Management of early pregnancy loss by reproductive endocrinologists: does access to mifepristone matter?

Objective: To describe patterns and variations in the medical and procedural management of early pregnancy loss (EPL) among reproductive endocrinology and infertility specialists, with attention to mifepristone use. Design: Cross-sectional. Setting: Online survey. Patients: Society for Reproductive Endocrinology and Infertility members. Intervention: Not applicable. Main Outcome Measure: Preferred management for EPL. Results: Of 101 completed surveys (response rate: 12.2%), 70.3% of respondents reported diagnosing EPL at least once per week. Half (50.5%) of respondents preferred medical management compared with 27.7% who preferred procedural management and 21.8% who preferred expectant management. Approximately one-quarter (26.7%) of respondents offer mifepristone for medical management of EPL. The most common reason cited for not prescribing mifepristone was a lack of access to the medication. Mifepristone prescribers were more likely to work in a hospital or university setting than private practice. Increasing years in practice was also associated with mifepristone use. The use of mifepristone for EPL did not vary by the respondent's age, gender, prior abortion training, or practice region. Conclusion: The most effective method of medical management uses both mifepristone and misoprostol. However, nearly three-quarters of reproductive endocrinology and infertility physicians do not offer mifepristone, which may be linked to access issues.

ANXA5 and VEGFA Gene Variants in Women with Early Pregnancy Losses from North Macedonia.

Early pregnancy loss (EPL) is the most common pregnancy complication, found in approximately 15% of all clinically recognized pregnancy complications. Up to date, various maternal as well as fetal factors are reported as a cause of EPLs. However, in approximately 50% of EPL cases, the exact cause is not clearly identified and these cases are referred as idiopathic. The aim of our study was to examine the association of four distinct variants in the ANXA5 gene and two variants within the VEGFA gene in a cohort of women with EPLs from North Macedonia. This group was compared to a control group of women matched by ethnic background without pregnancy loss and at least one live birth. We also aimed to establish an effective and cost-efficient method for their detection based on multiplex single-base extension. Among 190 women experiencing EPLs, and 190 samples from women without a history of pregnancy loss (control group), our results demonstrated a statistically significant prevalence of heterozygotes for the M2/ANXA5 haplotype in women with EPLs, compared to the control group (p=0.0006). In the analyses comparing genotypic frequencies for the variants in the VEGFA gene, higher frequencies were generally observed among women experiencing EPLs, however without statistical significance. Our study aligns with multiple studies showing that M2 and M1 ANXA5 haplotypes are more prevalent in patients with pregnancy loss and presents an affordable genotyping technique for the specific ANXA5 and VEGFA variants.

Witzenberg Women's experience of health care after a miscarriage: A descriptive qualitative study.

BACKGROUND:  Although some evidence is available from low- and middle-income countries, no South African data are available on how women experience healthcare during treatment for an incomplete miscarriage. AIM:  This study sets out to explore and describe the experiences of healthcare among women who suffered an incomplete spontaneous miscarriage in the Witzenberg subdistrict, a rural area in the Western Cape province of South Africa. SETTING:  Witzenberg subdistrict, Western Cape province, South Africa. METHODS:  This study used a descriptive exploratory qualitative study design. In-person interviews were held with women who experienced a miscarriage. Interviews followed a semi-structured format by a single interviewer to explore the various aspects involving experiences of healthcare. RESULTS:  Eight interviews were conducted and analysed. The five themes that arose from transcribed data were: (1) a need for safety, (2) pain management, (3) moderating behaviours and attitudes, (4) disorienting healthcare systems and (5) abandonment. Several factors contributed to the loss of physical and emotional safety in the emergency centre environment. Timeous emotional and pharmacological pain management were found to be a gap while patients awaited care. Clear communication and staff attitude were found to be integral to the patient's experience and could avoid the perception of abandonment. CONCLUSION:  There is a universal need for basic respectful, supportive and safe care in patients who attend an emergency centre for early pregnancy complications in rural South African. Specific focus should be given to clear communication and appropriate emotional support during and after the miscarriage.Contribution: This study can be used as a guide to improve services by ensuring respectful, transparent, informed, and appropriate continuity of care.

