Pregnancies at the Uterotubal Junction: A Review of Terminology (Interstitial, Cornual, and Angular) and Recommendations for Management.

Ectopic pregnancies are one of the most common causes of obstetric mortality worldwide. Interstitial ectopic pregnancies, defined as an extracavitary pregnancy within the portion of the Fallopian tube that transverses the myometrium, have reported mortality rates approximately seven times higher than all types of ectopic pregnancy combined. In contrast, intracavitary eccentric gestations, often labeled as "cornual" or "angular" pregnancies, have reportedly high rates of live birth. Unfortunately, the terms "interstitial," "cornual," and "angular" have long been used with varying diagnostic criteria and often interchangeably to describe a pregnancy near the uterotubal junction. The inconsistency in nomenclature and lack of clear diagnostic criteria to distinguish among these pregnancies has resulted in a paucity of data to provide accurate prognostic information and guide appropriate management. This review article aims to provide historical context for the terms "interstitial," "cornual," and "angular;" discuss previous and more recent innovations of diagnostic methods; and provide recommendations for concise terminology and inform management.

Multiplexed Serum Biomarkers to Discriminate Nonviable and Ectopic Pregnancy.

OBJECTIVE: The use of multiplexed biomarkers may improve the diagnosis of normal and abnormal early pregnancies. In this study we assessed 24 markers with multiple machine learning-based methodologies to evaluate combinations of top candidates to develop a multiplexed prediction model for identification of 1) viability and 2) location of an early pregnancy. DESIGN: A nested case-control design evaluating the predictive ability and discrimination of biomarkers in patients at risk of early pregnancy failure in the first trimester to classify viability and location SUBJECTS: 218 individuals with a symptomatic (pain and/or bleeding) early pregnancy: 75 with an ongoing intrauterine gestation, 68 ectopic pregnancies, and 75 miscarriages. INTERVENTIONS: Serum values of 24 biomarkers were assessed in the same patients. Multiple machine learning-based methodologies to evaluate combinations of these top candidates to develop a multiplexed prediction model for identification of 1) a nonviable pregnancy (ongoing intrauterine pregnancy vs miscarriage or ectopic pregnancy) and 2) an ectopic pregnancy (ectopic pregnancy vs ongoing intrauterine pregnancy or miscarriage). MAIN OUTCOME MEASURES: The predicted classification by each model was compared to actual diagnosis and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), conclusive classification, and accuracy were calculated. RESULTS: Models using classification regression tree analysis using three markers (PSG3, CG-Alpha and PAPPA) were able to predict a maximum sensitivity 93.3%, a maximum specificity 98.6%. The model with the highest accuracy was 97.4% (with 70.2% receiving classification). Models using an overlapping group of three markers (sFLT, PSG3 and TFP12) achieved a maximum sensitivity of 98.5%. and a maximum specificity of 95.3%. The model with the highest accuracy was 94.4% (with 65.6% receiving classification). When the models were used simultaneously the conclusive classification increased to 72.7% with an accuracy 95.9%. The predictive ability of the biomarkers random forest produced similar test characteristics when using 11 predictive markers. CONCLUSION: We have demonstrated a pool of biomarkers from divergent biological pathways that can be used to classify individuals with potential early pregnancy loss. The biomarkers CG-Alpha, PAPPA and PSG3 can be used to predict viability and sFLT, TPFI2 and PSG3 can be used to predict pregnancy location.

Evaluation of novel biomarkers for early pregnancy outcome prediction†.

