the failure of labor progress (OR 2.4; 95% CI 1.3-4.4) and induction (OR 3.2; 95% CI 1.2-9.0). CONCLUSION: Intramural non-cavity-distorting myomas have a significant impact on the placental histopathology with a higher incidence of dysfunctional labor.

In vitro injection of osteoporotic cadaveric femurs with a triphasic calcium-based implant confers immediate biomechanical integrity.

Current pharmaceutical therapies can reduce hip fractures by up to 50%, but compliance to treatment is low and therapies take up to 18 months to reduce risk. Thus, alternative or complementary approaches to reduce the risk of hip fracture are needed. The AGN1 local osteo-enhancement procedure (LOEP) is one such alternative approach, as it is designed to locally replace bone lost due to osteoporosis and provide immediate biomechanical benefit. This in vitro study evaluated the initial biomechanical impact of this treatment on human cadaveric femurs. We obtained 45 pairs of cadaveric femurs from women aged 77.8 ± 8.8 years. One femur of each pair was treated, while the contralateral femur served as an untreated control. Treatment included debridement, irrigation/suction, and injection of a triphasic calcium-based implant (AGN1). Mechanical testing of the femora was performed in a sideways fall configuration 24 h after treatment. Of the 45 pairs, 4 had normal, 16 osteopenic, and 25 osteoporotic BMD T-scores. Altogether, treatment increased failure load on average by 20.5% (p < 0.0001). In the subset of osteoporotic femurs, treatment increased failure load by 26% and work to failure by 45% (p < 0.01 for both). Treatment did not significantly affect stiffness in any group. These findings provide evidence that local delivery of the triphasic calcium-based implant in the proximal femur is technically feasible and provides immediate biomechanical benefit. Our results provide strong rationale for additional studies investigating the utility of this approach for reducing the risk of hip fracture. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.