Correlation Between Serum Markers and Midluteal Phase Doppler Assessment of Uterine Arterial Blood Flow in Unexplained Recurrent Pregnancy Loss.

This study aimed to determine changes in uterine artery Doppler parameters in unexplained recurrent pregnancy loss (URPL) and to explore serum markers possibly associated with them. This retrospective case-control study included 107 URPL women and 107 control women. The mean pulsatility index (PI), resistive index (RI), and systolic-to-diastolic values for uterine arteries in URPL women were significantly higher than those in the controls (P < 0.05). The cutoff values of PI and RI differentiating the women with URPL from the controls were confirmed by ROC and Youden's index. Given a PI cutoff value of 2.6, the prevalence of URPL was significantly elevated in the high-PI group (74.58%) compared with that in the low-PI group (40.65%, P < 0.0001), with sensitivity and specificity of 63% and 69%, respectively. With an RI cutoff value of 0.86, the prevalence of URPL in the high-RI group (65.28%) was significantly elevated compared with that in the low-RI group (42.25%, P = 0.001), with sensitivity and specificity of 66% and 75%, respectively. The levels of serum D-dimers and anticardiolipin antibody (ACA)-IgM in URPL women were significantly higher than those in the controls. A positive correlation existed between the levels of ACA-IgM and uterine artery RI in URPL women (r = 0.43, P < 0.01). These results indicated that URPL women may be at a relatively high risk of a prothrombotic state, and the increased ACA-IgM deserves attention for its role in the elevated uterine artery Doppler parameters in URPL women.

Genetic Insights Into Early Pregnancy Loss: A Case Study of Trisomy 22 and an Enlarged Yolk Sac.

The first trimester of pregnancy is crucial for organ development but also carries a high risk of complications, with early pregnancy loss being the most common. Anomalies in the yolk sac, the first extra-embryonic structure seen by ultrasonography, can indicate severe fetal growth abnormalities and are linked to higher rates of first-trimester loss. This case report details a 38-year-old woman with a history of recurrent pregnancy loss (RPL) who presented with per vaginal bleeding and mild abdominal pain. Transvaginal ultrasonography revealed a yolk sac larger than 10 mm, prompting further genetic investigation. Chromosomal microarray analysis confirmed Trisomy 22. The presence of an enlarged yolk sac, correlated with Trisomy 22, highlights the importance of early detection through sonography and genetic testing. This approach aids in managing RPL by identifying genetic causes, thereby informing pre-conception counseling and future pregnancy management. An abnormal yolk sac size necessitates thorough evaluation, including cytogenetic microarray testing and quantitative fluorescent-polymerase chain reaction analysis, to guide clinical decisions and improve pregnancy outcomes.

Cell-Free DNA Analysis of Fetal Aneuploidies in Early Pregnancy Loss.

Background: Products of conception samples are often collected and analyzed to try to determine the cause of an early pregnancy loss. However, sample collection may not always be possible, and maternal cell contamination and culture failure can affect the analysis. Cell-free DNA-based analysis of a blood sample could be used as an alternative method in early pregnancy loss cases to detect if aneuploidies were present in the fetus. Methods: In this prospective study, blood samples from early pregnancy loss patients were analyzed for the presence of fetal aneuploidies using a modified version of a noninvasive prenatal testing assay for cell-free DNA analysis. Results from cell-free DNA analysis were compared against the gold standard, microarray analysis of products of conception samples. This study was registered with ClinicalTrials.gov, identifier: NCT04935138. Results: Of the 76 patient samples included in the final study cohort, 11 were excluded from performance calculations. The 65 patient samples included in the final analysis included 49 with an abnormal microarray result and 16 with a normal microarray result. Based on results from these 65 samples, the study found that genome-wide cell-free DNA analysis had a sensitivity of 73.5% with a specificity of 100% for the detection of fetal aneuploidies in early pregnancy loss cases. Conclusions: This prospective study provides further support for the utility of cell-free DNA analysis in detecting fetal aneuploidies in early pregnancy loss cases. This approach could allow for a noninvasive method of investigating the etiology of miscarriages to be made available clinically.

