Nontubal ectopic pregnancies: overview of diagnosis and treatment.

Nontubal ectopic pregnancies occur as a result of embryo implantation outside the uterine cavity and fallopian tubes. Sites include ovary, cervix, abdominal cavity, interstitial portion of fallopian tube, and cesarean scar. Nontubal pregnancies are uncommon. Nonspecific signs and symptoms of nontubal ectopic pregnancies make diagnosis challenging and, in many cases, significantly delayed, resulting in a high rate of morbidity. Although surgical management remains the mainstay of treatment, there is growing evidence that some of these can be managed medically or with the use of a combination of medical and surgical approaches with good outcome. This review summarizes the current diagnostic modalities, therapeutic options, and outcomes for nontubal ectopic pregnancies. Diagnostic and management options may be limited, especially in resource-restricted settings. Therefore, an understanding of the available options is critical. It needs to be emphasized that the rarity of cases and the difficulties in organizing ethically justified randomized trials result in the lack of well-established management guidelines for nontubal ectopic pregnancies.

Genetic and Epidemiological Similarities, and Differences Between Postoperative Intraperitoneal Adhesion Development and Other Benign Fibro-proliferative Disorders.

Intraperitoneal adhesions complicate over half of abdominal-pelvic surgeries with immediate, short, and long-term sequelae of major healthcare concern. The pathogenesis of adhesion development is similar to the pathogenesis of wound healing in all tissues, which if unchecked result in production of fibrotic conditions. Given the similarities, we explore the published literature to highlight the similarities in the pathogenesis of intra-abdominal adhesion development (IPAD) and other fibrotic diseases such as keloids, endometriosis, uterine fibroids, bronchopulmonary dysplasia, and pulmonary, intraperitoneal, and retroperitoneal fibrosis. Following a literature search using PubMed database for all relevant English language articles up to November 2020, we reviewed relevant articles addressing the genetic and epidemiological similarities and differences in the pathogenesis and pathobiology of fibrotic diseases. We found genetic and epidemiological similarities and differences between the pathobiology of postoperative IPAD and other diseases that involve altered fibroblast-derived cells. We also found several genes and single nucleotide polymorphisms that are up- or downregulated and whose products directly or indirectly increase the propensity for postoperative adhesion development and other fibrotic diseases. An understanding of the similarities in pathophysiology of adhesion development and other fibrotic diseases contributes to a greater understanding of IPAD and these disease processes. At a very fundamental level, blocking changes in the expression or function of genes necessary for the transformation of normal to altered fibroblasts may curtail adhesion formation and other fibrotic disease since this is a prerequisite for their development. Similarly, applying measures to induce apoptosis of altered fibroblast may do the same; however, apoptosis should be at a desired level to simultaneously ameliorate development of fibrotic diseases while allowing for normal healing. Scientists may use such information to develop pharmacologic interventions for those most at risk for developing these fibrotic conditions.

Ultrasonographic technique to differentiate enhanced myometrial vascularity/arteriovenous malformation from retained products of conception.

PURPOSE: To objective of this study is to discuss the ultrasonographic technique to diagnose uterine enhanced myometrial vascularity/arteriovenous malformation (EMV/AVM) and differentiate it from retained products of conception. The study also reviews the management and outcome of EMV/AVM. METHODS: We present a series of three women who developed EMV after early pregnancy loss and a control case of incomplete abortion, where colour Doppler ultrasound was used to distinguish retained products of conception from features of EMV. Clinical status and imaging findings, including peak systolic velocity (PSV), were used for the initial risk stratification of the patients. All cases with EMV/AVM were managed expectantly with serial ultrasound imaging and trending human chorionic gonadotropin levels. The patient with retained products of conception was managed by hysteroscopy and curettage. RESULTS: In all cases, presentation was suggestive of incomplete abortion with retained products of conception. However, colour Doppler ultrasound demonstrated hypoechoic areas within the endometrium extending into the myometrium with a high maximum PSV. In the control case, colour Doppler ultrasound noted a heterogeneous area in the left uterine cavity; however, vascular flow in this area was distinct from the endometrium, suggesting retained products of conception. All three women with EMV were managed expectantly with close monitoring and good outcomes. CONCLUSION: In patients with early pregnancy loss and bleeding or persistently elevated human chorionic gonadotropin levels, clinical status and appropriate use of ultrasound imaging with colour Doppler, including PSV measurement, can assist in recognition of EMV/AVM. Expectant management with serial ultrasound evaluation is a safe treatment option for EMV/AVM with low PSV and can minimise complications such as need for blood transfusion, uterine artery embolization, and hysterectomy.

