Cost-effectiveness of Mifepristone Pretreatment for the Medical Management of Nonviable Early Pregnancy: Secondary Analysis of a Randomized Clinical Trial.

Importance: Early pregnancy loss (EPL) is the most common complication of pregnancy. A multicenter randomized clinical trial compared 2 strategies for medical management and found that mifepristone pretreatment is 25% more effective than the standard of care, misoprostol alone. The cost of mifepristone may be a barrier to implementation of the regimen. Objective: To assess the cost-effectiveness of medical management of EPL with mifepristone pretreatment plus misoprostol vs misoprostol alone in the United States. Design, Setting, and Participants: This preplanned. prospective economic evaluation was performed concurrently with a randomized clinical trial in 3 US sites from May 1, 2014, through April 30, 2017. Participants included 300 women with anembryonic gestation or embryonic or fetal demise. Cost-effectiveness was computed from the health care sector and societal perspectives, with a 30-day time horizon. Data were analyzed from July 1, 2018, to July 3, 2019. Interventions: Mifepristone pretreatment plus misoprostol administration vs misoprostol alone. Main Outcomes and Measures: Costs in 2018 US dollars, effectiveness in quality-adjusted life-years (QALYs), and treatment efficacy. Incremental cost-effectiveness ratios (ICERs) of mifepristone and misoprostol vs misoprostol alone were calculated, and cost-effectiveness acceptability curves were generated. Results: Among the 300 women included in the randomized clinical trial (mean [SD] age, 30.4 [6.2] years), mean costs were similar for groups receiving mifepristone pretreatment and misoprostol alone from the health care sector perspective ($696.75 [95% CI, $591.88-$801.62] vs $690.88 [95% CI, $562.38-$819.38]; P = .94) and the societal perspective ($3846.30 [95% CI, $2783.01-$4909.58] vs $4845.62 [95% CI, $3186.84-$6504.41]; P = .32). The mifepristone pretreatment group had higher QALYs (0.0820 [95% CI, 0.0815-0.0825] vs 0.0806 [95% CI, 0.0800-0.0812]; P = .001) and a higher completion rate after first treatment (83.8% vs 67.1%; P < .001) than the group receiving misoprostol alone. From the health care sector perspective, mifepristone pretreatment was cost-effective relative to misoprostol alone with an ICER of $4225.43 (95% CI, -$195 053.30 to $367 625.10) per QALY gained. From the societal perspective, mifepristone pretreatment dominated misoprostol alone (95% CI, -$5 111 629 to $1 801 384). The probabilities that mifepristone pretreatment was cost-effective compared with misoprostol alone at a willingness-to-pay of $150 000 per QALY gained from the health care sector and societal perspectives were approximately 90% and 80%, respectively. Conclusions and Relevance: This study found that medical management of EPL with mifepristone pretreatment was cost-effective when compared with misoprostol alone. Trial Registration: ClinicalTrials.gov Identifier: NCT02012491.

Initial hazard assessment of benzyl salicylate: In vitro genotoxicity test and combined repeated-dose and reproductive/developmental toxicity screening test in rats.

Benzyl salicylate is used as a fragrance ingredient and an ultraviolet light absorber, but its toxicity is unknown. Therefore, toxicity tests and hazard classification were conducted for screening assessment under the Japanese Chemical Substances Control Law. Benzyl salicylate was found to be non-genotoxic in vitro based on the chromosomal aberration test using Chinese hamster lung cells. However, the combined repeated-dose and reproductive/developmental screening toxicity test, in which male and female rats were administered benzyl salicylate by gavage at 0, 30, 100, or 300 mg/kg/day for 42 and 41-46 days, respectively, from 14 days before mating until postnatal Day 4, showed that repeated doses had major effects on the thymus, liver, epididymis, and femur at 100 and/or 300 mg/kg/day. Furthermore, although benzyl salicylate had no effect on the estrus cycle, fertility, corpus lutea, or implantation rate, embryonic resorption, offspring mortality, and neural tube defects were observed at 300 mg/kg/day, and the offspring had lower body weights at 30 and 100 mg/kg/day, suggesting teratogenicity similar to other salicylates. Based on the developmental toxicity, this chemical was classified as hazard class 2, with a lowest observed adverse effect level (LOAEL) of 30 mg/kg/day and a D-value of 0.003 mg/kg/day.

The ART of selecting the best embryo: A review of early embryonic mortality and bovine embryo viability assessment methods.