Performance of Massive Parallel Sequencing-Based Cell-Free DNA Testing in Compromised Pregnancies.

Background/Objectives: Non-Invasive prenatal test (NIPT) is used as a universal or contingent test after prior risk assessment. Screening is mainly performed for common trisomies (T21, T13, T18), although other chromosomal anomalies may be detected. Our objective was to study the performance of GWNIPT in the detection of chromosomal abnormalities in pregnancies in which an invasive prenatal study was performed and in early pregnancy losses, in comparison with the reference test. Method: VeriSeqTM NIPT Solution v2, a genome-wide NIPT (GWNIPT), was performed prior to invasive testing in fetal diagnostic study cases (FDS, n = 155) and in early pregnancy losses (EPL, n = 68). Results: In the FDS group, the diagnostic test (QFPCR, array and karyotype) detected anomalies in 32 pregnancies (21%), in twenty of them (61%) also detected by GWNIPT. Eleven of the twelve cases undetected by GWNIPT were balanced translocations (n = 4) or deletions/duplications <7 Mb (n = 7). In the EPL group, GWNIPT detected anomalies in 46% of cases (31/68) but comparison with reference test (QFPCR and karyotype) in products of conception (POC) was only possible in 18 cases. Concordant results between POC and GWNIPT test were obtained in 16 of the 18 cases. In EPL, with GWNIPT testing, common trisomies accounted for 25.8% of cases (8/31), rare trisomies 54.8% (17/31) and microdeletions/duplications 16.1% (5/31). Conclusions: The GWNIPT test may be useful in clinical practice in prenatal and in EPL's genetic diagnosis when the appropriate sample is not available.

Telemedicine Follow-up After Medication Management of Early Pregnancy Loss.

Objective: Our objective was to evaluate the feasibility of a new protocol for telemedicine follow-up after medication management of early pregnancy loss. Study Design: The study was designed to assess the feasibility of planned telemedicine follow-up after medication management of early pregnancy loss. We compared these follow-up rates with those after planned in-person follow-up of medication management of early pregnancy loss and planned telemedicine follow-up after medication abortion. We conducted a retrospective cohort study, including patients initiating medication management of early pregnancy loss <13w0d gestation and medication abortion ≤10w0d with a combination of mifepristone and misoprostol between April 1, 2020, and March 28, 2021. As part of a new clinical protocol, patients could opt for telemedicine follow-up one week after treatment and a home urine pregnancy test 4 weeks after treatment. Our primary outcome was completed follow-up as per clinical protocol. We also examined outcomes related to complications across telemedicine and in-person follow-up groups. Results: Of patients reviewed, 181 were eligible for inclusion; 75 had medication management of early pregnancy loss, and 106 had medication abortion. Thirty-six out of 75 patients elected for telemedicine follow-up after early pregnancy loss. Of patients scheduled for telemedicine follow-up, 29/36 (81%, 95% CI: 64-92) with early pregnancy loss and 64/69 (93%, 95% CI: 84-98) undergoing medication abortion completed follow-up as per protocol (p = 0.06). Completed follow-up was also similar among patients undergoing medication management of early pregnancy loss who planned for in-person follow-up (p = 0.135). Complications were rare and did not differ across early pregnancy loss and medication abortion groups. Conclusions: Telemedicine follow-up is a feasible alternative to in-person assessment after medication management of early pregnancy loss.

Laparoscopic Management of a 12-Week Pregnancy Loss in a Rudimentary Uterine Horn.

