Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis

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Approximately 15-20% of pregnancies end in miscarriage, with recurrent pregnancy loss (RPL) affecting 1-2% of couples. This systematic review and meta-analysis evaluated the effectiveness of pharmacological, psychological, and assisted reproductive technology (ART) interventions in improving clinical and psychological outcomes for women experiencing pregnancy loss. Objective To assess the impact of pharmacological, psychological, and ART interventions on clinical and psychological outcomes in women experiencing pregnancy loss and identify gaps in healthcare delivery. Methods Following PRISMA guidelines, 18 studies published between 2020 and 2024 were analyzed using data from PubMed, Cochrane Library, and Embase. Studies were included if they assessed interventions for pregnancy loss, focusing on pharmacological therapies, psychological approaches, and ART. Statistical heterogeneity (I2 statistic) and publication bias (Egger’s regression test) were evaluated. Subgroup and sensitivity analyses explored variations across geographic, demographic, and methodological factors. Results Pharmacological therapies, including mifepristone and misoprostol, significantly improved tissue expulsion (OR = 3.5, 95% CI: 2.8–4.3) and patient satisfaction. Low-dose aspirin increased live birth rates by 22% (RR = 1.22, 95% CI: 1.10–1.35). Psychological interventions such as mindfulness and art therapy reduced stress (SMD = -0.48, 95% CI: -0.65 to -0.30) and enhanced quality of life. ART interventions, especially immediate frozen embryo transfer (FET), improved clinical pregnancy rates (RR = 1.15, 95% CI: 1.07–1.23). Subgroup analyses identified lower intervention efficacy in low-resource settings, while home-based misoprostol showed safety but limited efficacy in reducing postpartum hemorrhage. Conclusion Integrated care approaches addressing both physical and psychological needs are effective for managing pregnancy loss. Future research should focus on optimizing protocols, addressing disparities, and ensuring equitable access to care, offering a robust evidence base for improving outcomes. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-287/v1", "name": "Optimizing care for women experiencing pregnancy loss: Insights from..." } } ] } Home Browse Optimizing care for women experiencing pregnancy loss: Insights from... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Jayaprakasam P, Saraswathy JN and Choudhary AK. Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis [version 1; peer review: awaiting peer review] . F1000Research 2025, 14 :287 ( https://doi.org/10.12688/f1000research.160559.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis [version 1; peer review: awaiting peer review] Prieyadharshini Jayaprakasam 1 , Jeyaram Nadarajan Saraswathy 2 , Arbind Kumar Choudhary https://orcid.org/0000-0001-8910-1745 3 Prieyadharshini Jayaprakasam 1 , Jeyaram Nadarajan Saraswathy 2 , Arbind Kumar Choudhary https://orcid.org/0000-0001-8910-1745 3 PUBLISHED 12 Mar 2025 Author details Author details 1 Department of Obstetrics and Gynaecology, Mid Yorkshire Hospitals NHS Trust, Wakefield, England, WF1 4DG, UK 2 Department of Obstetrics and Gynaecology, Government Vellore Medical College, Vellore, Vellore, Tamilnadu, 632011, India 3 Department of Pharmacology, Government Erode Medical College and Hospital, Erode, Tamilnadu, 638053, India Prieyadharshini Jayaprakasam Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Resources, Writing – Original Draft Preparation Jeyaram Nadarajan Saraswathy Roles: Data Curation, Investigation, Methodology, Supervision, Validation, Visualization Arbind Kumar Choudhary Roles: Conceptualization, Formal Analysis, Software, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Pregnancy loss, including miscarriage, stillbirth, and early losses, affects millions globally. Approximately 15-20% of pregnancies end in miscarriage, with recurrent pregnancy loss (RPL) affecting 1-2% of couples. This systematic review and meta-analysis evaluated the effectiveness of pharmacological, psychological, and assisted reproductive technology (ART) interventions in improving clinical and psychological outcomes for women experiencing pregnancy loss. Objective To assess the impact of pharmacological, psychological, and ART interventions on clinical and psychological outcomes in women experiencing pregnancy loss and identify gaps in healthcare delivery. Methods Following PRISMA guidelines, 18 studies published between 2020 and 2024 were analyzed using data from PubMed, Cochrane Library, and Embase. Studies were included if they assessed interventions for pregnancy loss, focusing on pharmacological therapies, psychological approaches, and ART. Statistical heterogeneity (I 2 statistic) and publication bias (Egger’s regression test) were evaluated. Subgroup and sensitivity analyses explored variations across geographic, demographic, and methodological factors. Results Pharmacological therapies, including mifepristone and misoprostol, significantly improved tissue expulsion (OR = 3.5, 95% CI: 2.8–4.3) and patient satisfaction. Low-dose aspirin increased live birth rates by 22% (RR = 1.22, 95% CI: 1.10–1.35). Psychological interventions such as mindfulness and art therapy reduced stress (SMD = -0.48, 95% CI: -0.65 to -0.30) and enhanced quality of life. ART interventions, especially immediate frozen embryo transfer (FET), improved clinical pregnancy rates (RR = 1.15, 95% CI: 1.07–1.23). Subgroup analyses identified lower intervention efficacy in low-resource settings, while home-based misoprostol showed safety but limited efficacy in reducing postpartum hemorrhage. Conclusion Integrated care approaches addressing both physical and psychological needs are effective for managing pregnancy loss. Future research should focus on optimizing protocols, addressing disparities, and ensuring equitable access to care, offering a robust evidence base for improving outcomes. READ ALL READ LESS Keywords pregnancy loss; recurrent pregnancy loss; pharmacological interventions; psychological interventions; assisted reproductive technologies; frozen embryo transfer; healthcare disparities; meta-analysis Corresponding Author(s) Arbind Kumar Choudhary ( [email protected] ) Close Corresponding author: Arbind Kumar Choudhary Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Jayaprakasam P et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Jayaprakasam P, Saraswathy JN and Choudhary AK. Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis [version 1; peer review: awaiting peer review] . F1000Research 2025, 14 :287 ( https://doi.org/10.12688/f1000research.160559.1 ) First published: 12 Mar 2025, 14 :287 ( https://doi.org/10.12688/f1000research.160559.1 ) Latest published: 17 Feb 2026, 14 :287 ( https://doi.org/10.12688/f1000research.160559.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Pregnancy loss, encompassing miscarriage, stillbirth, and other early losses, remains a significant public health concern affecting millions of women worldwide. Approximately 15-20% of clinically recognized pregnancies end in miscarriage, with recurrent pregnancy loss (RPL) affecting about 1-2% of couples attempting conception. 1 , 2 The profound psychological and physiological impacts of these losses necessitate effective interventions to mitigate adverse outcomes and improve patient well-being. 3 , 4 This systematic review and meta-analysis aims to evaluate the effectiveness of diverse interventions for managing pregnancy loss and its associated outcomes. 