Animal reproductive biotechnology is continually evolving. Significant advances have been made in our understanding of early embryonic mortality and embryo development in domestic animals, which has improved the selection and success of in vitro technologies. Yet our knowledge is still relatively limited such that identifying a single embryo with the highest chance of survival and development for transfer remains challenging. While invasive methods such as embryo biopsy can provide useful information regarding the genetic status of the embryos, morphological assessment remains the most common evaluation. A recent shift, however, favors alternative, adjunct approaches for non-invasive assessment of an embryo's viability and developmental potential. Various analytical techniques have facilitated the evaluation of cellular health through the metabolome, the assessment of end products of cellular metabolism, or by analyzing spent media for small RNAs. This review discusses the application of noninvasive approaches for ascertaining the health and viability of in vitro-produced bovine embryos. A comparative analysis of noninvasive techniques for embryo assessment currently being investigated in cattle and humans is also discussed.

Twins less frequent than expected among male births in risk averse populations.

Male twin gestations exhibit higher incidence of fetal morbidity and mortality than singleton gestations. From an evolutionary perspective, the relatively high rates of infant and child mortality among male twins born into threatening environments reduce the fitness of these gestations, making them more vulnerable to fetal loss. Women do not perceive choosing to spontaneously abort gestations although the outcome may result from estimates, made without awareness, of the risks of continuing a pregnancy. Here, we examine whether the non-conscious decisional biology of gestation can be linked to conscious risk aversion. We test this speculation by measuring the association between household surveys in Sweden that gauge financial risk aversion in the population and the frequency of twins among live male births. We used time-series regression methods to estimate our suspected associations and Box-Jenkins modeling to ensure that autocorrelation did not confound the estimation or reduce its efficiency. We found, consistent with theory, that financial risk aversion in the population correlates inversely with the odds of a twin among Swedish males born two months later. The odds of a twin among males fell by approximately 3.5% two months after unexpectedly great risk aversion in the population. This work implies that shocks that affect population risk aversion carry implications for fetal loss in vulnerable twin pregnancies.

[Forensic medical assessment of the origin of the missed early post-traumatic abortions].

The objective of the present study was to develop an algorithm for the forensic medical assessment of the origin of the missed early post-traumatic abortions. The analysis of the available data on the main variants of traumatic pregnancy interruption was carried out. Diagnostic features of the missed early post-traumatic abortions are considered along with the possible errors in the use of the current approaches to forensic medical assessment of their origin. The proposed algorithm for the forensic medical assessment of the origin of the missed early post-traumatic abortions takes into consideration the specific features of the objects of interest and includes the analysis of the results of ultrasonic studies of the uterine cavity and histological investigations of the scraps of endometrial tissue. Absolute and probabilistic criteria for spontaneous and traumatic origin of the missed early post-traumatic abortions. The proposed algorithm is recommended for the use in routine clinical practice for the elucidation of the causes of the missed early post-traumatic abortions.

Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening.

Identifying genes that are important for embryo development is a crucial first step towards understanding their many functions in driving the ordered growth, differentiation and organogenesis of embryos. It can also shed light on the origins of developmental disease and congenital abnormalities. Current international efforts to examine gene function in the mouse provide a unique opportunity to pinpoint genes that are involved in embryogenesis, owing to the emergence of embryonic lethal knockout mutants. Through internationally coordinated efforts, the International Knockout Mouse Consortium (IKMC) has generated a public resource of mouse knockout strains and, in April 2012, the International Mouse Phenotyping Consortium (IMPC), supported by the EU InfraCoMP programme, convened a workshop to discuss developing a phenotyping pipeline for the investigation of embryonic lethal knockout lines. This workshop brought together over 100 scientists, from 13 countries, who are working in the academic and commercial research sectors, including experts and opinion leaders in the fields of embryology, animal imaging, data capture, quality control and annotation, high-throughput mouse production, phenotyping, and reporter gene analysis. This article summarises the outcome of the workshop, including (1) the vital scientific importance of phenotyping embryonic lethal mouse strains for basic and translational research; (2) a common framework to harmonise international efforts within this context; (3) the types of phenotyping that are likely to be most appropriate for systematic use, with a focus on 3D embryo imaging; (4) the importance of centralising data in a standardised form to facilitate data mining; and (5) the development of online tools to allow open access to and dissemination of the phenotyping data.

New decision-tree model for defining the risk of reproductive failure.