Fertility considerations in targeted biologic therapy with tyrosine kinase inhibitors: a review.

PURPOSE: To review the impact of tyrosine kinase inhibitors (TKIs) on fertility in men and women, embryo development, and early pregnancy, and discuss considerations for fertility preservation in patients taking TKIs. METHODS: A comprehensive literature search using the PubMed database was performed through February 2021 to evaluate the current literature on imatinib, nilotinib, dasatinib, and bosutinib as it relates to fertility and reproduction. Published case series were analyzed for pregnancy outcomes. RESULTS: TKIs adversely affect oocyte and sperm maturation, gonadal function, and overall fertility potential in a self-limited manner. There are insufficient studies regarding long-term consequences on fertility after discontinuation of TKIs. A total of 396 women and 236 men were on a first- or second-generation TKI at the time of conception. Of the women with detailed pregnancy and delivery outcomes (n = 361), 51% (186/361) resulted in a term birth of a normal infant, 4.3% (16/361) of pregnancies had a pregnancy complication, and 5% (20/361) of pregnancies resulted in the live birth of an infant with a congenital anomaly. About 22% of pregnant women (87/396) elected to undergo a termination of pregnancy, while 16% (63/396) of pregnancies ended in a spontaneous abortion. In contrast, of the 236 men, 87% conceived pregnancies which resulted in term deliveries of normal infants. Elective terminations, miscarriage rate, pregnancy complication rate, and incidence of a congenital malformation were all less than those seen in females (4%, 3%, 2%, and 2.5%, respectively). CONCLUSION: Women should be advised to avoid conception while taking a TKI. Women on TKIs who are considering pregnancy should be encouraged to plan the pregnancy to minimize inadvertent first trimester exposure. In women who conceive while taking TKIs, the serious risk of relapse due to discontinuation of TKI should be balanced against the potential risks to the fetus. The risk of teratogenicity to a fathered pregnancy with TKI use is considerably lower. Fertility preservation for a woman taking a TKI can be considered to plan a pregnancy with a minimal TKI-free period. With careful monitoring, providers may consider a TKI washout period followed by controlled ovarian stimulation to cryopreserve oocytes or embryos, with a plan to resume TKIs until ready to conceive or to transfer an embryo to achieve pregnancy quickly. Fertility preservation is also indicated if a patient on TKI is requiring a gonadotoxic therapy or reproductive surgery impacting fertility.

Availability of Fertility Preservation Information on the Websites of U.S. News and World Report Top-Ranked Pediatric Cancer Programs.

Purpose: To evaluate the availability of fertility preservation (FP) services and educational resources on the websites of top-ranked U.S. pediatric cancer programs. Methods: Cross-sectional survey of information and resources related to FP on websites from top-ranked pediatric cancer programs according to the 2018-2019 U.S.-News & World Report (USNWR) ranking. Factors that predicted the website availability of FP information or a fertility team were analyzed, as was availability in Spanish and for specific groups by sex and puberty status. As a surrogate marker of comprehensive oncological services, the availability of resources for psychological support was compared to FP. Results: A fertility team was referenced on the website of 36% of programs, but only 32% provided FP educational resources for patients. Among them, 100%, 93.8%, 93.8%, and 68.8% provided specific information for postpubertal females, prepubertal females, postpubertal males, and prepubertal males, respectively. The majority (93.8%) did not provide information in Spanish. The ranking on USNWR (p < 0.05) and patient volume (p < 0.05) positively correlated with the availability of FP information and fertility team on the program's website. Information regarding psychological support was provided more often than information regarding FP (96% vs. 32%, p < 0.05). Conclusion: The majority of the top-ranked pediatric cancer programs in the United States do not list FP resources or a fertility team on their website. The lack of resources is particularly concerning for the Spanish-speaking population, as well as for prepubertal males. This may be potentially hindering access to FP and contributing to health care disparities.

Is There a Genetic Predisposition to Postoperative Adhesion Development?