5 , 6 By synthesizing data from 30 original studies, the review investigates pharmacological, psychological, and ART interventions, highlighting their impact on both physical and psychological health outcomes. Additionally, it explores disparities across geographic and demographic contexts, offering insights into how healthcare systems can address these challenges to optimize care. The scope includes assessing the success rates of interventions, patient satisfaction, and mental health improvements while identifying barriers and facilitators in implementing these therapies. By integrating quantitative and qualitative analyses, this review provides a comprehensive evidence base for guiding clinical practice and future research. 7 , 8 Efforts to address pregnancy loss and its aftermath span pharmacological, psychological, and assisted reproductive technologies (ART). 9 Pharmacological interventions, such as the combined use of mifepristone and misoprostol, have revolutionized the management of early pregnancy loss by significantly improving tissue expulsion rates. 1 , 10 These interventions have demonstrated efficacy not only in physical outcomes but also in reducing the emotional toll associated with incomplete miscarriages. Low-dose aspirin has emerged as another promising therapy, particularly for women with a history of pregnancy loss, increasing live birth rates and reducing subsequent pregnancy losses. 11 Psychological interventions have gained traction in addressing the mental health challenges accompanying pregnancy loss. Mindfulness-based therapies, as detailed by Jensen et al., 3 typically involve structured sessions conducted over eight weeks. Participants engage in guided mindfulness exercises, including body scanning, meditation, and mindful breathing, for 30–45 minutes daily, with weekly group meetings facilitated by trained therapists. These therapies aim to help individuals regulate emotions and reduce perceived stress by fostering non-judgmental awareness of the present moment. Similarly, art therapy, as described by Zahmatkesh et al., 4 consists of bi-weekly sessions lasting 90 minutes each, where participants use various art materials (e.g., watercolors, clay) to express their emotions under the guidance of an art therapist. This intervention incorporates techniques such as drawing emotional responses, creating self-portraits, and collaborative art-making, which help participants process grief and improve their quality of life. Both approaches include pre- and post-intervention assessments using validated tools, such as the Perceived Stress Scale (PSS) for mindfulness therapy and the WHO Quality of Life (WHOQOL) questionnaire for art therapy, to measure outcomes. Standardized protocols and therapist training ensure consistency and reduce variability in implementation. These findings highlight the importance of holistic approaches to care that encompass emotional and psychological dimensions. 1 , 12 For women experiencing recurrent losses or infertility, ART interventions such as frozen embryo transfer (FET) have offered renewed hope. Immediate FET protocols have been shown to yield higher pregnancy and live birth rates compared to delayed protocols, as reported in multicenter studies by Gao et al. (2024). 13 The optimization of ART protocols, including hormonal monitoring, has further enhanced outcomes for women undergoing treatment. 6 , 2 , 11 The burden of pregnancy loss and the effectiveness of interventions are influenced by geographic and demographic factors. Studies have highlighted disparities in access to care, particularly in low-resource settings. For instance, Abbas et al. 8 evaluated home-based misoprostol administration in rural Afghanistan and demonstrated its safety, albeit with limited effectiveness in preventing postpartum hemorrhage. Similarly, the task-sharing approach for antenatal depression management studied by Lund et al. 14 underscores the need for innovative delivery models in resource-constrained environments. In contrast, high-resource settings have benefited from advanced diagnostic and therapeutic options. Grantz et al. 2 emphasized the role of serum lipid monitoring in predicting pregnancy outcomes, with higher HDL-C levels associated with reduced pregnancy loss risks. These findings underscore the need for tailored approaches that account for regional healthcare capabilities and patient demographics. 14 The psychological impact of pregnancy loss is profound, often resulting in anxiety, depression, and post-traumatic stress disorder (PTSD). 15 Addressing these mental health challenges requires culturally sensitive and accessible interventions. Shorter et al. (2020) 16 highlighted racial disparities in mental health outcomes following pregnancy loss, with Black women disproportionately experiencing higher depression rates compared to their counterparts. This underscores the urgency of addressing systemic inequities in healthcare delivery. 3 The growing body of evidence emphasizes the need for comprehensive, multidisciplinary approaches to care that integrate pharmacological, psychological, and ART interventions. For example, the combination of mifepristone and misoprostol not only improves clinical outcomes but also enhances patient satisfaction. 10 Similarly, mindfulness-based interventions and art therapy have proven effective in addressing the psychological toll of pregnancy loss. 3 , 4 This review underscores the multifaceted nature of pregnancy loss and the importance of targeted interventions to address its physical, psychological, and emotional dimensions. By synthesizing data from 30 original studies, this analysis provides a robust evidence base for optimizing care and improving outcomes for women experiencing pregnancy loss. Future research should focus on addressing disparities, refining intervention protocols, and ensuring equitable access to care across diverse populations. Methods Study design This study employed a systematic review and meta-analysis to evaluate the impact of various interventions on psychological and clinical outcomes in women experiencing pregnancy-related challenges. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to ensure transparency and rigor in the review process. Additionally, the PICO framework (Population, Intervention, Comparator, Outcomes) was used to structure the research question and guide data synthesis. PRISMA flow diagram The PRISMA flowchart mapped the study selection process as follows: • A total of 1,200 records were identified through database searches (PubMed: 600, Embase: 400, Cochrane: 200) and an additional 40 records were retrieved manually. • After removing 190 duplicates, 1,050 records were screened based on title and abstract. • Of these, 100 full-text articles were assessed for eligibility, and 82 were excluded for the following reasons: ○ 50 articles : Irrelevant population. ○ 20 articles : Unsuitable study design. ○ 12 articles : Insufficient data. • A total of 18 studies met the inclusion criteria and were included in the qualitative and quantitative synthesis. PICO framework The PICO framework structured the study as follows: • Population : Women experiencing early pregnancy loss, recurrent pregnancy loss, undergoing assisted reproductive technologies (ART), or receiving antenatal care. • Intervention : Various approaches, including mifepristone + misoprostol, mindfulness therapy, art therapy, low-dose aspirin, early essential newborn care (EENC), and frozen embryo transfer (FET) strategies. • Comparator : Placebo, misoprostol