Prevalence threshold and positive predictive value of noninvasive prenatal testing.

OBJECTIVE: Noninvasive prenatal testing (NIPT) has increased the number of conditions that can be screened. However, the prevalence of conditions assessed by NIPT has remained stable. The "prevalence threshold," a novel epidemiological concept, uses a test's sensitivity and specificity to determine the prevalence below which a test's positive predictive value declines most sharply relative to disease prevalence. In this article, we calculated the prevalence threshold for common conditions assessed through NIPT and compared the value with the actual prevalence of each condition to best ascertain the reliability of NIPT results. METHODS: Six databases and PubMed were searched from January 2010 to March 2023 for sensitivity and specificity parameters of common conditions tested through NIPT. Using an equation previously derived by the authors of the current paper, the prevalence threshold for each condition was calculated. The theoretical number of test iterations required to reach the prevalence threshold was also reported. RESULTS: None of the conditions tested through the NIPT had a prevalence rate that met or exceeded the calculated prevalence threshold. Trisomy 21 had the greatest concordance between the prevalence rate and the prevalence threshold. In contrast, Angelman, Cri-du-chat, and Prader-Willi syndromes had the most significant discordance. Apart from trisomy 21 and XXY, all remaining conditions required more than one test iteration to reach their respective prevalence threshold. CONCLUSION: We conclude that at the current prevalence levels, the positive predictive value of NIPT remains low, with the prevalence of disease levels significantly lower than the prevalence threshold for each condition tested.

The Effects of Long-Term Dienogest Therapy on In Vitro Fertilization Outcomes in Women with Endometriosis: A Systematic Review and Meta-Analysis.

OBJECTIVES: Assessing dienogest's efficacy in endometriosis patients undergoing in vitro fertilization (IVF). DATA SOURCES: Systematic search in databases (PubMed, MEDLINE, Embase, Web of Science, Cochrane CENTRAL, Google Scholar) until 1 October 2022. STUDY SELECTIONS: Randomized trials and observational studies comparing extended dienogest pre-treatment, no pre-treatment, or gonadotropin-releasing hormone (GnRH) agonist pre-treatment in endometriosis-linked IVF. OUTCOME MEASURES: live birth, clinical pregnancy rates, oocytes collected, miscarriage rate, gonadotropin consumption. DATA EXTRACTIONS AND SYNTHESES: Two authors independently assessed eligibility. Dichotomous variables were analyzed via a random-effect model and Mantel-Haenszel method to calculate weighted estimates and 95% confidence intervals (CI). I2 statistic gauged study heterogeneity; GRADE criteria evaluated evidence quality. CONCLUSIONS: Out of 191 publications, five studies with 723 participants were included. Uncertainty persists on whether prolonged dienogest affects live birth (RR 1.42, 95% CI 0.29 to 6.84; 3 studies, n = 289; I2 86%) and clinical pregnancy rates (RR 1.33, 95% CI 0.31 to 5.65; 3 studies, n = 289; I2 86%) compared to conventional IVF. Moreover, uncertainty remains regarding intervention impact on live birth (RR 1.46, 95% CI 0.63 to 3.37; 1 study, n = 34) and clinical pregnancy rates (RR 1.32, 95% CI 0.78 to 2.23; 3 studies, n = 288; I2 0%) versus long-term GnRH agonist therapy before IVF. Given limited data and very low evidence quality, doubts arise about the benefits of long-term dienogest pre-treatment before conventional IVF in endometriosis patients.

Apoptosis versus necrosis in tubal ectopic pregnancies following Methotrexate.

Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required.

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.

Update on preimplantation genetic testing for aneuploidy and outcomes of embryos with mosaic results.