Adhesions are permanent fibrovascular bands between peritoneal surfaces, which develop following virtually all body cavity surgeries. The susceptibility to develop, and the severity, of adhesions following intra-abdominal surgery varies within and between individuals, suggesting that heritable factors influence adhesion development. In this manuscript, we discuss the pathophysiology of adhesion development from the perspective of genetic susceptibility. We restrict our discussion to genes and single-nucleotide polymorphisms (SNPs) that are specifically involved in, or that cause modification of, the adhesion development process. We performed a literature search using the PubMed database for all relevant English language articles up to March 2020 (n = 186). We identified and carefully reviewed all relevant articles addressing genetic mutations or single-nucleotide polymorphisms (SNPs) that impact the risk for adhesion development. We also reviewed references from these articles for additional information. We found several reported SNPs, genetic mutations, and upregulation of messenger RNAs that directly or indirectly increase the propensity for postoperative adhesion development, namely in genes for transforming growth factor beta, vascular endothelial growth factor, interferon-gamma, matrix metalloproteinase, plasminogen activator inhibitor-1, and the interleukins. An understanding of genetic variants could provide insight into the pathophysiology of adhesion development. The information presented in this review contributes to a greater understanding of adhesion development at the genetic level and may allow modification of these genetic risks, which may subsequently guide management in preventing and treating this challenging complication of abdominal surgery. In particular, the information could help identify patients at greater risk for adhesion development, which would make them candidates for anti-adhesion prophylaxis. Currently, agents to reduce postoperative adhesion development exist, and in the future, development of agents, which specifically target individual genetic profile, would be more specific in preventing intraperitoneal adhesion development.

Nerve-Sparing Modified Radical Hysterectomy for Severe Endometriosis and Complex Pelvic Pathology.

Background Laparoscopic nerve-sparing modified radical hysterectomy with or without robotic assistance is known for its benefits as a definitive treatment for severe endometriosis. Undiagnosed endometriosis is common in patients with symptomatic fibroids or chronic pelvic pain. There are minimal studies that outline the safety and feasibility of nerve-sparing modified radical hysterectomy for other complex pelvic pathology in addition to endometriosis. Objectives The aim of this study is to evaluate the incidence of hospital readmission, intraoperative and postoperative complications, and long-term pain relief after laparoscopic nerve-sparing modified radical hysterectomy for severe endometriosis and complex benign pelvic pathology. Study design We performed a retrospective observational study of patients who underwent laparoscopic nerve-sparing modified radical hysterectomy with and without robotic-assistance with a high-volume minimally invasive endoscopic surgeon between November 2017 and December 2019. Results A total of 112 patients met the inclusion criteria. There were no cases of vaginal cuff dehiscence, venous thromboembolism, genitourinary system injury, gastrointestinal tract injury, vessel injury, nerve injury, sepsis, or death. Three patients required postoperative hospital admission for the management of umbilical cellulitis, acute blood loss anemia, and possible Addison's crisis. Other postoperative complications included allergic reaction to adhesives (1.8%) and urinary retention (0.9%). All patients reported significant pain relief at the time of their postoperative visits. Three patients reported return of pain symptoms within the first seven months after surgery, with one requiring an additional surgery for persistent pain. Conclusions Laparoscopic nerve-sparing modified radical hysterectomy with or without robotic assistance is a safe and feasible alternative that provides long-term symptom relief in patients undergoing hysterectomy for a variety of indications.

Reproductive and oncologic outcomes after fertility-sparing surgery for early stage cervical cancer: a systematic review.

This review sought to evaluate the current literature on reproductive and oncologic outcomes after fertility-sparing surgery for early stage cervical cancer (stage IA1-IB1) including cold-knife conization/simple trachelectomy, vaginal radical trachelectomy, abdominal radical trachelectomy, and laparoscopic radical trachelectomy with or without robotic assistance. A systematic review using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist to evaluate the current literature on fertility-sparing surgery for early stage cervical cancer and its subsequent clinical pregnancy rate, reproductive outcomes, and cancer recurrence was performed. Sixty-five studies were included encompassing 3,044 patients who underwent fertility-sparing surgery, including 1,047 pregnancies with reported reproductive outcomes. The mean clinical pregnancy rate of patients trying to conceive was 55.4%, with the highest clinical pregnancy rate after vaginal radical trachelectomy (67.5%). The mean live-birth rate was 67.9% in our study. Twenty percent of pregnancies after fertility-sparing surgery required assisted reproductive technology. The mean cancer recurrence rate was 3.2%, and the cancer death rate was 0.6% after a median follow-up period of 39.7 months with no statistically significant difference across surgical approaches. Fertility-sparing surgery is a reasonable alternative to traditional radical hysterectomy for early-stage cervical cancer in women desiring fertility preservation. Vaginal radical trachelectomy had the highest clinical pregnancy rate, and minimally invasive approaches to fertility-sparing surgery had equivalent oncologic outcomes compared with an abdominal approach. The results of our study allow for appropriate patient counseling preoperatively and highlight the importance of a multidisciplinary approach to achieve the best outcomes for each patient.