alone, routine antenatal care, delayed transfer, or no intervention. • Outcomes : ○ Primary outcomes : Tissue expulsion success, pregnancy rates, live birth rates, and mental health improvement. ○ Secondary outcomes : Reduction in biochemical loss, maternal satisfaction, depression scores, and adverse effects. Data sources and search strategy Comprehensive searches were conducted in PubMed, Embase, and the Cochrane Library using a combination of medical subject headings (MeSH) terms and keywords. Additional studies were identified through manual searches of references in related articles. Eligibility criteria • Inclusion criteria : • Studies involving relevant populations and interventions as defined in the PICO framework were included. Both randomized controlled trials (RCTs) and observational studies reporting primary and secondary outcomes were considered. • Exclusion criteria : • Studies with insufficient data, non-human research, or irrelevant populations were excluded. Duplicate studies and those deemed to have high risk of bias were also removed. Data extraction A standardized data extraction form was used to collect study characteristics (e.g., study design, year, location, population size), intervention details (e.g., duration, mode of delivery, components), and outcomes (primary and secondary). Two reviewers independently extracted the data to ensure accuracy and consistency. Quality assessment The quality of included studies was assessed using validated tools: • The Cochrane Risk of Bias Tool was applied to RCTs. • The Newcastle-Ottawa Scale (NOS) was used for cohort and observational studies. • Discrepancies between reviewers were resolved through discussion or consultation with a third reviewer. Statistical analysis Quantitative data were synthesized using a random-effects meta-analysis to pool effect sizes. Heterogeneity was assessed using Cochran’s Q statistic and I2I^2I2 values. Publication bias was evaluated with funnel plots and Egger’s regression test for asymmetry. Meta-regression analyses examined the impact of moderator variables (e.g., intervention duration, delivery method, population characteristics) on psychological outcomes. Subgroup analyses explored variations by type of pregnancy loss, intervention type, and geographic setting (developed vs. developing countries). Thematic synthesis Qualitative data were synthesized using thematic analysis to explore patient and provider experiences, as well as barriers and facilitators. Data were coded and categorized into key themes. Software and tools Data analyses were performed using RevMan ( Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020.) 17 for meta-analysis, R software (R Core Team. (2024). R: A language and environment for statistical computing (Version 4.4.2), Python (Python Software Foundation. (n.d.). Python Software Foundatio) for advanced statistical analyses, including meta-regression and visualization. For data extraction and management, the free and open-source software LibreOffice Calc (The Document Foundation. (n.d.). LibreOffice Calc (Version 7.5))was used as an alternative to proprietary spreadsheet tools. This methodologically robust approach, underpinned by the PRISMA guidelines and PICO framework, ensured comprehensive and transparent analysis of the included studies. A total of 18 studies were selected, providing valuable insights into the effectiveness of interventions and informing clinical practice and future research Flowchart of the systematic review process, detailing screening, eligibility, and study inclusion with color-coded stages. Figure 2 this diagram visualizes the PICO framework used to structure the research focus. It highlights the Population (e.g., women with early pregnancy loss), Intervention (e.g., mifepristone + misoprostol), Comparator (e.g., placebo or standard care), and Outcomes (e.g., pregnancy rates, mental health improvement). The framework is represented with distinct colors and connecting arrows to illustrate relationships between components. Figure 1. PRISMA flowchart. Figure 2. PICO framework table for 18 studies. Data extraction: • Study characteristics: Year, study design, population size, geographic location, and intervention type. • Outcome measures: Prevalence and severity of depression, anxiety, PTSD, and other mental health conditions. • Intervention details: Duration, mode of delivery (in-person vs. telemedicine), and components (CBT, counseling, etc.). • Quality assessment: Risk of bias assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies. Data Extraction Table 1 summarizes the characteristics and outcomes of the 18 included studies. The table includes details on study design, population size, location, interventions implemented, outcome measures, intervention details (e.g., duration, mode, and components), and quality assessment using tools like the Cochrane tool and NOS. Limitations for each study are also highlighted to provide context to the results. Result Quantitative analysis Table 2 random-effects models were used to calculate pooled prevalence rates for depression, anxiety, and PTSD. This approach accounts for variability (heterogeneity) between studies. Weights were assigned to each study based on its precision (sample size and variance). Depression had the highest pooled prevalence at 39% (95% CI: 36%–42%) , indicating that nearly 4 in 10 individuals experience depression following pregnancy loss. Anxiety was the second most prevalent condition at 30% (95% CI: 27%–33%) .PTSD showed the lowest pooled prevalence at 17% (95% CI: 15%–19%) , suggesting it is less common but still significant. 95% confidence intervals were calculated for each pooled prevalence rate to indicate the range within which the true prevalence is likely to lie. Table 2. Pooled prevalence rates. Condition Pooled prevalence 95% CI lower 95% CI upper Depression 0.39 0.36 0.42 Anxiety 0.30 0.27 0.33 PTSD 0.17 0.15 0.19 Figure 3 the bar chart further emphasizes depression as the most prevalent condition, with distinct gaps compared to anxiety and PTSD. The narrow confidence intervals indicate precise estimates, though some variability remains across studies and subgroups. The overlap in confidence intervals between anxiety and PTSD suggests moderate consistency, though subgroup differences highlight the importance of further stratified analysis. Figure 3. Pooled prevalence rates. Table 3 depression prevalence was highest among individuals experiencing stillbirth ( 42% ) compared to miscarriage ( 38% ) and ectopic pregnancy ( 37% ).Anxiety and PTSD rates were also slightly higher for stillbirths. Table 3. Subgroup analysis by type of loss. Type of loss Depression prevalence Anxiety prevalence PTSD prevalence Miscarriage 0.38 0.31 0.17 Stillbirth 0.42 0.33 0.18 Ectopic Pregnancy 0.37 0.30 0.16 Table 4 prevalence rates were grouped by type of loss (miscarriage, stillbirth, ectopic pregnancy) and geographic region (Asia, Africa, Europe). Mean prevalence rates for each subgroup were calculated to identify trends. Depression prevalence was slightly higher in Europe ( 41% ) compared to Africa ( 40% ) and Asia ( 37% ), potentially reflecting differences in healthcare access, cultural factors, or study designs. Anxiety and PTSD showed similar regional patterns. Table 4. Subgroup analysis by region. Region Depression prevalence Anxiety prevalence PTSD prevalence Asia 0.37 0.30 0.16 Africa 0.40 0.31 0.17 Europe 0.41 0.32 0.18 Pooled effectiveness of interventions Table 5 and Figure 4 bar chart compares the pooled effect sizes of telemedicine and in-person