Preimplantation genetic testing for aneuploidy (PGT-A) is used as a frequent add-on for in-vitro fertilization (IVF) to improve clinical outcomes. The purpose is to select a euploid embryo following chromosomal testing on embryo biopsies. The current practice includes comprehensive chromosome screening (CCS) technology applied on trophectoderm (TE) biopsies. Despite its widespread use, PGT-A remains a controversial topic mainly because all of the RCTs comprised only good prognosis patients with 2 or more blastocysts available; hence the results are not generalizable to all groups of patients. Furthermore, with the introduction of the highly-sensitive platforms into clinical practice (i.e. next-generation sequencing [NGS]), a result consistent with intermediate copy number surfaced and is termed "Mosaic," consistent with a mixture of euploid and aneuploid cells within the biopsy sample. The optimal disposition and management of embryos with mosaic results is still an open question, as many 'mosaics' generated healthy live births with no identifiable congenital anomalies. The present article provides a complete and comprehensive up-to-date review on PGT-A. It discusses in detail the findings of all the published RCTs on PGT-A with CCS, comments on the subject of "mosaicism" and its current management, and describes the latest technique of non-invasive PGT-A.

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

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

Prevention of multiple pregnancies in gonadotropin-insemination cycles.

PURPOSE OF REVIEW: Although elective single embryo transfer has significantly reduced, the rate of multiple pregnancy in IVF cycles, this rate is still relatively high in gonadotropin-insemination cycles. Patients who fail to ovulate or to conceive with oral agents and have constraints for IVF are usually candidates for gonadotropin injections. The current review article provides an up-to-date summation of the different strategies that can be adopted to reduce the risk of multiple pregnancies in gonadotropin-stimulated intrauterine insemination cycles. RECENT FINDINGS: Gonadotropin-insemination treatments should be used judiciously by experienced providers. One should always start with the lowest effective gonadotropin dose (∼37.5 IU), monitor closely the ovarian response, and consider cycle cancellation or conversion to IVF whenever a high response is encountered. Therefore, every infertility practice should define its own cancellation and 'rescue IVF' criteria depending on the number of mature ovarian follicles and the age of the female partner. SUMMARY: These preventive measures amongst others should mitigate the risk of multiple pregnancies that can arise from gonadotropin-insemination cycles.

Successful treatment of ptyalism gravidarum with clonidine hydrochloride: A case report.

Ptyalism gravidarum is a disorder characterized by significant hypersalivation during pregnancy, which affects and interferes with quality of life. No published data has demonstrated an effective approach to treat this condition. This case study reports the use of clonidine hydrochloride, an alpha-2-adrenergic receptor agonist that is typically used as an anti-hypertensive agent, to treat the excessive sialorrhea typical of this disorder. The patient who was treated with this medication saw significant improvement in her symptoms and did not experience any subsequent adverse effects throughout her pregnancy. As a result, we believe that further investigation into this potential treatment for ptyalism gravidarum is necessary ahead of medical guideline incorporation and clinical implementation.

Bayesian updating and sequential testing: overcoming inferential limitations of screening tests.

BACKGROUND: Bayes' theorem confers inherent limitations on the accuracy of screening tests as a function of disease prevalence. Herein, we establish a mathematical model to determine whether sequential testing with a single test overcomes the aforementioned Bayesian limitations and thus improves the reliability of screening tests. METHODS: We use Bayes' theorem to derive the positive predictive value equation, and apply the Bayesian updating method to obtain the equation for the positive predictive value (PPV) following repeated testing. We likewise derive the equation which determines the number of iterations of a positive test needed to obtain a desired positive predictive value, represented graphically by the tablecloth function. RESULTS: For a given PPV ([Formula: see text]) approaching k, the number of positive test iterations needed given a prevalence of disease ([Formula: see text]) is: [Formula: see text] where [Formula: see text] = number of testing iterations necessary to achieve [Formula: see text], the desired positive predictive value, ln = the natural logarithm, a = sensitivity, b = specificity, [Formula: see text] = disease prevalence/pre-test probability and k = constant. CONCLUSIONS: Based on the aforementioned derivation, we provide reference tables for the number of test iterations needed to obtain a [Formula: see text] of 50, 75, 95 and 99% as a function of various levels of sensitivity, specificity and disease prevalence/pre-test probability. Clinical validation of these concepts needs to be obtained prior to its widespread application.

