Ovarian stimulation for fertility treatments and risk of breast cancer: a matched cohort study.

STUDY QUESTION: Is there a difference in the breast cancer risk among women who underwent ART treatments compared to those who underwent medically assisted reproduction (MAR) infertility treatments or women of reproductive age in the general population? SUMMARY ANSWER: The risk of breast cancer among women treated by ART was similar to the risk among women treated by MAR and women who did not undergo fertility treatments. WHAT IS KNOWN ALREADY: Studies investigating breast cancer risk in women who have undergone fertility treatments have provided conflicting results. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study included women who underwent ART or MAR treatments and women who did not undergo fertility treatments from 1994 to 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who underwent ART were matched one to one with women who underwent MAR treatments and one to one with woman from the general population of reproductive age, by year of birth and year of first delivery or nulliparity status. MAR women were also matched to ART women by treatment initiation calendar year. All included women were members of Maccabi Healthcare Services. Data regarding demographics, fertility treatments, BRCA mutation and possible confounders were obtained from the computerized database of electronic health records. The incidence of breast cancer after fertility treatments was compared to the matched controls. MAIN RESULTS AND THE ROLE OF CHANCE: Of 8 25 721 women of reproductive age, 32 366 women who underwent ART were matched with patients treated by MAR (n = 32 366) and 32 366 women of reproductive age. A total of 984 women (1.0%) were diagnosed with breast cancer (mean follow-up period, 9.1 ± 6.3 years; interquartile range [IQR], 3.8-13.7 years). The incidence rates of breast cancer per 10 000 person-years were 11.9 (95% CI, 10.7-13.3), 10.7 (95% CI, 9.6-11.9) and 10.7 (95% CI, 9.6-12.0) in the ART group, MAR group and general population, respectively. The crude risk for breast cancer was similar in the ART group compared with the general population (hazard ratio (HR) = 1.10, 95% CI, 0.94-1.28) and in the ART group compared with the MAR group (HR = 1.00, 95% CI, 0.86-1.16). Further adjustment for age, BMI, smoking, socioeconomic status and parity did not substantially impact the hazard rates for breast cancer (ART vs general population: HR = 1.10, 95% CI, 0.94-1.28; ART vs MAR: HR = 0.99, 95% CI, 0.85-1.16). Among women diagnosed with breast cancer, the prevalence of BRCA1/2 mutations and tumour staging did not differ between the ART, MAR and general population groups. Among women who underwent ART, no correlation was found between breast cancer and the number of ART cycles or the use of recombinant medications or urine-derived medications. LIMITATIONS, REASONS FOR CAUTION: The mean age of women at the end of follow-up was only 42 years thus the study was not powered to detect potential differences in the risk of postmenopausal breast cancer. In addition, we did not sub-classify the exposed patients by the reason for infertility. WIDER IMPLICATIONS OF THE FINDINGS: Breast cancer incidence following ART was comparable to that in the general population or following MAR. Women undergoing fertility treatments and their clinicians may be reassured about the safety of assisted reproduction technologies in terms of premenopausal breast cancer risk. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

The impact of embryo vitrification on placental histopathology features and perinatal outcome in singleton live births.