OBJECTIVE: To assess performance and discriminatory capacity of commercially available enzyme-linked immunosorbent assays of biomarkers for predicting first trimester pregnancy outcome in a multi-center cohort. DESIGN: In a case-control study at three academic centers of women with pain and bleeding in early pregnancy, enzyme-linked immunosorbent assays of biomarkers were screened for assay performance. Performance was assessed via functional sensitivity, assay reportable range, recovery/linearity, and intra-assay precision (%Coefficient of Variation). Top candidates were analyzed for discriminatory capacity for viability and location among 210 women with tubal ectopic pregnancy, viable intrauterine pregnancy, or miscarriage. Assay discrimination was assessed by visual plots, area under the curve with 95% confidence intervals, and measures of central tendency with two-sample t-tests. RESULTS: Of 25 biomarkers evaluated, 22 demonstrated good or acceptable assay performance. Transgelin-2, oviductal glycoprotein, and integrin-linked kinase were rejected due to poor performance. The best biomarkers for discrimination of pregnancy location were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 1, insulin-like growth factor binding protein 1, kisspeptin (KISS1), pregnancy-specific beta-1-glycoprotein 3, and beta parvin (PARVB). The best biomarkers for discrimination of pregnancy viability were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 3, EH domain-containing protein 3, KISS1, WAP four-disulfide core domain protein 2 (HE4), quiescin sulfhydryl oxidase 2, and pregnancy-specific beta-1-glycoprotein 1. CONCLUSION: Performance of commercially available enzyme-linked immunosorbent assays was acceptable for a panel of novel biomarkers to predict early pregnancy outcome. Of these, six and seven candidates demonstrated good discriminatory capacity of pregnancy location and viability, respectively, when validated in a distinct external population. Four markers demonstrated good discrimination for both location and viability.

Evaluation of a New Model for Human Chorionic Gonadotropin Rise in Pregnancies of Unknown Viability.

OBJECTIVE: To evaluate the performance of a new human chorionic gonadotropin (hCG) threshold model to classify pregnancies as viable or nonviable using a longitudinal cohort of individuals with pregnancy of unknown viability. The secondary objective was to compare the new model with three established models. METHODS: This is a single-center, retrospective cohort study of individuals seen at the University of Missouri from January 1, 2015, until March 1, 2020, who had at least two consecutive quantitative hCG serum levels with an initial level greater than 2 milli-international units/mL and 5,000 milli-international units/mL or less, with the first interval between laboratory draws no greater than 7 days. Prevalence of correct classification of viable intrauterine pregnancies, ectopic pregnancies, and early pregnancy losses was evaluated with a new proposed hCG threshold model and compared with three established models describing minimum expected rates of hCG rise for a viable intrauterine pregnancy. RESULTS: Of an initial cohort of 1,295 individuals, 688 patients met inclusion criteria. One hundred sixty-seven individuals (24.3%) had a viable intrauterine pregnancy; 463 (67.3%) had an early pregnancy loss; and 58 (8.4%) had an ectopic pregnancy. A new model based on the total additive percent rise of hCG at 4 and 6 days after initial hCG (70% or greater and 200% or greater rise, respectively) was created. The new model was able to correctly identify 100% of viable intrauterine pregnancies while minimizing incorrect classification of early pregnancy losses and ectopic pregnancies as normal pregnancies. At 4 days after initial hCG, 14 ectopic pregnancies (24.1%) and 44 early pregnancy losses (9.5%) were incorrectly classified as potentially normal pregnancies. At 6 days after initial hCG, only seven ectopic pregnancies (12.1%) and 25 early pregnancy losses (5.6%) were incorrectly classified as potentially normal pregnancies. In established models, up to nine intrauterine pregnancies (5.4%) were misclassified as abnormal pregnancies and up to 26 ectopic pregnancies (44.8%) and 58 early pregnancy losses (12.5%) were incorrectly classified as potentially normal pregnancies. CONCLUSION: The proposed new hCG threshold model optimizes a balance between identifying potentially viable intrauterine pregnancies and minimizing misdiagnosis of ectopic pregnancies and early pregnancy losses. External validation in other cohorts is needed before widespread clinical use.

Ectopic Pregnancy and Lifesaving Care.

This JAMA Insights Clinical Update discusses the management of ectopic pregnancy and the urgency of prompt intervention.

Validation of a multiple marker test for early pregnancy outcome prediction.

PURPOSE: To validate the use of a multiple biomarker test panel for predicting first trimester pregnancy outcome in a multi-center cohort. METHODS: A case-control study of women presenting with pain and bleeding in early pregnancy at 5-10 weeks gestational age was performed at three academic centers. Sera from women with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage (SAB) were analyzed via immunoassay for Activin A (AA), Progesterone (P4), A Disintegrin And Metalloprotease-12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), glycodelin (Glyc), and human chorionic gonadotropin (hCG). Biomarkers were assessed for reproducibility using medians, ranges, standard deviations, and area under receiver-operating characteristic curve (AUC) and accuracy in early pregnancy outcome classification compared to a previous derivation population. RESULTS: In 192 pregnancies, the biomarkers demonstrated good reproducibility with similar medians, ranges, and AUCs when compared to the derivation population except glycodelin. Pregnancy location was conclusively classified in 53% (n = 94) of the whole study sample with 78% accuracy. Pregnancy viability was conclusively classified in 58% (n = 112) of the new sample with 89% accuracy. Results were similar with subsequent model revisions where glycodelin was excluded and in the subgroups of subjects with a hCG below 2000 mIU/mL and a gestational age less than 6 weeks. CONCLUSION: The use of a panel of biomarkers to maximize test accuracy of a prediction of pregnancy location and prediction of pregnancy viability was reproducible and validated in an external population from which it was derived, but clinical utility is limited based on the test characteristics obtained.