PROBLEM: Natural killer (NK) cells play a key role in embryo implantation and pregnancy success, whereas blood and uterine NK expansions have been involved in the pathophysiology of reproductive failure (RF). Our main goal was to design in a large observational study a tree-model decision for interpretation of risk factors for RF. METHODS OF STUDY: A hierarchical multivariate decision model based on a classification and regression tree was developed. NK and NKT-like cell subsets were analyzed by flow cytometry. RESULTS: By multivariate analysis, blood NK cells expansion was an independent risk factor for RF (both recurrent miscarriages and implantation failures). We propose a new decision-tree model for the risk interpretation of women with RF based on a combination of main risk factors. CONCLUSIONS: Women with age above 35 years and >13% CD56⁺CD16⁺ NK cells showed the highest risk of further pregnancy loss (100%).

First trimester assessment of pentraxin-3 levels in women with primary unexplained recurrent pregnancy loss.

OBJECTIVE: To evaluate the potential role of measuring first-trimester maternal Pentraxin-3 levels in patients with primary unexplained recurrent pregnancy loss. STUDY DESIGN: A case control study was conducted in Ain Shams University Maternity Hospital. Cases included 45 women with primary unexplained recurrent pregnancy loss and early pregnancy failure admitted for medical or surgical termination of pregnancy. Controls (45 women) included a matched group of apparently healthy pregnant women who had at least one previous uneventful pregnancy with no previous obstetric history of adverse pregnancy outcomes. Maternal venous blood samples were collected for assay of Pentraxin-3 using enzyme-linked immunosorbent assay. The main outcome measure was the pregnancy outcome in women with elevated Pentraxin-3 levels. RESULTS: 90 participants were statistically analyzed. In the patient group, the mean Pentraxin-3 level was 12.00 ± 4.07 ng/ml, while in the control group it was 1.69 ± 0.91 ng/ml. The difference was statistically significant (p<0.001). In the patient group, Pentraxin-3 showed a significant positive correlation with the number of previous miscarriages (p=0.038). CONCLUSION: Abnormally elevated Pentraxin-3 levels indicate the presence of an abnormally exaggerated intrauterine inflammatory or innate immune response that may cause pregnancy failure in women with primary unexplained recurrent pregnancy loss.

Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss.

OBJECTIVE: To compare the cost of two strategies for managing the patient with recurrent pregnancy loss (RPL). DESIGN: Cost analysis using a decision analytic model was used to compare obtaining an evidence-based workup (EBW) for RPL versus obtaining a karyotype of the products of conception (POC) and proceeding with an EBW only in the setting of euploid POC. SETTING: Outpatient care. PATIENT(S): A simulated cohort of patients experiencing a second pregnancy loss. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Total cost of investigating the cause of RPL after a second pregnancy loss. RESULT(S): For all age categories, obtaining a karyotype of POC was less costly than an evidenced-based RPL evaluation. Monte Caro analysis demonstrated a net economic benefit for the karyotype strategy ($4,498 [±$792] vs. $5,022 [±$1,130]). CONCLUSION(S): Our model suggests an economic advantage for obtaining a karyotype of POC in women with second miscarriage.

Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation.

OBJECTIVE: To compare the cost of selective recurrent pregnancy loss (RPL) evaluation, which is defined as RPL evaluation if the second miscarriage is euploid, versus universal RPL evaluation, which is defined as RPL evaluation after the second miscarriage. Traditionally, an RPL evaluation is instituted after the third miscarriage. However, recent studies suggest evaluation after the second miscarriage, which dramatically increases health care costs. Alternatively, chromosome testing of the second miscarriage, to determine whether an RPL evaluation is required, has been proposed. DESIGN: Decision-analytic model. SETTING: Academic medical center. PATIENT(S): Couples experiencing a second miscarriage of less than 10 weeks size. INTERVENTION(S): Selective versus universal RPL evaluation after the second miscarriage. MAIN OUTCOME MEASURE(S): Estimated cost for selective versus universal RPL evaluation. RESULT(S): The estimated cost of selective RPL evaluation after the second miscarriage was $3,352, versus $4,507 for universal RPL evaluation, resulting in a cost savings of $1,155. With stratification by maternal age groups, selective RPL evaluation resulted in increased cost savings with advancing maternal age groups. CONCLUSION(S): Selective RPL evaluation, which is based upon chromosome testing of the second miscarriage, is a cost-saving strategy for couples with RPL when compared with universal RPL evaluation. With advancing maternal age groups, the cost savings increased.

The cynomolgus monkey as a model for developmental toxicity studies: variability of pregnancy losses, statistical power estimates, and group size considerations.