STUDY QUESTION: Does embryo vitrification affect placental histopathology pattern and perinatal outcome in singleton live births? SUMMARY ANSWER: Embryo vitrification has a significant effect on the placental histopathology pattern and is associated with a higher prevalence of dysfunctional labor. WHAT IS KNOWN ALREADY: Obstetrical and perinatal outcomes differ between live births resulting from fresh and frozen embryo transfers. The effect of embryo vitrification on the placental histopathology features associated with the development of perinatal complications remains unclear. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study evaluating data of all live births from one academic tertiary hospital resulting from IVF treatment with autologous oocytes during the period from 2009 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients had placentas sent for pathological evaluation irrelevant of maternal or fetal complications status. Placental, obstetric and perinatal outcomes of pregnancies resulting from hormone replacement vitrified embryo transfers were compared with those after fresh embryo transfers. A multivariate analysis was conducted to adjust the results for determinants potentially associated with the development of placental histopathology abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1014 singleton live births were included in the final analysis and were allocated to the group of pregnancies resulting from fresh (n = 660) and hormone replacement frozen (n = 354) embryo transfers. After the adjustment for confounding factors the frozen embryo transfers were found to be significantly associated with chorioamnionitis with maternal (odds ratio (OR) 2.0; 95% CI 1.2-3.3) and fetal response (OR 2.6; 95% CI 1.2-5.7), fetal vascular malperfusion (OR 3.9; 95% CI 1.4-9.2), furcate cord insertion (OR 2.3 95% CI 1.2-5.3), villitis of unknown etiology (OR 2.1; 95% CI 1.1-4.2), intervillous thrombi (OR 2.1; 95% CI 1.3-3.7), subchorionic thrombi (OR 3.4; 95% CI 1.6-7.0), as well as with failure of labor progress (OR 2.5; 95% CI 1.5-4.2). LIMITATIONS, REASONS FOR CAUTION: Since the live births resulted from frozen-thawed embryos included treatment cycles with previously failed embryo transfers, the factors over embryo vitrification may affect implantation and placental histopathology. WIDER IMPLICATIONS OF THE FINDINGS: The study results contribute to the understanding of the perinatal future of fresh and vitrified embryos. Our findings may have an implication for the clinical decision to perform fresh or frozen-thawed embryo transfer. STUDY FUNDING/COMPETING INTEREST(S): Authors have not received any funding to support this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Definition and sonographic reporting system for Cesarean scar pregnancy in early gestation: modified Delphi method.

OBJECTIVE: To develop a standardized sonographic evaluation and reporting system for Cesarean scar pregnancy (CSP) in the first trimester, for use by both general gynecology and expert clinics. METHODS: A modified Delphi procedure was carried out, in which 28 international experts in obstetric and gynecological ultrasonography were invited to participate. Extensive experience in the use of ultrasound to evaluate Cesarean section (CS) scars in early pregnancy and/or publications concerning CSP or niche evaluation was required to participate. Relevant items for the detection and evaluation of CSP were determined based on the results of a literature search. Consensus was predefined as a level of agreement of at least 70% for each item, and a minimum of three Delphi rounds were planned (two online questionnaires and one group meeting). RESULTS: Sixteen experts participated in the Delphi study and four Delphi rounds were performed. In total, 58 items were determined to be relevant. We differentiated between basic measurements to be performed in general practice and advanced measurements for expert centers or for research purposes. The panel also formulated advice on indications for referral to an expert clinic. Consensus was reached for all 58 items on the definition, terminology, relevant items for evaluation and reporting of CSP. It was recommended that the first CS scar evaluation to determine the location of the pregnancy should be performed at 6-7 weeks' gestation using transvaginal ultrasound. The use of magnetic resonance imaging was not considered to add value in the diagnosis of CSP. A CSP was defined as a pregnancy with implantation in, or in close contact with, the niche. The experts agreed that a CSP can occur only when a niche is present and not in relation to a healed CS scar. Relevant sonographic items to record included gestational sac (GS) size, vascularity, location in relation to the uterine vessels, thickness of the residual myometrium and location of the pregnancy in relation to the uterine cavity and serosa. According to its location, a CSP can be classified as: (1) CSP in which the largest part of the GS protrudes towards the uterine cavity; (2) CSP in which the largest part of the GS is embedded in the myometrium but does not cross the serosal contour; and (3) CSP in which the GS is partially located beyond the outer contour of the cervix or uterus. The type of CSP may change with advancing gestation. Future studies are needed to validate this reporting system and the value of the different CSP types. CONCLUSION: Consensus was achieved among experts regarding the sonographic evaluation and reporting of CSP in the first trimester. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Adnexal torsion recurrence-is the adnexal twist degree a risk factor? A retrospective cohort study.