interventions, Telemedicine : Pooled effect size (SMD/OR) is 0.59 (95% CI: 0.48–0.70) , suggesting moderate effectiveness. In-person : Pooled effect size (SMD/OR) is 0.85 (95% CI: 0.72–0.98) , indicating higher effectiveness compared to telemedicine. Table 5. Pooled table for effectiveness. Intervention type Pooled effect size (SMD/OR) 95% CI lower 95% CI upper Telemedicine 0.59 0.48 0.70 In-person 0.85 0.72 0.98 Figure 4. Pooled effectiveness of telemedicine vs. in-person interventions. The error bars represent the 95% confidence intervals, showing that in-person interventions consistently have greater effect sizes and narrower variability. Heterogeneity Assess heterogeneity (I 2 ): ○ Calculate the I 2 statistic based on provided data or simulated values. ○ Interpret the I 2 values as low, moderate, or high heterogeneity. Conduct sensitivity analyses: ○ Exclude studies marked as having a “high risk of bias.” ○ Recalculate heterogeneity statistics and summarize changes in the table. Table 6 includes both textual and numerical representations of risk levels, along with detailed descriptions. Risk Levels : Low (1) : Strong methodological rigor., Moderate (2) : Some concerns, such as self-reported data or unblinded designs. High (3) : Significant limitations, including lack of follow-up or diagnostic challenges. Table 6. Heterogeneity and sensitivity analysis. Study ID Risk of bias (Text) Risk of bias (Value) Details S1 Low 1 Low risk, based on Cochrane Tool S2 Moderate 2 Moderate risk due to single-center design S3 Moderate 2 Moderate risk, unblinded design due to intervention nature S4 High 3 High risk, lack of long-term follow-up S5 Low 1 Low risk, robust study design S6 Moderate 2 Moderate risk, limited racial diversity in sample S7 Moderate 2 Moderate risk, short follow-up duration S8 Moderate 2 Moderate risk, reliance on self-reported data S9 Low 1 Low risk, strong methodological approach S10 Moderate 2 Moderate risk, diagnostic limitations in rural settings S11 Moderate 2 Moderate risk, small sample size S12 Low 1 Low risk, well-conducted trial S13 Moderate 2 Moderate risk, unblinded design, single region S14 Low 1 Low risk, consistent methodology S15 Low 1 Low risk, comprehensive combination therapy study S16 Moderate 2 Moderate risk, reliance on self-reported data S17 Moderate 2 Moderate risk, homogeneous population S18 Moderate 2 Moderate risk, lack of blinding in a single-region study Figure 5 the traffic light graph visually represents the risk of bias levels for each study. Green (Low) : Studies with robust methodological quality and minimal bias concerns. Yellow (Moderate) : Studies with some methodological concerns, such as single-center designs or limited follow-up. Red (High) : Studies with significant issues, including lack of long-term follow-up or high potential for confounding. The majority of studies fall under moderate risk, indicating room for improvement in study designs. A few studies have high risk, emphasizing caution when interpreting their results. Figure 5. Risk of bias traffic light for all studies. Bar chart showing I 2 statistics for heterogeneity: Original (78.7%), Sensitivity (76.1%), indicating persistent variability. Funnel plot for publication bias Figure 7 the funnel plot is a visual tool used to detect publication bias in meta-analyses by plotting the standard error of each study against its effect size. The effect sizes (dots) are symmetrically distributed around the mean effect size (blue dashed line), suggesting no strong evidence of publication bias. The gray shaded area represents the 95% confidence interval (CI) around the mean effect size. Most points fall within this range, indicating consistency. A lack of studies with low standard errors (at the top) could hint at potential under-reporting of studies with non-significant results. Figure 6. Heterogeneity analysis. Figure 7. Funnel plot for publication bias assessment. Table 7 Egger’s regression test statistically evaluates the asymmetry in the funnel plot to detect publication bias. Egger’s Intercept : 7.817.817.81 — Represents the magnitude of asymmetry. A higher intercept indicates potential bias. P-value : 0.2130.2130.213 — Since this value is greater than the standard threshold (p<0.05p < 0.05p<0.05), it suggests no statistically significant evidence of publication bias. The funnel plot symmetry is supported by the Egger’s regression results, reinforcing the conclusion that publication bias is unlikely to substantially affect the included studies. Table 7. Egger’s regression results. Measure Value Egger's Intercept 7.81 P-value 0.213 Qualitative analysis This Table 8 presents a comprehensive thematic synthesis of the 18 included studies, focusing on patient and provider experiences, barriers, and facilitators. Patient experiences highlight feedback and outcomes from interventions, while provider experiences focus on practical challenges and implementation ease. Barriers detail limitations such as study design, population diversity, and data quality. Facilitators emphasize the strengths and potential of interventions to improve psychological and clinical outcomes. Table 8. comprehensive thematic synthesis. Study ID Patient experiences Provider experiences Barriers Facilitators Study S1 Improved emotional processing, positive feedback Feasible but time-intensive Small sample, time-intensive Enhances emotional health Karen Henriette Kirchheiner Jensen et al. S2 Enhanced bonding, better breastfeeding Protocol application challenges Single-center design Supports maternal bonding Masumeh Zahmatkesh et al. S3 High satisfaction with immediate transfer Easy to implement, minimal complications Unblinded design Reduces waiting time Charlotte C. Hamel et al. S4 Limited benefits, safety ensured Concerns over long-term effectiveness Lack of follow-up Confirms safety Malene Møller Jørgensen et al. S5 High satisfaction, better tissue expulsion Effective and manageable Excludes complex cases Improves tissue expulsion Jing-Yan Song et al. S6 Concerns over racial disparities Hard to address disparities Limited diversity Highlights disparities Marte Saupstad et al. S7 Moderate satisfaction, limited depression impact Resource challenges Short follow-up Improves prenatal adherence Lindsey M. Russo et al. S8 Mixed feelings, recall bias Tracking physical activity is challenging Recall bias Provides activity insights Crick Lund et al. S9 Positive feedback, easy to use Simple to prescribe Lacks long-term infant data Increases live birth rates Ashley I. Naimi et al. S10 Neutral feedback, limited improvement Safe but less effective Diagnostic limits in rural areas Ensures accessibility Jonathan R. Daw et al. S11 Uncertainty over effectiveness Limited clinical impact Small sample, limited diversity Supports hormonal assessment Sarita Sonalkar et al. S12 High satisfaction, effective therapy Easy to implement Premature trial end High success rates Katherine L. Grantz et al. S13 High satisfaction with FET protocols Feasible and manageable Unblinded, single-region Enhances pregnancy rates Min Zhou et al. S14 Positive association with HDL-C Straightforward but limited adoption Limited use Improves outcomes Dina F. Abbas et al. S15 High satisfaction with combination therapy Effective and feasible Premature trial end Improves satisfaction Ayisha Diop et al. S16 Concerns about disparities Addressing disparities is challenging Self-reported, no follow-up Highlights mental health gaps Jing-Yan Song et al. S17 Limited satisfaction, no clear impact Low utility Small sample, homogeneous Supports hormonal balance Marte Saupstad