Unicornuate uterus with rudimentary horn is a rare structural uterine anomaly resulting from incomplete Mullerian duct development and/or fusion. Pregnancy in rudimentary horn is an uncommon presentation of a Mullerian anomaly and may lead to substantial morbidity and mortality due to high risk of uterine rupture with intraabdominal hemorrhage. Medical and/or surgical management may be undertaken; however, currently, no treatment guidelines exist. We describe the management of a 12-week rudimentary horn pregnancy in a 25-year-old multiparous patient with a prior spontaneous preterm breech vaginal delivery and one spontaneous early term cephalic vaginal delivery in whom this congenital uterine condition was previously unknown. The rudimentary horn, nonviable pregnancy, and contiguous ipsilateral fallopian tube were excised laparoscopically without complication. Given the infrequency of rudimentary horn pregnancies and the high risk for obstetric complications, a high index of suspicion should be maintained. We emphasize that a history of preterm birth or malpresentation should raise suspicion for maternal Mullerian anomaly, and that a minimally invasive approach can be feasible for treatment of a rudimentary horn pregnancy.

The Success of Mifepristone and Misoprostol in the Management of Early Pregnancy Loss at a Community Hospital: A Prospective Study.

OBJECTIVES: This prospective single-arm study was conducted to understand the expulsion rate of the gestational sac in the management of early pregnancy loss (EPL). METHODS: We recruited 441 participants; 188 met the eligibility criteria. Participants were 18 years of age and older who experienced a confirmed EPL (<12 weeks gestational age) defined by an intrauterine pregnancy with a non-viable embryonic or anembryonic gestational sac with no fetal heart activity. Participants were given 200 mg of mifepristone pre-treatment orally followed by 2 doses of misoprostol 800 µg vaginally after 24 and 48 hours. Participants were seen in follow-up on day 14 to confirm the absence of a gestational sac, classified as treatment success. For failed treatment (defined by retained gestational sac), we offered expectant management or a third dose of misoprostol and/or dilatation and curettage. We followed all participants for 30 days. We collected data on overtreatment for retained products of conception and hospital admissions for adverse events. RESULTS: Overall, 181 participants followed the protocol and 169 (93.3%) participants had a complete expulsion of the gestational sac by the second visit (day 14). Twelve (6.6%) failed the treatment and 1 had an adverse event of heavy vaginal bleeding requiring dilatation and curettage. Despite the expulsion of the gestational sac, 29 cases (17.1%) at subsequent follow-up were diagnosed as retained products of conception based on ultrasound assessment of thickened endometrium. CONCLUSIONS: Pretreatment with mifepristone followed by 2 doses of misoprostol with a 14-day follow-up resulted in a high expulsion rate and is a safe management option for EPL.

Inflammatory markers in systemic immune-inflammatory index and inflammatory response index to predict early pregnancy loss.

OBJECTIVES: To uncover the predictive value of systemic immune-inflammatory index (SII) and systemic inflammatory response index (SIRI) on early pregnancy loss. METHODS: A total of 535 individuals were enrolled in this retrospective analysis. The early pregnancy losses (EPL) group included patients between 18-35 years old who experienced EPL. The control group comprised healthy pregnant women who gave birth at ≥37 weeks. RESULTS: The EPL group had significantly lower plateletcrit (p=0.04), platelet distribution width (PDW, p<0.0001), and RDW (p<0.0001) and higher monocyte (p<0.0001) and SIRI (p<0.0001) values than the control group. The hemoglobin, white blood cells, platelet count, neutrophil count, lymphocyte count, mean platelet volume, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and SII values were not significantly different between the EPL and control groups (p>0.05). The cut-off value for the SIRI that offers the best sensitivity/specificity balance was 1.48 (sensitivity of 63%; specificity of 63%) in the receiver operating characteristics curve. Among the inflammatory parameters for predicting EPL, PDW had highest specificity (84%), and RDW had the highest sensitivity (80%). CONCLUSION: This study provides compelling evidence that various inflammatory pathways may significantly contribute to EPL pathogenesis. Moreover, our findings suggest that SIRI could be a more effective marker than NLR, PLR, MLR, and SII in predicting EPL in an ongoing pregnancy, thereby potentially revolutionizing early pregnancy loss diagnostics.

Economic analysis of foregoing Rh immunoglobulin for bleeding in pregnancy <12 weeks gestation.