OBJECTIVE: To evaluate whether the adnexal twist degree is related to torsion recurrence and whether there is a dose-dependent correlation. DESIGN: A retrospective cohort study. SETTING: Single tertiary medical centre. POPULATION: The study includes non-pregnant patients operated, for the first time, for adnexal torsion, between 2011 and 2018. METHODS: Information regarding the degree of adnexal twist was collected from surgical reports. Recurrence was identified using a computerised database and ascertained via telephone with a response rate of 87.2% (253/290). MAIN OUTCOME MEASURES: Adnexal torsion recurrence rate. RESULTS: A total of 182 women who had undergone laparoscopic detorsion met the inclusion criteria. Twenty-two had torsion recurrence (12.1%). Adnexal twist degree in the primary event was associated with a higher recurrence risk: 4.3% of women with twist degree ≤360 (n = 3/70), 14.5% of women with twist degree of 361-720 (n = 9/62) and 20% of women with twist degree >720 (n = 10/50) (P = 0.03). The median twist degree was 540 (interquartile range [IQR] 360-855) and 720 (IQR 675-1080) degrees in the control and study groups, respectively (P = 0.005). Additional possibly associated factors for recurrence were evaluated. Age emerged as a possible risk factor, with a median age of 19 years in the recurrence group (IQR 14-27 years) versus 28.5 (IQR 19-36 years) in the non-recurrence group (P < 0.01). Logistic regression analysis revealed that together with age, adnexal twist degree remained significantly associated with torsion recurrence (odds ratio [OR] 1.98, 95% CI 1.09-3.61; P = 0.02). CONCLUSION: Adnexal twist degree was found to be positively associated with the risk of torsion recurrence. TWEETABLE ABSTRACT: Adnexal twist degree was found to be positively associated with the risk of torsion recurrence.

Sonographic examination of uterine niche in non-pregnant women: a modified Delphi procedure.

OBJECTIVE: To generate guidance for detailed uterine niche evaluation by ultrasonography in the non-pregnant woman, using a modified Delphi procedure amongst European experts. METHODS: Twenty gynecological experts were approached through their membership of the European Niche Taskforce. All experts were physicians with extensive experience in niche evaluation in clinical practice and/or authors of niche publications. By means of a modified Delphi procedure, relevant items for niche measurement were determined based on the results of a literature search and recommendations of a focus group of six Dutch experts. It was predetermined that at least three Delphi rounds would be performed (two online questionnaires completed by the expert panel and one group meeting). For it to be declared that consensus had been reached, a consensus rate for each item of at least 70% was predefined. RESULTS: Fifteen experts participated in the Delphi procedure. Consensus was reached for all 42 items on niche evaluation, including definitions, relevance, method of measurement and tips for visualization of the niche. A niche was defined as an indentation at the site of a Cesarean section with a depth of at least 2 mm. Basic measurements, including niche length and depth, residual and adjacent myometrial thickness in the sagittal plane, and niche width in the transverse plane, were considered to be essential. If present, branches should be reported and additional measurements should be made. The use of gel or saline contrast sonography was preferred over standard transvaginal sonography but was not considered mandatory if intrauterine fluid was present. Variation in pressure generated by the transvaginal probe can facilitate imaging, and Doppler imaging can be used to differentiate between a niche and other uterine abnormalities, but neither was considered mandatory. CONCLUSION: Consensus between niche experts was achieved regarding ultrasonographic niche evaluation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Does use of a sex-specific model improve the accuracy of sonographic weight estimation?