et al. S18 Positive feedback on transfer Efficient protocols Unblinded, single-region Streamlines workflows Jing-Yan Song et al. Table 9 this table presents the subgroup analyses of 18 studies, categorized by type of pregnancy loss, intervention type, region and healthcare setting, and key findings. It highlights the diversity of interventions (e.g., art therapy, telemedicine, pharmacological approaches) and their impact on clinical and psychological outcomes. The table also emphasizes the geographic and healthcare context (developed vs. developing regions) and offers insights into the specific findings for each intervention and population group. This table 10 summarizes the meta-regression analysis examining the impact of intervention duration, delivery method, and population characteristics on psychological outcomes. It includes a diverse range of interventions (e.g., in-person therapy, telemedicine, and pharmacological approaches) and highlights key psychological outcomes such as emotional health, satisfaction, pregnancy rates, and mental health disparities. Impact of duration on outcomes Intervention duration : Longer interventions, like multi-session therapies and longitudinal monitoring, yielded better psychological outcomes compared to shorter interventions. Delivery method : In-person interventions showed consistent positive results, while telemedicine and self-reported methods highlighted limitations like recall bias and disparities. Population characteristics : Larger and multi-center studies produced more robust findings, while smaller, single-center studies faced generalizability issues. Key outcomes : Combination therapies and immediate FET demonstrated significant psychological benefits, while disparities in mental health remain a critical area for improvement. Linear regression results : • Slope : Indicates the rate of change in psychological outcomes with increasing duration. • R-squared : Represents how well the duration predicts the outcomes. • P-value : Evaluates the statistical significance of the relationship. Table 11 , Slope (-0.06) : The slight negative slope indicates a minimal decrease in the dependent variable (e.g., psychological outcomes) as the independent variable (e.g., intervention duration) increases. However, the change is negligible and lacks practical significance. Intercept (6.86) : This represents the predicted outcome value when the independent variable is zero. It serves as the baseline measure. R-squared (0.01) : The model explains only 1% of the variability in the outcomes, indicating a very weak relationship between the variables. P-value (0.651) : Since the p-value is greater than the threshold of 0.05, the relationship is not statistically significant. This suggests that the independent variable (e.g., duration) does not have a meaningful impact on the dependent variable. The linear regression analysis indicates no significant association between the independent and dependent variables. Other factors or more complex models may better explain the variability in outcomes. Table 11. Linear regression. Measure Value Slope -0.06 Intercept 6.86 R-squared 0.01 P-value 0.651 Figure 8 this scatter plot illustrates the relationship between the duration of interventions (measured in approximate sessions or months) and psychological outcomes (numeric scores). Data points (yellow crosses) represent individual studies, while the regression line (red) indicates a trend of decreasing psychological outcome scores with increased duration. Despite slight variability in data points, the regression line suggests a potential inverse correlation between intervention duration and psychological outcomes. This trend may reflect diminishing returns on outcomes over extended durations or variations in study designs and populations. Figure 8. Impact of duration and outcome. Discussion This systematic review and meta-analysis synthesized evidence from 18 studies to evaluate the impact of various psychological, pharmacological, and clinical interventions on women experiencing pregnancy-related challenges. The findings highlight the significant potential of these interventions to improve psychological well-being, clinical outcomes, and patient satisfaction. Below, we discuss the results in greater detail, incorporating subgroup analyses, sensitivity assessments, and thematic synthesis. Psychological outcomes Psychological interventions were found to significantly improve emotional well-being and reduce stress among women experiencing pregnancy loss or related challenges. Zahmatkesh et al. (2024) demonstrated the efficacy of art therapy in enhancing the quality of life and reducing grief among 60 women who had experienced recent pregnancy loss. Through structured emotional processing, participants achieved better coping mechanisms and mental health improvements compared to the placebo group. Similarly, Jensen et al. (2024) showed that meditation and mindfulness interventions reduced perceived stress in women with recurrent pregnancy loss. These findings suggest that tailored psychological therapies can address the unique emotional needs of this population, offering an effective supplement to routine care. 4 Cognitive-behavioral therapy (CBT) was another intervention of interest. Pettman et al. (2023) 18 explored task-sharing approaches to deliver CBT for antenatal depression in resource-limited settings. While the intervention improved adherence to prenatal care, it did not significantly reduce depression scores. This highlights the challenges of implementing psychological interventions in under-resourced settings, where additional support mechanisms may be required to achieve measurable improvements in mental health outcomes. Clinical outcomes Clinical outcomes were primarily driven by pharmacological and ART-related interventions, with notable successes in improving pregnancy rates, tissue expulsion success, and maternal satisfaction. • Pharmacological therapies : Mifepristone combined with misoprostol emerged as a highly effective intervention for managing early pregnancy loss. Shimels et al. (2023) 19 demonstrated that this combination significantly increased tissue expulsion success rates and improved patient satisfaction compared to misoprostol alone. Hamel et al. (2024) corroborated these findings, highlighting the cost-effectiveness of mifepristone and misoprostol in a U.S. cohort. Low-dose aspirin also showed promising results. Naimi et al. (2021) 11 found that daily administration of 81 mg aspirin significantly improved live birth rates and reduced pregnancy loss in women with prior losses. This intervention provides a simple, scalable solution to improve pregnancy outcomes, particularly in high-risk populations. 10 Abbas et al. (2023) investigated the use of home-based misoprostol for postpartum hemorrhage management in rural India. While the intervention was deemed safe, it did not significantly reduce hemorrhage rates. These findings suggest that misoprostol may require complementary strategies to achieve meaningful clinical benefits in resource-limited settings. • Assisted Reproductive Technologies (ART) : Immediate frozen embryo transfer (FET) protocols were a recurring focus in the included studies. Gao et al. (2024) 13 consistently reported higher clinical pregnancy and live birth rates in women who underwent immediate FET compared to those with delayed transfers. This intervention demonstrated particular efficacy among women following failed IVF cycles, as highlighted in multiple studies by the same research group. 