OBJECTIVES: To perform cost analyses of foregoing RhD blood type testing and administration of Rh immunoglobulin (RhIg) for bleeding in pregnancy at <12 weeks gestation in the United States. STUDY DESIGN: We created a decision-analytic model comparing the current standard treatment pathway for patients who have threatened, spontaneous, or induced abortion in the United States, with a new pathway foregoing RhD testing and administration of RhIg for those who are RhD-negative at <12 weeks gestation, assuming that the risk of sensitization is 0%. We derived population and cost estimates from the current literature and calculated the number needed to treat (NNT) and number needed to screen to avoid one case of fatal hemolytic disease of the fetus and newborn. We performed sensitivity analyses assuming Rh-sensitization risks of 1.5% and 3% and varying the subsequent pregnancy rates from 44% to 100%. RESULTS: The annual savings to health care payers in the United States of foregoing RhD testing and RhIg administration with bleeding events at <12 weeks are $5.5 million/100,000 total pregnancies, assuming the sensitization risk is 0%. In sensitivity analyses with a sensitization risk of 1.5% and subsequent pregnancy rate of 84.3% foregoing Rh testing and RhIg administration would save $2.8 million/100,000 pregnancies, with a NNT of 7322 and a number needed to screen of 48,816. At a 3% sensitization rate, the current standard treatment pathway is most economical. CONCLUSIONS: There is an opportunity to save as much as $5.5 million/100,000 pregnancies by withholding RhIg in specific situations and conserving it for use later in pregnancy. IMPLICATIONS: Cost analyses support foregoing RhD blood type screening and RhIg administration at <12 weeks gestation if the sensitization rate is <3%. By deimplementing this low-value care, payers in the United States can save as much as $5.5 million/100,000 pregnancies and conserve RhIg for use later in pregnancy.

"That's a tricky one": Access to misoprostol for early pregnancy loss in retail pharmacies across Arizona.

OBJECTIVES: This study aimed to describe the same-day availability of misoprostol for medical management of early pregnancy loss (EPL) at Arizona pharmacies. STUDY DESIGN: We performed a simulated-patient mixed methods study of Arizona pharmacies from October 2022 to February 2023, documenting misoprostol availability and describing pharmacy staff responses. RESULTS: Of 941 pharmacies included, 703 (75%) could fill a misoprostol prescription same day. Ability to fill prescriptions and reasons why the prescription could not be filled varied by pharmacy type. National chain pharmacies most frequently had misoprostol available but also most commonly reported policies restricting dispensing. CONCLUSIONS: Barriers exist to filling misoprostol prescriptions for early pregnancy loss in Arizona that could impact patient care.

Differential mRNA and lncRNA Expression Profiles Associated with Early Pregnancy Loss in ART Patients.

Early pregnancy loss (EPL) is the most common complication in assisted reproductive technology (ART). However, the precise causes for nearly 50% patients remain unexplained. In the current study, we aimed to discover the differentially expressed profiling of mRNAs and lncRNAs by RNA sequencing (RNA-seq). Human chorionic villi tissues were collected from patients with EPL and natural control (NC) group. RNA sequencing (RNA-seq) of these specimens was performed for transcriptome analysis. As a result, we identified a total of 141 mRNAs and 137 lncRNAs that were significantly differentially expressed between villi tissues from EPL and NC. Functional enrichment analyses indicated enrichment of differentially expressed genes involved in pathways were associated with growth hormone receptor binding, PI3K-Akt signaling pathway, Jak-STAT signaling pathway, transcriptional misregulation in cancer, metabolic pathways and Rap1 signaling pathway. Additionally, the co-expression networks (lncRNA-miRNA-mRNA) was constructed based on the correlation analysis between the differentially expressed RNAs.7 mRNAs and 6 lncRNAs were successfully technically validated with RT-PCR. In conclusion, our results suggest a direction for the further study of EPL-related mRNAs and lncRNAs and may ultimately assist in understanding the pathogenesis of EPL.

High incidence of decidualization failure in infertile women.