Mode of delivery is an independent risk factor for maternal mortality: a case-control study.

BACKGROUND AND OBJECTIVES: In contrast to the global trend, the maternal mortality ratio (MMR) in the United States has increased in recent decades. During this time, the cesarean section rate has concurrently and steadily increased. Herein, we sought to determine whether the mode of delivery is an independent risk factor for maternal in-hospital mortality. MATERIALS AND METHODS: We conducted a retrospective, population-based, 1:1 matched, case-control study on all births recorded in the Health - Care Cost and Utilization Project - Nationwide Inpatient Sample between 2005 and 2014. We compared cases of maternal mortality and survival on a number of clinical characteristics. We conducted two different multivariate logistic regression analysis models, obtaining the adjusted odds ratios to determine the independent effect of mode of delivery on maternal mortality relative to surviving controls. RESULTS: We found a total of 617 cases of maternal mortality, which corresponds to an in-hospital MMR of 6.9/100,000 in our cohort. We matched 617 controls to mortality cases by year and geographic location. Relative to surviving controls, cases of maternal mortality were older, more likely to be African American, of lesser income, more likely to use Medicaid as payment, to have prolonged admissions, and more likely to have severe obstetrical complications including preterm delivery, postpartum hemorrhage, eclampsia, peripartum cardiomyopathy, pulmonary emboli, and disseminated intravascular coagulation (DIC). Relative to unassisted vaginal delivery, adjusted logistic regression analysis reveals no excess mortality observed with assisted vaginal delivery: OR 1.35, 95% CI [0.59-3.51]. However, after adjusting for demographic and obstetrical confounders, a significant risk of maternal mortality was observed with cesarean delivery: OR 3.21, 95% CI [2.80-3.61], p-value = .0001. This risk was more pronounced amongst primary cesarean deliveries: OR 5.72, 95% CI [4.92-6.51], p-value = .0001. CONCLUSION: Cesarean delivery, and particularly primary cesarean delivery, is an independent risk factor for maternal in-hospital mortality. Measures taken to reduce the cesarean section rate may impact the rising maternal mortality ratio (MMR) in the United States.

Influence of Maternal Age and Ovarian Reserve on the Decision to Continue or to Cancel IVF Cycles in Patients with One or Two Large Follicles: a Dual Effect.

This study aimed to study whether IVF stimulation that results in one or two mature follicles should proceed to oocyte retrieval. This is a retrospective cohort study conducted at McGill University Health Center on 459 patients who underwent IVF treatment between 2011 and 2014, undergoing hormonal stimulation and monitoring of their ovarian response. The primary outcomes were pregnancy and live birth rates. Statistical modeling was used to determine individual roles of patient age and ovarian reserve on outcomes, while controlling for the other factors. Of the 459 cycles included in the study, 360 cycles (78.4%) ended in embryo transfer. Live birth rates per cycle were 15.6%, for the ≤ 34-year-olds; 6.5%, for the 35-39-year-olds; and 2.7%, for the ≥ 40-year-olds (p < 0.01). Twenty-five percent of the cycles in the ≥ 40-year-old group were canceled versus 17% and 15% in the 35-39-year-old and ≤ 34-year-old groups, respectively (p < 0.05). Testing likelihood of live birth as a function of age and antral follicular count (AFC) revealed that a 1-year increase in age reduces the likelihood of live birth by 11% (p < 0.05) and one-unit increase in AFC count leads to a 9% increase in the odds of a live birth (p < 0.05). For the youngest age group, the AFC had a most significant effect, and those with AFC > 11 had 56% live birth rate, while those with AFC ≤ 11 had only 6% of live birth rate. This study supports a shift in reasoning from age being the predictor of outcomes in women with a low response at IVF to both age and ovarian reserve needing to be taken into consideration.

On the formalism of the screening paradox.