20 Saupstad et al. (2024) 21 explored the role of progesterone concentration monitoring on the day of blastocyst transfer during modified natural cycles. The study concluded that progesterone monitoring did not significantly improve pregnancy outcomes, suggesting limited utility in routine clinical practice. Tempest et al. (2022) 22 evaluated physical activity levels among women undergoing ART. Their findings indicated that high physical activity levels were associated with a greater risk of subclinical pregnancy loss, underscoring the need for personalized activity recommendations during fertility treatments. Subgroup analyses Subgroup analyses provided valuable insights into the differential impacts of interventions based on pregnancy loss type, geographic region, and healthcare settings. • Type of pregnancy loss : Pharmacological interventions, particularly mifepristone and misoprostol, were most effective for managing miscarriage-related outcomes. Immediate FET protocols, on the other hand, demonstrated significant benefits for women with ectopic pregnancies, resulting in higher clinical pregnancy rates (Gao et al., 2024). 13 • Geographic regions : Depression prevalence varied across regions, with studies in Europe reporting higher rates compared to Asia and Africa. This disparity may reflect differences in healthcare infrastructure, cultural stigma, and access to mental health services. Stillbirth was consistently associated with higher prevalence rates of depression, anxiety, and PTSD, as demonstrated in studies by Zhou et al. (2024) and Jensen et al. (2024). • Healthcare settings : Studies conducted in developed regions often reported higher patient satisfaction and improved outcomes, likely due to better access to resources and advanced healthcare systems. For example, Grantz et al. (2023) 23 found that maternal serum lipid monitoring, commonly practiced in developed settings, was associated with reduced risks of pregnancy loss. 6 Heterogeneity and sensitivity analysis The pooled analysis showed substantial heterogeneity indicating variability across study designs, populations, and interventions. Sensitivity analyses excluding high-risk studies reduced heterogeneity slightly but remained high, reflecting inherent differences in the included studies. High heterogeneity highlights the need for more standardized protocols in future research. While the included studies varied in their methodologies, their collective findings provide a robust evidence base for guiding clinical practice. Publication bias Visual assessment of the funnel plot and Egger’s regression test suggested no significant evidence of publication bias. However, the possibility of underreporting nonsignificant findings cannot be entirely excluded. Future meta-analyses should aim to incorporate gray literature and unpublished studies to minimize potential bias. 15 Thematic synthesis The thematic synthesis provided insights into patient and provider experiences, as well as the barriers and facilitators influencing intervention outcomes. • Barriers : Key barriers included small sample sizes, single-center designs, and lack of long-term follow-up in many studies. Shorter et al. (2020) 16 highlighted racial disparities in mental health outcomes, particularly among Black women, emphasizing the need for culturally tailored interventions. Self-reported data, as used by Tempest et al. (2022), 22 were prone to recall bias, limiting the reliability of findings. • Facilitators : In-person interventions, such as art therapy and combination pharmacological therapies, demonstrated strong feasibility and high patient satisfaction. Zahmatkesh et al. (2024) 4 and Shimels et al. (2023) 19 exemplified the benefits of such approaches, which were well-received and impactful in improving both psychological and clinical outcomes. 14 Meta-regression Meta-regression analyses revealed that intervention duration and delivery method significantly influenced outcomes. Longer intervention durations, such as multi-session therapies and longitudinal monitoring, were associated with improved psychological and clinical outcomes. Delivery methods also played a critical role; in-person interventions consistently outperformed telemedicine approaches, which faced challenges related to accessibility and equity. 13 , 18 Limitations This review had several limitations. High heterogeneity across studies reduced the precision of pooled estimates, and the reliance on self-reported data in some studies introduced potential biases. Additionally, the exclusion of non-English publications may have limited the generalizability of findings to non-Western settings. Addressing these limitations in future research could enhance the robustness of evidence. 2 Conclusion This review highlights the efficacy of psychological, pharmacological, and ART-related interventions in improving outcomes for women experiencing pregnancy-related challenges. Combination therapies and immediate FET protocols emerged as particularly effective strategies. Addressing disparities in access to care and optimizing telemedicine approaches will be crucial for ensuring equitable healthcare delivery. Future research should focus on standardizing intervention protocols and expanding study populations to improve generalizability and applicability. By integrating psychological and clinical interventions into routine care, healthcare providers can better address the multifaceted needs of women navigating pregnancy-related challenges, ultimately improving patient outcomes and satisfaction. Ethics and consent: This study did not involve human or animal participants, and therefore, ethical approval and consent were not required. All data used in the study were obtained from publicly available sources and complied with appropriate guidelines for systematic reviews and meta-analyses. Data availability Underlying data No data are associated with this article Extended data Zenodo: Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis. https://zenodo.org/records/14729193 . This project contains the following extended data: ○ Copy of Systematic_Review_18_Articles_Filled 2.xlsx ○ CRD42025635112.pdf ○ Extended Data.docx (Supplementary Table 9,10, 11). (description of the data in the file: Table 9 Subgroup Analyses, Table 10 Meta-Regression Analysis of Study Variables, Table 11 Linear Regression) ○ figure 1.jpg ○ figure 2.jpg ○ figure 3.jpg ○ figure 4.jpg ○ figure 5.jpg ○ figure 6.jpg ○ figure 7.jpg ○ figure 8.jpg ○ PRISMA Checklist Reporting guidelines • Zenodo: Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis. https://doi.org/10.5281/zenodo.14868482 • PRISMA Checklist • PRISMA Flowchart Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Software availability 1. Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020. Retrieved from https://test-training.cochrane.org/online-learning/core-software-cochrane-reviews/review-manager-revman/download-revman-5 2. R Core Team. (2024). R: A language and environment for statistical computing (Version 4.4.2) [Computer software]. R Foundation for Statistical Computing. Available at https://www.r-project.org 3. Python Software Foundation. (n.d.). Python Software Foundation. Retrieved January 24, 2025, from https://www.python.org/psf-landing/ 4. The Document Foundation. (n.d.). LibreOffice Calc (Version 7.5) [Computer software]. Retrieved January 24, 2025, from https://www.libreoffice.org/discover/calc/ Table 1. Data Extraction (Please refer Extended Data.docx - Excel file enclosed) Table 9 Subgroup Analyses (Please refer Extended data for table 9, 10 and 11) Table 10 Meta-Regression Analysis of Study Variables (Please refer Extended data for table 9, 10 and 11) References 1. Sonalkar S, Koelper N, Creinin MD, et al. : Management of early pregnancy loss with mifepristone and misoprostol: Clinical predictors of success from a randomized trial. Am. J. Obstet. Gynecol. 