Purpose: Decidualization is an important event for embryo implantation and successful pregnancy. Impaired decidualization leads to implantation failure and miscarriage. However, it is unclear how often decidualization failure occurs in infertile women. By analyzing the endometrium at late-secretory phase, we investigated the incidence and pathogenesis of decidualization failure among infertile women. Methods: Endometrial dating was performed on the endometria obtained in the late-secretory phase from 33 infertile women. Endometrial dating of more than 2 days delay was taken as an indication of decidualization failure. The expression of essential transcription factors for decidualization (FOXO1, WT1, and C/EBPß) was examined by immunohistochemistry. Results: Among 32 cases, 20 cases (62.5%) showed decidualization failure. These patients tended to have a history of more frequent miscarriages than those without decidualization failure. The percentage of cells that immunostained positive for the expression of three transcription factors was significantly lower in the patients with decidualization failure than in those without decidualization failure. Serum progesterone levels measured in the mid- and late-secretory phase were not significantly different between the cases with and without decidualization failure. Conclusions: The incidence of decidualization failure is high in infertile women.

Clinical factors associated with subsequent surgical intervention in women undergoing early medical termination of viable or non-viable pregnancies.

Introduction: Mifepristone-misoprostol treatment for medical abortion and miscarriage are safe and effective. This study aimed to assess clinical factors associated with subsequent surgical intervention after medical termination of early viable or non-viable pregnancy. Methods: This retrospective, single-center study included women who underwent medical abortion at Taipei Medical University between January 2010 and December 2019. A total of 1,561 subjects, with 1,080 viable and 481 non-viable pregnancies, who were treated with oral mifepristone 600 mg followed by misoprostol 600 mg 48 h later were included. Data of all pregnancies and medical termination of pregnancy were evaluated using regression analysis. The main outcome was successful termination of pregnancy. Results: The success rate of medical abortion was comparable in women with viable and non-viable (92.13% vs. 92.93%) pregnancies. Besides retained tissue, more existing pregnancies with ultrasonographic findings were found in the non-viable pregnancy group than in the viable pregnancy group (29.4% vs. 14.1%, p = 0.011). Multivariate analysis showed that previous delivery was an independent risk factor for failed medical abortion among all included cases. In women with viable pregnancy, longer gestational age [adjusted odds ratio (aOR): 1.483, 95% confidence interval (CI): 1.224-1.797, p < 0.001] and previous Cesarean delivery (aOR: 2.177, 95% CI: 1.167-40.62, p = 0.014) were independent risk factors for failed medical abortion. Number of Cesarean deliveries (aOR: 1.448, 95% CI: 1.029-2.039, p = 0.034) was an independent risk factor for failed medication abortion in women with non-viable pregnancies. Conclusion: This is the first cohort study to identify risk factors for subsequent surgical intervention in women with viable or non-viable pregnancies who had undergone early medically induced abortions. The success rate of medical abortion is comparable in women with viable and non-viable pregnancies. Previous delivery is an independent risk factor for failed medical abortion. Clinical follow-up may be necessary for women who are at risk of subsequent surgical intervention.

Innovative Machine Learning Strategies for Early Detection and Prevention of Pregnancy Loss: The Vitamin D Connection and Gestational Health.

Early pregnancy loss (EPL) is a prevalent health concern with significant implications globally for gestational health. This research leverages machine learning to enhance the prediction of EPL and to differentiate between typical pregnancies and those at elevated risk during the initial trimester. We employed different machine learning methodologies, from conventional models to more advanced ones such as deep learning and multilayer perceptron models. Results from both classical and advanced machine learning models were evaluated using confusion matrices, cross-validation techniques, and analysis of feature significance to obtain correct decisions among algorithmic strategies on early pregnancy loss and the vitamin D serum connection in gestational health. The results demonstrated that machine learning is a powerful tool for accurately predicting EPL, with advanced models such as deep learning and multilayer perceptron outperforming classical ones. Linear discriminant analysis and quadratic discriminant analysis algorithms were shown to have 98 % accuracy in predicting pregnancy loss outcomes. Key determinants of EPL were identified, including levels of maternal serum vitamin D. In addition, prior pregnancy outcomes and maternal age are crucial factors in gestational health. This study's findings highlight the potential of machine learning in enhancing predictions related to EPL that can contribute to improved gestational health outcomes for mothers and infants.