OBJECTIVE: To determine whether the use of a sex-specific sonographic model improves the accuracy of fetal weight estimation. METHODS: New regression models (sex-independent and sex-specific) were developed, based on 1708 sonographic weight estimations performed within 3 days prior to delivery. The accuracy of these models was compared to that of several published models including two of the original Hadlock models (which incorporate the biometric indices abdominal circumference (AC), biparietal diameter (BPD), femur diaphysis length (FL) and head circumference (HC) as follows: AC-FL-BPD and AC-FL-HC, designated here as Hadlock I and Hadlock II, respectively), modified versions of the Hadlock I and II models for which coefficients were adjusted to our local cohort, sex-specific versions of the Hadlock I and II models and Schild's model (a previously published sex-specific model). RESULTS: The unadjusted models of Hadlock and Schild were associated with the highest systematic error (1.6-4.9%; P < 0.001) which was significantly higher for females (2.3-4.9%) compared to males (1.6-2.0%; P < 0.001). Adjustment of model coefficients to the local population decreased the systematic error (-1.4% to 1.5%) and resulted in a systematic error that was of similar magnitude (P = 0.3) but opposite in direction for male and female fetuses. The sex-specific models (adjusted or newly developed) were associated with the lowest systematic error (-0.4 to 0.5%) and were the only models for which the systematic error was similar for male and female fetuses. There were no differences in the systematic error between adjusted sex-specific versions of the Hadlock I and II models and the newly developed sex-specific models (0.0% to 0.4% vs. - 0.4% to 0.5%; P = 0.4). The random error was similar for all models and, for most of the models, was unrelated to fetal sex. CONCLUSIONS: The use of sex-specific models appears to improve the accuracy of fetal weight estimation, principally because the optimal set of model coefficients differs for male and female fetuses. The improved accuracy is mainly the result of a decrease in systematic error, as the random error was not affected by the use of such sex-specific models.

Accuracy of sonographic fetal weight estimation: a matter of presentation.

OBJECTIVES: To assess the accuracy of sonographic weight estimation for fetuses in breech presentation, and to determine whether certain sonographic models perform better than others in cases of breech presentation. METHODS: This was a retrospective cohort study of all sonographic weight estimations of fetuses in breech presentation performed within 3 days prior to delivery (n = 165). The accuracy of weight estimation was evaluated using eight sonographic models and was compared with a control group of fetuses in vertex presentation matched to the study group by birth weight and fetal gender (n = 165). RESULTS: After exclusion of a model based on femur diaphysis length alone, which was found to be highly inaccurate, the systematic error for fetuses in breech presentation was smaller than that observed for fetuses in vertex presentation (mean of all models - 0.14% vs. 2.0%, P = 0.01). The random error was higher in cases of breech presentation (9.4-13.2% vs. 7.5-8.9%, P < 0.05), and was lower for models that are based on three to four biometric indices (9.4-9.5%) compared with models that incorporate one to two biometric indices (10.8-13.6%, P < 0.05). Overall, the higher random error outweighed the decrease in the systematic error, as reflected by the lower fraction of weight estimations within 10% of birth weight among fetuses in breech presentation. Models based on three to four biometric indices were more accurate in detecting the weight thresholds beyond which a trial of vaginal delivery is usually not recommended. CONCLUSION: Sonographic weight estimation appears to be less accurate for fetuses in breech presentation, principally because of a larger random error. The use of sonographic models that are based on three to four biometric indices, training aimed at improving measurement in breech fetuses and the development of sonographic models derived from fetuses in breech presentation, may improve the accuracy of weight estimation in these cases.

Prediction of fetal macrosomia: effect of sonographic fetal weight-estimation model and threshold used.

OBJECTIVE: To compare the accuracy of 21 sonographic fetal weight-estimation models and abdominal circumference (AC) as a single measure for the prediction of fetal macrosomia (> 4000 g) using either fixed or optimal model-specific thresholds. METHODS: A total of 4765 sonographic weight estimations performed within 3 days prior to delivery were analyzed. The predictive accuracy of 21 published sonographic fetal weight-estimation models was calculated using three different thresholds: a fixed threshold of 4000 g; a model-specific threshold obtained from the inflexion point of the receiver-operating characteristics (ROC) curve; and a model-specific threshold associated with the highest overall accuracy. Cluster analysis was used to determine whether a certain combination of fetal biometric indices is associated with a higher predictive accuracy than others. RESULTS: For a fixed threshold of > 4000 g, there was considerable variation among the models in sensitivity (range, 13.6-98.5%) and specificity (range, 63.6-99.8%) for fetal macrosomia. Use of the threshold derived from the inflexion point of the ROC curve decreased the intermodel variation to a minimum (sensitivity, 84.4-91.4%; and specificity, 79.5-86.3%). Even when this optimal model-specific threshold was applied, models based on three to four biometric indices were more accurate than were models based on only two biometric indices or on AC as a single measure (P=0.03). CONCLUSIONS: Sonographic fetal weight-estimation models based on three to four biometric indices appear to be more accurate than are models based on two indices or on AC as a single measure, for the diagnosis of macrosomia. In these cases, the use of an optimal, model-specific threshold is associated with a higher degree of accuracy than is the uniform use of a fixed threshold of an estimated weight of > 4000 g.