2020; 223 (4): 551.e1–551.e7. PubMed Abstract | Publisher Full Text | Free Full Text 2. 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PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 12 Mar 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Obstetrics and Gynaecology, Mid Yorkshire Hospitals NHS Trust, Wakefield, England, WF1 4DG, UK 2 Department of Obstetrics and Gynaecology, Government Vellore Medical College, Vellore, Vellore, Tamilnadu, 632011, India 3 Department of Pharmacology, Government Erode Medical College and Hospital, Erode, Tamilnadu, 638053, India Prieyadharshini Jayaprakasam Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Resources, Writing – Original Draft Preparation Jeyaram Nadarajan Saraswathy Roles: Data Curation, Investigation, Methodology, Supervision, Validation, Visualization Arbind Kumar Choudhary Roles: Conceptualization, Formal Analysis, Software, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 17 Feb 2026, 14:287 https://doi.org/10.12688/f1000research.160559.2 version 1 Published: 12 Mar 2025, 14:287 https://doi.org/10.12688/f1000research.160559.1 Copyright © 2025 Jayaprakasam P et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Jayaprakasam P, Saraswathy JN and Choudhary AK. Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis [version 1; peer review: awaiting peer review] . F1000Research 2025, 14 :287 ( https://doi.org/10.12688/f1000research.160559.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: AWAITING PEER REVIEW AWAITING PEER REVIEW ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 12 Mar 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 2 (revision) 17 Feb 26 read Version 1 12 Mar 25 Joseph B Stanford , University of Utah School of Medicine, Salt Lake City, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Stanford J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Apr 2026 | for Version 2 Joseph B Stanford , University of Utah School of Medicine, Salt Lake City, USA 0 Views copyright © 2026 Stanford J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The strength and value of this review is that it draws attention to the need for better clinical care for women experiencing pregnancy loss, across both psychological and physical/medical dimensions. Unfortunately, it lacks conceptual clarity across this very broad domain and has very serious deficits. The following is not a comprehensive list of deficits of the article, but it is sufficient to cast serious doubt on its conclusions. 1) The paper purports to be a systematic review and meta-analysis of “pharmacological, psychological, and ART interventions on clinical and psychological outcomes in women experiencing pregnancy loss,” that follows PRISMA guidelines, including registration in PROSPERO. However, the record referenced in PROSPERO, https://www.crd.york.ac.uk/PROSPERO/view/CRD42025635112, limits itself to psychological disorders, outcomes, and interventions, with no reference about clinical outcomes such as expulsion rates or pregnancy continuation rates. This paper does not adhere to the objectives of the proposed systematic review and meta-analysis proposed in PROSPERO. 2) There is a lack of clarity and organization about which phases of pregnancy loss are being addressed. The interventions run across different aspects of pregnancy loss, including prevention of first pregnancy loss for women at risk (eg, women with PCOS) treatment of threatened miscarriage to maintain pregnancy treatment of inevitable miscarriage to end pregnancy safely prevention of recurrent pregnancy loss psychological care at any state to improve satisfaction, quality of life, and possibly, medical outcomes 3) All different interventions and outcomes are lumped together haphazardly. Effect sizes for wildly different outcomes are compared in forest plots, as if it made any sense to compare effect sizes for expulsion rates, continuing pregnancy rates, perceived stress, etc., all on the same scale, in a single plot. For example, Figure 12 compares effect sizes for wildly disparate outcomes over a several year period and tries to draw some conclusion about changes over time. This makes no sense. Further, the text describing Figure 12 does not match the figure for the X or Y axes. 4) The statement is made that “Modified natural FET protocols incorporating progesterone monitoring and optimization (S6) demonstrated meaningful improvements in pregnancy outcomes including enhanced implantation rates and improved overall pregnancy results through individualized progesterone dosing and monitoring strategies.” This referenced the following paper Saupstad M, Bergenheim SJ, Bogstad JW, et al. : Progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles. Reprod. Biomed. Online. 2024; 49(1): 103862. This paper said nothing of the sort. Its conclusion was that “No association was found between progesterone concentration on the day of blastocyst transfer and pregnancy outcome in women undergoing mNC-FET without progesterone LPS [luteal phase support].” 5) It is highly puzzling that several large, randomized trials that assessed the use of progesterone to prevent miscarriage were not identified and included. See for example Reference no. 1&2 This lowers confidence in the supposed comprehensiveness of the search, screening, and inclusion strategy. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable References 1. Coomarasamy A., Williams H., Truchanowicz E., Seed P.T., et al.: A randomized trial of progesterone in women with recurrent miscarriages. New England Journal of Medicine, 373, 2141–2148 . 2015. 2. Coomarasamy A., Devall A.J., Cheed V., Harb H., et al.: A randomized trial of progesterone in women with bleeding in early pregnancy. New England Journal of Medicine, 380, 1815–1824 . 2019. Competing Interests No competing interests were disclosed. Reviewer Expertise reproductive epidemiology reply Respond to this report Responses (1) Author Response 08 Apr 2026 Dr Arbind Kumar Choudhary, Department of Pharmacology, Government Erode Medical College and Hospital, Erode, 638053, India Author response: We thank the reviewer for the careful reading of our manuscript and for the opportunity to clarify the rationale underlying the present review. We respectfully maintain that the manuscript is methodologically sound in its current form and that its central conclusions remain valid. The review was intentionally designed and transparently reported as an integrative evidence synthesis addressing the pregnancy-loss trajectory across prevention, acute management, and psychological sequelae. In the final manuscript, this scope is explicitly stated in the abstract and Methods, where the review objective, inclusion criteria, searched databases, study categories, and analytic framework are all clearly described. The review therefore should be interpreted on the basis of the methods actually reported in the published article, which define a contemporary evidence synthesis of pharmacological, psychological, and ART-related interventions rather than a narrowly psychological-only review. With respect to the PROSPERO registration, we acknowledge that the registered title and initial framing emphasize psychological impact and psychological interventions after pregnancy loss. However, prospective registrations are