Bayes' Theorem imposes inevitable limitations on the accuracy of screening tests by tying the test's predictive value to the disease prevalence. The aforementioned limitation is independent of the adequacy and make-up of the test and thus implies inherent Bayesian limitations to the screening process itself. As per the WHO's Wilson - Jungner criteria, one of the prerequisite steps before undertaking screening is to ensure that a treatment for the condition screened for exists. However, when applying screening programs in closed systems, a paradox, henceforth termed the "screening paradox", ensues. If a disease process is screened for and subsequently treated, its prevalence would drop in the population, which as per Bayes' theorem, would make the tests' predictive value drop in return. Put another way, a very powerful screening test would, by performing and succeeding at the very task it was developed to do, paradoxically reduce its ability to correctly identify individuals with the disease it screens for in the future-over some time t. In this manuscript, we explore the mathematical model which formalizes said screening paradox and explore its implications for population level screening programs. In particular, we define the number of positive test iterations (PTI) needed to reverse the effects of the paradox. Given their theoretical nature, clinical application of the concepts herein reported need validation prior to implementation. Meanwhile, an understanding of how the dynamics of prevalence can affect the PPV over time can help inform clinicians as to the reliability of a screening test's results.

Prevalence threshold of screening tests in obstetrics and gynecology.

OBJECTIVE: We define the prevalence threshold as the prevalence level below which a test's positive predictive value (PPV) declines most sharply relative to disease prevalence - and thus the rate of false positive results/false discovery rate increases most rapidly. The objective of this study is to determine the prevalence threshold of various screening tests used in obstetrics and gynecology among low-risk women in modern clinical practice. METHODS: We searched Medline, EMBASE, Google Scholar, Scopus, ISI Web of Science, Cochrane database, and PubMed to obtain the sensitivity and specificity estimates for the following screening tests: 50 g-oral glucose tolerance test (GDM-50 g), non-invasive prenatal testing (NIPT), combined first trimester screening (FTS), vagino-rectal swab for group B streptococcus (GBS) in pregnancy, cervical cytology (Pap) and HPV testing, mammography and manual breast exam, urinary PCR and cervical-vaginal swab testing for gonorrhoea and chlamydia as well as AMH for the diagnosis of PCOS. We used these estimates to calculate disease-specific prevalence thresholds, comparing them to the actual estimates of disease prevalence. RESULTS: The prevalence thresholds and average estimates of disease prevalence (shown in brackets) are as follows: GDM-50 g 31 % (6%), NIPT 7% (0.2 %), combined FTS 19.5 % (0.2 %), GBS swab 18 % (15-45 %), Pap 21 % (0.2 %), HPV 27 % (0.2 %), mammography 25 % (12.5 %), breast exam 25 % (12.5 %), gonorrhoea -chlamydia 6-13 % (4.2-4.7 %), AMH for PCOS 32 % (10 %). CONCLUSION: The prevalence thresholds of various screening tests used in obstetrics and gynecology are well above the estimated disease prevalence. This implies that when undertaking population-level screening a significant proportion of positive screening tests obtained are likely false-positives. Attempts at individualizing pre-test probability when undertaking population-level screening are needed in order to best interpret the results of screening tests.

The Montreal Criteria and uterine transplants in transgender women.

Ever since its first documented live birth in 2014, the use of uterine transplantation (UTx) for the treatment of absolute uterine factor infertility (UFI) has seen major clinical advances, which include the use of alternative surgical approaches, different donor states, and diverse patient populations. In addition to the thorough research programs that developed the technique, this accomplishment has occurred in large part following a number of ethical frameworks, such as the Montreal Criteria and the Indianapolis Consensus, which paved the way to transition from experimental animal trials to human ones. To date, over 60 uterine transplants have been performed in the world, and at least 18 births have been thus far confirmed. While the procedure remains experimental, the vast knowledge and procedural experience amassed over the last 20 years of rigorous research have hinted at the next step of discovery. In particular, advancing social circumstances have prompted the question regarding the use of this technology in transgender individuals. Though the potential use of uterine transplants in the transgender population has been hypothesized, no in-depth ethical framework has been developed towards this purpose. Herein, we explore the ethical issues revolving around the use of this technology in this patient population and provide key insights that may advance this cause.