Accuracy of sonographic weight estimation as a function of fetal sex.

OBJECTIVES: To determine whether the accuracy of sonographic fetal weight estimation is related to fetal sex. METHODS: The accuracy of sonographic fetal weight estimation was compared between male and female fetuses using 3672 sonographic weight estimations performed within 3 days prior to delivery. Fetal weight was estimated using eight regression models that are based on different combinations of the following biometric parameters: abdominal circumference (AC), femur diaphysis length (FL), biparietal diameter (BPD) and head circumference (HC). RESULTS: In seven out of the eight models tested, the presence of a male fetus was associated with a significantly lower systematic error compared with a female fetus (-0.2 to 2.1% vs. 1.3 to 6%, P<0.001). On multivariate analysis, fetal sex was independently associated with sonographic accuracy so that the likelihood of a weight estimation within 10% of birth weight was 30% higher for male fetuses compared with female fetuses. The biometric parameters that contributed most to these sex-related differences were FL and AC, while models that included HC were associated with the lowest differences in the systematic error between male fetuses and female fetuses. For most models, the random error and correlation between estimated weight and birth weight were not affected by fetal sex (8.1-12.8% vs. 8.2-13.6%, and 0.856-0.944 vs. 0.842-0.944, respectively). CONCLUSION: Sonographic estimation of fetal weight is more accurate for male fetuses than for female fetuses. The use of sex-specific models may improve the accuracy of fetal weight estimation for female fetuses.

Sonographic estimation of fetal head circumference: how accurate are we?

OBJECTIVES: To assess the accuracy of sonographic estimation of fetal head circumference (HC). METHODS: We compared sonographic estimations of fetal HC with actual measurements performed immediately after delivery using 3008 sonographic examinations performed within 3 days prior to delivery. The following measures of accuracy were calculated: correlation with actual HC, systematic error, random error, simple error, mean absolute percentage error and fraction of estimates within 5% of actual HC. Multivariate logistic regression analysis was used to identify factors affecting the accuracy of sonographic HC estimation. RESULTS: There was a high correlation between sonographic and postnatal measurements of HC (r = 0.845, P < 0.001). Overall, sonographic HC measurements consistently underestimated actual HC measured postnatally (mean simple error, - 13.6 mm; 95% CI, - 13.2 to - 13.9), and the difference increased with gestational age. A high cephalic index (> 0.81) (odds ratio (OR), 0.3; 95% CI, 0.2-0.4), HC > 90(th) centile (OR, 0.5; 95% CI, 0.3-0.6), delivery by vacuum extraction (OR, 0.6; 95% CI, 0.4-0.8), gestational week (OR, 0.7; 95% CI, 0.6-0.9) and male fetal gender (OR, 0.8; 95% CI, 0.6-0.9) were associated with decreased sonographic accuracy. At term, breech presentation at the time of sonographic examination was associated with a higher sonographic accuracy compared with vertex presentation (-12.0; 95% CI, - 10.5 to - 13.5 vs. - 13.9 mm; 95% CI, - 13.6 to - 14.3; P = 0.02). The random error was relatively constant, and was unaffected by any of the obstetric factors studied. CONCLUSION: Sonographic estimation of HC is associated with significant underestimation compared with the actual postnatal HC. This measurement error may have important clinical implications and should be taken into account in the interpretation of sonographically measured HC.

Differentiation between right tubo-ovarian abscess and appendicitis using CT--a diagnostic challenge.