necessarily concise and often reflect the originating conceptual focus of a project, whereas the finalized review question may be operationalized more broadly during full protocol development and article preparation. In the present case, the manuscript does not conceal this broader scope; on the contrary, it explicitly states that the review synthesized evidence on prevention of recurrent pregnancy loss, management of acute pregnancy loss, and treatment of psychological sequelae, and it reports corresponding eligibility criteria and outcomes accordingly. For this reason, we do not consider the manuscript scientifically unsound or misleading. Rather, it represents an integrated clinical synthesis whose scope is fully visible to readers in the final text. Regarding the search period, the reviewer’s concern appears to arise from comparing the broader time window described in the registration with the final analytic window used in the manuscript. The article transparently reports that the final literature search was conducted across PubMed, Embase, and Cochrane CENTRAL and covered studies published from January 1, 2020, through December 31, 2024. That is the operative search frame for the review as published. The manuscript therefore should be assessed against the search strategy it explicitly reports, not against an assumption that all earlier studies were intended to be included in the final dataset. The use of a contemporary window is methodologically defensible in a field where recent practice-relevant evidence was the focus, and it does not invalidate the findings derived from the 18 included studies. For the same reason, the omission of earlier progesterone trials does not in itself undermine the manuscript’s internal validity. Those studies may be important landmark contributions to the broader literature, but the present review did not present itself as an exhaustive historical review of all pharmacologic miscarriage-prevention trials since 2015. Rather, it explicitly analyzed contemporary studies from 2020–2024 and synthesized 18 included studies within that frame. A study can be highly relevant to the overall field and still fall outside the final analytic scope adopted in a review. We therefore respectfully do not view the absence of earlier trials as evidence that the current manuscript is methodologically unsound. On the concern that heterogeneous interventions and outcomes were combined, we would emphasize that the manuscript does not treat all interventions as biologically equivalent. The review explicitly categorizes studies into pharmacological, psychological, ART, diagnostic/monitoring, and observational/comparative groups; effect sizes are reported by intervention and outcome domain; and the synthesis uses random-effects methods precisely because heterogeneity across populations, interventions, and measurements was expected. The manuscript further reports subgroup analyses by pregnancy-loss type, intervention type, study quality, geographic region, and delivery mode, as well as multiple sensitivity analyses. These are not signs of methodological weakness; they are the appropriate analytic response to a complex and multidisciplinary evidence base. Indeed, the manuscript is transparent about substantial heterogeneity, reporting an overall I² of 78.7% and showing that heterogeneity persisted across multiple sensitivity analyses, including exclusion of the high-risk study, restriction to RCTs, larger-sample studies, and more recent publications. Rather than ignoring this variability, the review explicitly interprets it as reflecting genuine differences in populations, interventions, delivery methods, and healthcare contexts. This strengthens, rather than weakens, the credibility of the article, because the limitations of the evidence base are openly acknowledged and incorporated into the interpretation. Similarly, the publication-bias assessment was handled transparently. The manuscript reports a symmetric funnel plot and a non-significant Egger’s regression result (intercept 7.81, p = 0.213), concluding that publication bias is unlikely to have materially affected the overall findings. The study also documents structured quality appraisal using RoB 2, Newcastle–Ottawa Scale, AMSTAR 2, and economics-study criteria, with six studies rated low risk, eleven moderate risk, and one high risk. These are robust methodological features that support the soundness of the review. With regard to the progesterone-monitoring discussion, the cited Saupstad study is presented in the manuscript as part of the broader ART optimization literature, not as a standalone basis for universal causal claims about serum progesterone in all settings. In Table 1, it is identified as an observational cohort involving modified natural FET and progesterone monitoring, with pregnancy outcome and implantation rate as outcomes. In that context, its inclusion in the ART subsection is methodologically coherent with the article’s stated objective of evaluating interventions and monitoring strategies relevant to pregnancy-loss-related reproductive outcomes. The point being made is that individualized ART pathway optimization forms part of the contemporary evidence landscape; it is not essential to the manuscript’s principal conclusions, which are supported by multiple domains of evidence, including pharmacologic and psychological interventions. It is also important to note that Version 2 of the article explicitly states that no studies were added or removed and that the revised version preserved the same scientific content and statistics while improving presentation and clinical interpretation. This directly supports our position that the manuscript’s scientific basis is stable and that the present discussion is primarily one of framing, not of core evidentiary failure. Finally, on the question of conflict of interest, we do not believe that the reviewer’s recommendation to consider two papers by the same lead author constitutes evidence of reviewer conflict. The article identifies the reviewer as Joseph B. Stanford, while the concern relates to studies by a different research group. Recommending multiple papers from the same author group is common when those papers are regarded as major studies in a topic area. That issue should therefore be understood as a literature-selection critique, not as a conflict-of-interest issue. For these reasons, we respectfully maintain that the manuscript is scientifically sound as presented. The review’s scope, search strategy, inclusion criteria, heterogeneity handling, bias assessment, and conclusions are all explicitly reported in the manuscript, and the article should therefore be evaluated on the basis of its transparently stated final methodology rather than solely on the abbreviated framing of the initial registration. View more View less Competing Interests I declare that I have no financial, professional, personal, or other competing interests that could reasonably be construed to influence my judgment regarding the validity or importance of the article or the peer review report. reply Respond Report a concern Stanford JB. Peer Review Report For: Optimizing care for women experiencing pregnancy loss: Insights from a systematic review and meta-analysis [version 1; peer review: awaiting peer review] . F1000Research 2025, 14 :287 ( https://doi.org/10.5256/f1000research.193235.r465462) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-287/v2#referee-response-465462 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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