BACKGROUND: This work evaluates pregnancy and infant loss in 1,069 vehicle-treated cynomolgus monkeys from 78 embryo-fetal development (EFD) studies and 14 pre-postnatal development (PPND) studies accrued during 1981-2007. METHODS: Losses were analysed by survival function and hazard ratio using logistic regression for influence of year, study type (e.g., dose duration), and test item route of administration (ig, im, iv, sc). RESULTS: Neither study type nor route of dosing affected pregnancy outcome. Losses were higher pre-1990 (104 losses/347 pregnancies) compared to 1990 onwards (94 losses/722 pregnancies). Losses were greatest before gestation day 50 and at parturition. Using post-1989 data, Monte-Carlo simulations of pregnancy outcomes were created. The power associated with the comparison of vehicle survival curves and simulated adverse survival curves was examined. This showed that EFD studies with initial vehicle group sizes of 16 and 20 have an 80% probability of having 13 and 16 ongoing pregnancies at gestational day 100, respectively. For PPND studies with initial vehicle group sizes of 16, 20, or 28, there is an 80% likelihood of having 9, 11, or 16 infants at day 7 post-partum, respectively. A PPND study initiated with group size 20 could detect a threefold increase of test item-related pregnancy or infant loss. CONCLUSIONS: For designing and managing primate developmental toxicity studies, this type of analysis provides an objective tool to facilitate decisions either by supplementing groups with additional pregnant animals or stopping a group because an adverse effect on offspring survival has already been adequately revealed.

Assessment of sperm factors possibly involved in early recurrent pregnancy loss.

OBJECTIVE: To evaluate and compare standard sperm parameters, lipid peroxidation of sperm plasma membranes, antioxidant capacity of seminal plasma, and sperm chromatin integrity in ejaculates from men whose partners have a history of recurrent pregnancy loss and from a control group of men with recent fertility. DESIGN: Descriptive study. SETTING: Reproduction Program, University of Antioquia, Medellín, Colombia. PATIENT(S): Twenty-three couples with history of recurrent pregnancy loss and 11 men with recent fertility. INTERVENTION(S): Semen samples from control men and men whose partner had a history of recurrent pregnancy loss were examined for differences in semen parameters, lipid peroxidation, antioxidant capacity, DNA fragmentation index, and sperm preparation. MAIN OUTCOME MEASURE(S): Migration-sedimentation method was used to collect motile spermatozoa from fresh ejaculates for examination for semen parameters. RESULT(S): Men from the control group had spermatozoa with higher percentage of normal sperm morphology, concentration, progressive motility, and antioxidant capacity compared with men from the recurrent pregnancy loss group, who had spermatozoa with higher teratozoospermia and higher lipid peroxidation. Motile sperm fractions from both groups had spermatozoa with better sperm parameters compared with freshly ejaculated sperm. CONCLUSION(S): This study strengthens the current literature associating sperm quality with recurrent pregnancy loss, and emphasizes the importance of evaluating male factor by tests such as lipid peroxidation and measuring antioxidant capacity of seminal plasma in addition to conventional sperm parameters.

The scourge: moral implications of natural embryo loss.

It is often claimed that from the moment of conception embryos have the same moral status as adult humans. This claim plays a central role in many arguments against abortion, in vitro fertilization, and stem cell research. In what follows, I show that this claim leads directly to an unexpected and unwelcome conclusion: that natural embryo loss is one of the greatest problems of our time and that we must do almost everything in our power to prevent it. I examine the responses available to those who hold that embryos have full moral status and conclude that they cannot avoid the force of this argument without giving up this key claim.

Patient preferences, satisfaction, and resource use in office evacuation of early pregnancy failure.

OBJECTIVE: To examine patient treatment preferences and satisfaction with an office-based procedure for early pregnancy failure and to compare resource use and cost between office and operating room management of early pregnancy failure. METHODS: This study was a prospective observational study of 165 women presenting for surgical management of early pregnancy failure. Participants completed a preoperative questionnaire addressing treatment preferences and expectations and a postoperative questionnaire measuring level of pain experienced and satisfaction with care. Resource use was determined by measuring the time patients spent at the health care facility and the actual procedure time. Cost was estimated using an institutional database. RESULTS: One hundred fifteen women from the office and 50 from the operating room were enrolled. Patients selecting outpatient management scored "privacy," "avoiding going to sleep," and "previous experience" higher than the operating room group (P < .05). Patients who perceived that their physicians preferred one procedure over the other were more likely to select that procedure (P < .001). Satisfaction was high in both groups, and underestimating the procedure's discomfort was negatively associated with satisfaction (P < .002). Costs were greater than two-fold higher in the operating room group compared with the office group (P < .01). Complications were uncommon, but hemorrhage-related complications were four times more common in the operating room group than in the office group (P < .01). CONCLUSION: Office-based surgical management of early pregnancy failure is an acceptable option for many women and offers substantial resource and cost savings. LEVEL OF EVIDENCE: II-2.