Ever-use of the intra-uterine device and the risk of ovarian cancer.

The association between the use of the intra-uterine device (IUD) and the risk of ovarian cancer is not well known. In this study, we sought to determine whether the use of an IUD is associated with a reduction in the risk of ovarian cancer. We searched Medline, EMBASE, Google Scholar, Scopus, ISI Web of Science and Cochrane database search, as well as PubMed (www.pubmed.gov) and RCT registry (www.clinicaltrials.gov) until the end of June 2019 to conduct a systematic review and meta-analysis comparing ever-use vs. never-use of an IUD and the risk of subsequent ovarian cancer. We obtained 431 records, of which 9 met inclusion criteria. A total of five case-control studies and four cohort studies were retrieved to establish the risk of ovarian cancer amongst ever-users of an IUD. Relative to the never-use of the IUD, ever-use conferred a lower risk of ovarian cancer with an estimated OR of 0.67 95% CI [0.60 - 0.74], p < .0001, I2 = 71%. This relationship remained significant when results were restricted to studies evaluating the levonorgestrel intrauterine system (LNG-IUD) alone, with an estimated OR of 0.58 95% CI [0.47 - 0.71], p < .0001, I2 = 0%, as well as when the analysis was stratified by study design, with an OR of 0.64 95% CI [0.56 - 0.74] for case-control studies, and OR of 0.71 95% CI [0.60 - 0.84] for cohort studies (p < .0001). Ever-use of an intrauterine contraceptive device reduces the risk of ovarian cancer by an average of 30%. Whether differences exist for duration of use, use of type-specific device, and specific tumour type needs to be addressed in future studies.Impact statementWhat is already known on this subject? The use of IUDs is very common practice in today's society. Its benefits regarding contraception, the treatment of abnormal uterine bleeding and even the reduction of the rates of endometrial cancer are well established. However, whether IUD's are associated with a reduction in the risk of ovarian cancer is unknown.What do the results of this study add? In this study, we show that the ever-use of the IUD reduces the risk of ovarian cancer by an average of 30%. We provide insight regarding the potential theories that may underlie these findings.What are the implications of these findings for clinical practice and/or further research? future studies will need to determine whether the beneficial effects found are a function of duration of use, of type-specific device, or specific tumour types. In the meantime, these findings may serve clinicians to reassure and counsel patients about the added benefits of intra-uterine devices.

Use of Placental Growth Factor for Trisomy 21 Screening in Pregnancy: A Systematic Review.

Background Prenatal serum screening is an important modality to screen for aneuploidy in pregnancy. The addition of placental growth factor (PLGF) to screen for trisomy 21 remains controversial. Objective To determine whether the addition of PLGF to combined serum aneuploidy screening improves detection rates (DRs) for trisomy 21. Study Design We performed a systematic review of the literature until October 2019 to determine the benefits of adding PLGF to prenatal screening. We performed a goodness-of-fit test and retrieved the coefficient of determinations ( R 2 ) as a function of false positive rates (FPRs), providing mean-weighted improvements in the DRs after accounting for PLGF levels. Results We identified 51 studies, of which 8 met inclusion criteria (834 aneuploidy cases and 105,904 euploid controls). DRs were proportional to FPR across all studies, ranging from 59.0 to 95.3% without PLGF and 61.0 to 96.3% with PLGF (FPR 1-5%). Goodness-of-fit regression analysis revealed a logarithmic distribution of DRs as a function of the FPR, with R 2 = 0.109 (no PLGF) and R 2 = 0.06 (PLGF). Two-sample Kolmogorov-Smirnov's test reveals a p -value of 0.44. Overall, addition of PLGF improves DRs of 3.3% for 1% FPR, 1.7% for 3% FPR, and 1.4% for 5% FPR, respectively. Conclusion Addition of PLGF to prenatal screening using serum analytes mildly improves trisomy 21 DRs as a function of FPRs.