Turner syndrome: fertility counselling in childhood and through the reproductive lifespan.

PURPOSE OF REVIEW: The potential for fertility in Turner syndrome has improved in recent years. Understanding of associated risks and approaches is important for the care of girls and women with this condition. This review focuses on reproductive health, fertility options and appropriate counselling for women with Turner syndrome and their families. RECENT FINDINGS: Women with Turner syndrome have rapidly declining ovarian function beginning in utero . Therefore, counselling regarding fertility concerns should begin at a young age and involve discussion of options, including ovarian tissue cryopreservation, oocyte preservation and use of nonautologous oocytes. Clinical guidance on fertility management and pregnancy risk assessment based on karyotype, associated comorbidities and fertility is still not fully data driven. Realistic expectations regarding reproductive options and associated outcomes as well as the need for multidisciplinary follow-up during pregnancy are crucial to the ethical and safe care of these patients. SUMMARY: Fertility care in women with Turner syndrome is evolving as current management techniques improve and new approaches are validated. Early counselling and active management of fertility preservation is critical to ensure positive and well tolerated reproductive outcomes.

Perioperative Outcomes in Patients Who Underwent Fibula, Osteocutaneous Radial Forearm, and Scapula Free Flaps: A Multicenter Study.

Importance: Studies comparing perioperative outcomes of fibula free flaps (FFFs), osteocutaneous radial forearm free flaps (OCRFFFs), and scapula free flaps (SFFs) have been limited by insufficient sample size. Objective: To compare the perioperative outcomes of patients who underwent FFFs, OCRFFFs, and SFFs. Design, Setting, and Participants: This cohort study assessed the outcomes of 1022 patients who underwent FFFs, OCRFFFs, or SFFs for head and neck reconstruction performed at 1 of 6 academic medical centers between January 2005 and December 2019. Data were analyzed from September 17, 2021, to June 9, 2022. Main Outcomes and Measures: Patients were stratified based on the flap performed. Evaluated perioperative outcomes included complications (overall acute wound complications, acute surgical site infection [SSI], fistula, hematoma, and flap failure), 30-day readmissions, operative time, and prolonged hospital length of stay (75th percentile, >13 days). Patients were excluded if data on flap type or clinical demographic characteristics were missing. Associations between flap type and perioperative outcomes were analyzed using logistic regression, after controlling for other clinically relevant variables. Adjusted odds ratios (aORs) with 95% CIs were generated. Results: Perioperative outcomes of 1022 patients (mean [SD] age, 60.7 [14.5] years; 676 [66.1%] men) who underwent major osseous head and neck reconstruction were analyzed; 510 FFFs (49.9%), 376 OCRFFFs (36.8%), and 136 SFFs (13.3%) were performed. Median (IQR) operative time differed among flap types (OCRFFF, 527 [467-591] minutes; FFF, 592 [507-714] minutes; SFF, 691 [610-816] minutes). When controlling for SSI, FFFs (aOR, 2.47; 95% CI, 1.36-4.51) and SFFs (aOR, 2.95; 95% CI, 1.37-6.34) were associated with a higher risk of flap loss than OCRFFFs. Compared with OCRFFFs, FFFs (aOR, 1.77; 95% CI, 1.07-2.91) were associated with a greater risk of fistula after controlling for the number of bone segments and SSI. Both FFFs (aOR, 1.77; 95% CI, 1.27-2.46) and SFFs (aOR, 1.68; 95% CI, 1.05-2.69) were associated with an increased risk of 30-day readmission compared with OCRFFFs after controlling for Charlson-Deyo comorbidity score and acute wound complications. Compared with OCRFFFs, FFFs (aOR, 1.78; 95% CI, 1.25-2.54) and SFFs (aOR, 1.96; 95% CI, 1.22-3.13) were associated with a higher risk of prolonged hospital length of stay after controlling for age and flap loss. Conclusions and Relevance: Findings of this cohort study suggest that perioperative outcomes associated with OCRFFFs compare favorably with those of FFFs and SFFs, with shorter operative times and lower rates of flap loss, 30-day readmissions, and prolonged hospital length of stay. However, patients undergoing SFFs represented a more medically and surgically complex population than those undergoing OCRFFFs or FFFs.