AIM: To determine CT features that can potentially differentiate right tubo-ovarian abscess (TOA) from acute appendicitis (AA; including abscess formation). MATERIALS AND METHODS: The abdominal computed tomography (CT) images of 48 patients with right-sided TOA (average age 39.3 ± 9.8 years) and 80 patients (average age 53.5 ± 19.9 years) with AA (24 with peri-appendicular abscess) were retrospectively evaluated. Two experienced radiologists evaluated 12 CT signs (including enlarged, thickened wall ovary, appendix diameter and wall thickness, peri-appendicular fluid collection, adjacent bowel wall thickening, fat stranding, free fluid, and extraluminal gas) in consensus to categorize the studies as either TOA or AA. The diagnosis and the frequency of each of the signs were correlated with the surgical and clinical outcome. RESULTS: Reviewers classified 92% cases correctly (TOA=85%, AA=96.3%), 3% incorrectly (TOA=6.3%, AA=1.3%); 5% were equivocal (TOA=8.3%, AA=2.5%). In the peri-appendicular abscess group reviewers were correct in 100%. Frequent findings in the TOA group were an abnormal ovary (87.5%), peri-ovarian fat stranding (58.3%), and recto-sigmoid wall thickening (37.5%). An abnormal appendix was observed in 2% of TOA patients. Frequent findings in the AA group were a thickened wall (32.5%) and distended (80%) appendix. Recto-sigmoid wall thickening was less frequent in AA (12.5%). The appendix was not identified in 45.8% of the TOA patients compared to 15% AA. CONCLUSIONS: In the presence of a right lower quadrant inflammatory mass, peri-ovarian fat stranding, thickened recto-sigmoid wall, and a normal appearing caecum, in young patients favour the diagnosis of TOA. An unidentified appendix does not contribute to the differentiation between TOA and peri-appendicular abscess.

How Artificial Intelligence Can Improve Our Understanding of the Genes Associated with Endometriosis: Natural Language Processing of the PubMed Database.

Endometriosis is a disease characterized by the development of endometrial tissue outside the uterus, but its cause remains largely unknown. Numerous genes have been studied and proposed to help explain its pathogenesis. However, the large number of these candidate genes has made functional validation through experimental methodologies nearly impossible. Computational methods could provide a useful alternative for prioritizing those most likely to be susceptibility genes. Using artificial intelligence applied to text mining, this study analyzed the genes involved in the pathogenesis, development, and progression of endometriosis. The data extraction by text mining of the endometriosis-related genes in the PubMed database was based on natural language processing, and the data were filtered to remove false positives. Using data from the text mining and gene network information as input for the web-based tool, 15,207 endometriosis-related genes were ranked according to their score in the database. Characterization of the filtered gene set through gene ontology, pathway, and network analysis provided information about the numerous mechanisms hypothesized to be responsible for the establishment of ectopic endometrial tissue, as well as the migration, implantation, survival, and proliferation of ectopic endometrial cells. Finally, the human genome was scanned through various databases using filtered genes as a seed to determine novel genes that might also be involved in the pathogenesis of endometriosis but which have not yet been characterized. These genes could be promising candidates to serve as useful diagnostic biomarkers and therapeutic targets in the management of endometriosis.

Severe intraabdominal bleeding caused by endometriotic lesions during the third trimester of pregnancy.

OBJECTIVE: Endometriosis is known to be associated with an increased risk for early pregnancy complications, including ectopic pregnancy and miscarriage. However, little has so far been reported on complications linked to severe endometriosis occurring during the third trimester of pregnancy. STUDY DESIGN: A retrospective review of 800 women attending the endometriosis clinic of the Sheba Medical Center during the years 2002-2006 was performed. Cases with severe endometriosis and associated complications during late pregnancy were identified. RESULTS: Three women were found who experienced significant intraabdominal bleeding in the third trimester of pregnancy attributed to a lesion resulting from severe endometriosis. The intraabdominal bleeding occurred between 26-29 weeks of gestation. In all cases the major presenting prenatal symptom was severe lower abdominal pain. The pain was not relieved by the administration of tocolytics or mild analgesics. Explorative laparotomy, performed in all 3 cases, revealed the presence of significant intraabdominal bleeding requiring immediate transfusion of blood products stemming from endometriotic lesions. Fetal complications occurred in all 3 cases. CONCLUSION: The symptoms of endometriosis are often relieved during pregnancy. Yet lesions caused by severe endometriosis can lead to significant intraabdominal bleeding during the third trimester of the pregnancy. Physicians must be aware that close antenatal follow-up and prompt intervention may be required in such cases.

RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis.

Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).

Outcomes of prenatally diagnosed solitary functioning kidney during early life.

OBJECTIVE: To evaluate outcomes of congenital solitary functioning kidney (SFK) in early childhood. STUDY DESIGN: A retrospective study of 32 children diagnosed in utero with SFK owing to unilateral renal agenesis or multicystic dysplastic kidney and followed for 1 to 11.5 years. RESULTS: SFK length was in the compensatory hypertrophy range in 45% of fetal sonographic evaluations from mid-pregnancy, and in 85% on postnatal follow-up. Glomerular filtration rate was below normal range in 44.4%, 12.5% and 0% at <1 year, age 1 to 3 years and thereafter, respectively. Hyperfiltration was detected in 18.5% and 82.6% at <1 year and >3 years, respectively. Hypertension was documented in 35% at age 1 to 3 years but in none at an older age. Proteinuria was absent in all children. CONCLUSION: Congenital SFK is apparently associated with little or no renal damage in infancy or childhood. Compensatory enlargement of the functioning kidney begins in utero and might serve as a prognostic indicator for normal renal function after birth.

Prenatal ultrasound diagnosis of club foot: outcome and recommendations for counselling and follow-up.

Club foot was diagnosed by ultrasonography in 91 feet (52 fetuses) at a mean gestational age of 22.1 weeks (14 to 35.6). Outcome was obtained by chart review in 26 women or telephone interview in 26. Feet were classified as normal, positional deformity, isolated club foot or complex club foot. At initial diagnosis, 69 feet (40 fetuses) were classified as isolated club foot and 22 feet (12 fetuses) as complex club foot. The diagnosis was changed after follow-up ultrasound scan in 13 fetuses (25%), and the final ultrasound diagnosis was normal in one fetus, isolated club foot in 31 fetuses, and complex club foot in 20 fetuses. At birth, club foot was found in 79 feet in 43 infants for a positive predictive value of 83%. Accuracy of the specific diagnosis of isolated club foot or complex club foot was lower; 63% at the initial ultrasound scan and 73% at the final scan. The difference in diagnostic accuracy between isolated and complex club foot was not statistically significant. In no case was postnatal complex club foot undiagnosed on fetal ultrasound and all inaccuracies were overdiagnoses. Karyotyping was performed in 25 cases. Abnormalities were noted in three fetuses, all with complex club foot and with additional findings on ultrasound.

Methotrexate pneumonitis in nonsurgical treatment of ectopic pregnancy.

We describe a case of pneumonitis following local administration of methotrexate for nonsurgical termination of an ectopic pregnancy. The signs and symptoms were similar to those seen with systemic use of the drug for other ailments. We believe that methotrexate represents a relatively effective alternative to surgery in patients with early unruptured tubal pregnancy, but suggest that it be used with caution in view of possible systemic toxicity.

The relationship between sperm ultrastructural features and fertilizing capacity in vitro.

OBJECTIVE: To evaluate the relationship between ultramorphological features of the human sperm and its fertilizing capacity in vitro. DESIGN: The study was performed retrospectively. Ultrastructural features were assessed using scanning and transmission electron microscopes in sperm samples of individuals who underwent an in vitro fertilization (IVF) treatment cycle no more than 6 months before the study. SETTING: Institutional clinical care. PATIENTS: Fifty-six infertile couples in whom mechanical infertility was diagnosed in the female partner. Patients were categorized as fertilizing when fertilization of at least 30% of the oocytes occurred (n = 27) and nonfertilizing when none of the oocytes fertilized in at least two consecutive IVF treatment cycles (n = 29). RESULTS: The two groups differed significantly only in ultramorphological parameters of the sperm head and acrosome (head, F(8,36) = 2.8, P less than 0.02; acrosome, F(4,40) = 2.8, P less than 0.04), and especially in the following malformation patterns: hyperelongated head, acrosome deficiency, and acrosome damage. The suggested score based on these findings was able to predict 90% and 76% of the cases with and without fertilizing potential, respectively. CONCLUSION: The ultrastructural morphology of the sperm head components is a key parameter for assessing the sperm fertilizing capacity in vitro.