BCL-6 Overexpression as a Predictor for Endometriosis in Patients Undergoing In Vitro Fertilization.

OBJECTIVE: To evaluate the positive predictive value (PPV) of endometrial BCL-6 overexpression as a noninvasive screening test endometriosis in patients undergoing in vitro fertilization (IVF). METHODS: Retrospective cohort study at a university-affiliated private practice. Inclusion criteria were reproductive age females currently undergoing IVF with a diagnosis of unexplained infertility or unexplained recurrent pregnancy loss. Those with endometrial BCL-6 overexpression underwent laparoscopic surgery with an indication for treatment of suspected endometriosis. The primary outcome was the PPV of endometrial BCL-6 testing to surgically diagnose endometriosis. Statistical analysis was performed using SPSS v.25.0. RESULTS: Seventy-five patients met inclusion criteria for our study. The PPV of BCL-6 testing for endometriosis was 96%. Of those patients without endometriosis, 100% had other inflammatory pelvic pathologies, which were diagnosed and treated at the time of laparoscopy. CONCLUSIONS: Endometrial BCL-6 overexpression has a high PPV for diagnosing endometriosis and can help identify a patient population that may require surgical treatment before embryo transfer.

Risk factors for cervical ectopic pregnancy.

OBJECTIVE: To evaluate risk factors for cervical ectopic pregnancies. METHODS: Retrospective, quasi-experimental case-control study of cervical ectopic pregnancy (CEP) cases from 2000-2013. Two groups were selected as controls, patients with tubal ectopic (TEP) and intrauterine pregnancies (IUP) without a history of TEP, matched by year of pregnancy and randomly sampled in a 1:3 case-control ratio per each study group. RESULTS: 21 cases were identified and 126 controls included, 63 TEP and IUP each. A binary logistic regression model was used to analyze whether statistically significant preceding factors from a bivariate analysis could predict CEP. Compared to patients with IUP, CEP patients had a higher history of elective abortions, D&C and cervical excisional procedures, with a high effect size (>0.7). Compared to patients with TEP, CEP patients had a higher history of D&C and cervical excisional procedures, with a high effect size (>.7). The risk of CEP was significantly higher with a prior history of D&C compared to an IUP (aOR 1.4; 95% CI, 1.1-9.1; p=0.04) and a TEP (aOR 6.1; 95% CI, 1.8-21.2; p=0.04). CONCLUSION: D&C is a strong risk factor for CEP when compared to pregnancies in other locations. These findings confirm previous associations described in case series.

Decreased hazard of necrotizing enterocolitis in preterm neonates receiving red cell transfusions.

BACKGROUND AND OBJECTIVES: Many observational studies reporting a temporal association between red cell transfusions (RBCTs) and necrotizing enterocolitis (NEC) in preterm infants fail to take into account RBCTs in infants without NEC. The objective of this study was to investigate the association between RBCTs and NEC in an analytical retrospective cohort study with minimization of selection and measurement bias and controlling for clinical covariates. METHODS: Inborn preterm infants [23-32 weeks gestational age (GA)] without major congenital anomalies were eligible. Association of RBCT and modified Bell's Stage ≥2A NEC was explored using bivariate analyses and verified using multivariable Cox regression. RESULTS: Of 627 eligible infants, 305 neither received RBCT nor developed NEC and 12 developed NEC prior to RBCT. Of 310 infants with RBCT, 27 developed NEC. Compared to infants without NEC, infants with NEC received significantly lower number of RBCTs before diagnosis of NEC (p = 0.000). On multivariable Cox regression controlling for clinical covariates, dichotomous RBCT exposure was associated with 60% reduced hazard for NEC. CONCLUSIONS: RBCT exposure was associated with decreased hazards for NEC in preterm infants in this study; factors previously reported to be associated with NEC remained statistically significant predictors.

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

BACKGROUND: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE: To elucidate mechanisms underlying different forms of HIES. METHODS: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.