Differentiating pregnancies near the uterotubal junction (angular, cornual, and interstitial): a review and recommendations.

Eccentrically located intracavitary pregnancies, which include pregnancies traditionally termed as cornual and/or angular, have long presented complex diagnostic and management challenges given their inherent relationship to interstitial ectopic pregnancies. This review uses the existing literature to discriminate among interstitial, cornual, and angular pregnancies. Current arguments propose the outright abandonment of the terms cornual and angular may be justified in favor of the singular term, eccentric pregnancy. Disparate definitions and diagnostic approaches have compromised the literature's ability to precisely describe prognosis and ideal management practices for each of these types of pregnancies. Standardizing the classification of these pregnancies near the uterotubal junction is important to unify conservative, yet safe and effective management strategies. We advocate the use of early first trimester ultrasound to correctly differentiate between eccentric pregnancy and interstitial ectopic pregnancy as current research suggests substantially better outcomes with correctly diagnosed and expectantly managed eccentric pregnancies than past investigations may have shown. The expectant management of eccentric pregnancies will often result in a healthy term pregnancy, while interstitial ectopic pregnancies inherently have a poor likelihood of progressing to viability. When the terms and diagnosis of cornual, angular, and interstitial pregnancy are indistinct, there is substantial risk of intrauterine pregnancies to be inappropriately managed as ectopic pregnancies. Until we standardize terms and criteria, it will remain difficult, if not impossible, to determine true risk for pregnancy loss, preterm labor, abnormal placentation, and uterine or uterotubal rupture. The development of best practice guidelines will require standardized terminology and diagnostic techniques.

Refining Angular Pregnancy Diagnosis in the First Trimester: A Case Series of Expectant Management.

OBJECTIVE: To describe the natural history and outcomes of a large cohort of expectantly managed angular pregnancies diagnosed in the first trimester by specific ultrasound criteria. METHODS: We conducted a prospective case series of women with prenatally diagnosed angular pregnancy at a single academic tertiary care center from March 2017 to February 2019. Participants were identified at first-trimester ultrasound scan using specifically proposed diagnostic criteria for angular pregnancy and followed prospectively. Maternal and fetal data were gathered from the medical record. RESULTS: Forty-two cases of angular pregnancy were identified at first-trimester ultrasound scan. At presentation, 33 patients (79%) were asymptomatic, eight (19%) had vaginal bleeding, and two (5%) had pain. The mean gestational age at diagnosis was 7.4±1.0 weeks; the mean myometrial thickness was 5.1±1.6 mm (95% CI 4.6-5.6). At initial follow-up about 2 weeks later, 23 patients (55%) had ultrasound scans that normalized, 13 (31%) cases persisted as angular pregnancies, and six (14%) resulted in early pregnancy loss. After each gestation had been followed until completion, 33 (80%) pregnancies resulted in live birth and eight (20%) in early pregnancy loss. One patient was lost to follow-up. Of the 33 live births, 24 (73%) were vaginal deliveries, nine (27%) were cesarean deliveries, 27 (82%) were term deliveries, and six (18%) were preterm deliveries. There were no cases of uterine rupture, maternal death, abnormal placentation, or hysterectomy. CONCLUSIONS: In 42 cases of angular pregnancy diagnosed by first-trimester ultrasound examination, outcomes were largely positive, with an 80% live-birth rate and a 20% early pregnancy loss rate. Early diagnosis of angular pregnancy using the described criteria may represent an entity that more closely resembles a normal, noneccentric intrauterine pregnancy rather than an ectopic pregnancy. Therefore, most cases can be closely observed and efforts made to expectantly manage pregnancies while awaiting viability.

Seizures in Pregnancy.

Seizures are among the most serious neurologic complications encountered in pregnancy. This review provides a foundation for the initial diagnosis, evaluation, classification, and management of seizures during pregnancy.