Predictive value of transvaginal sonography performed before routine diagnostic hysteroscopy for evaluation of infertility.

OBJECTIVE: To compare transvaginal sonography with hysteroscopy for the evaluation of intrauterine disorders. DESIGN: Clinical study. SETTING: Academic research environment. PATIENT(S): Patients who were undergoing initial evaluation for primary or secondary infertility or investigation after three failed IVF attempts. INTERVENTION(S): Transvaginal sonography was performed, followed by hysteroscopy, between January 1998 and April 1999. The endometrial findings at sonography were compared with those at hysteroscopy, which served as the gold standard. The characteristic sonographic features of intrauterine adhesions were defined. MAIN OUTCOME MEASURE(S): Intrauterine adhesions, endometrial polyps. RESULT(S): The sensitivity, specificity, and positive and negative predictive values for transvaginal sonography in detecting abnormal uterine cavities were 100%, 96.3%, 91.3%, and 100%, respectively. The corresponding values for the specific diagnoses of intrauterine adhesions and endometrial polyps were 80%, 100%, 100%, and 97%, and 71.4%, 100%, 100%, and 97.1%, respectively. On transvaginal sonography, intrauterine adhesions appeared as hyperechoic endometrial foci and were differentiated from endometrial polyps by their irregular shape and more precise localization. The performance of transvaginal sonography at midcycle (three-layer endometrium) rather than after menstrual cessation (endometrial thickness <3 mm) enabled better imaging of small intrauterine adhesions. CONCLUSION(S): A regular myometrial-endometrial interface and homogeneous endometrial structure on transvaginal sonography congruent with the phase of the menstrual cycle indicated a normal endometrium and precluded the need for diagnostic hysteroscopy. Transvaginal sonography may be used as the initial diagnostic procedure to select patients for hysteroscopy.

Multifetal pregnancy reduction in cases of threatened abortion of triplets.

OBJECTIVE: To investigate the course of pregnancy and fetal outcome after first-trimester multifetal pregnancy reduction (MFPR) in patients with triplet pregnancies and uterine bleeding. DESIGN: Case series of patients with threatened triplet pregnancies considered for MFPR. SETTING: Department of Obstetrics and Gynecology, Rabin Medical Center, Petah-Tiqva, Israel. PATIENT(S): Forty-two patients with triplet pregnancies and first-trimester uterine bleeding. INTERVENTION(S): At 10-15 weeks' gestation, MFPR with intracardiac injection of potassium chloride was performed. The procedures were performed 7-10 days after cessation of bleeding (9-13 weeks) or in the presence of minimal uterine bleeding (14-15 weeks). In patients with heavy uterine bleeding, MFPR was postponed. MAIN OUTCOME MEASURE(S): Early- and late-pregnancy complications related to the procedure, pregnancy outcome, and fetal survival. RESULT(S): Performance of MFPR at 14-15 weeks was associated with a higher abortion rate (38.5%), lower mean gestational age at delivery (30.6 weeks), and lower mean twin birth weight (1,376+/-218 g and 1,014+/-202 g) than was performance of MFPR at 10-13 weeks (18.8%, 33.2 weeks, and 1,720+/-245 g and 1,596+/-170 g, respectively). Abortion occurred in four of the five patients with moderate to heavy uterine bleeding who did not undergo MFPR; the fifth patient gave birth prematurely at 28 weeks, and two of the newborns died. CONCLUSION(S): Pregnancy outcome and fetal mortality and morbidity in triplet pregnancy after MFPR are directly correlated with duration and amount of first-trimester bleeding.