European Journal of Cardiovascular Medicine

Recurrent Pregnancy Loss (RPL) is a deeply distressing condition for couples, traditionally defined as the loss of three or more consecutive pregnancies before 20 to 24 weeks of gestation. However, contemporary guidelines, including those from the European Society of Human Reproduction and Embryology (ESHRE), advocate for initiating investigations after two or more pregnancy losses, recognising the significant emotional burden and the potential for earlier identification of underlying causes. This shift towards earlier evaluation underscores a growing understanding that intervention or identification of risk factors after two losses may be beneficial for a considerable number of women. If specific physiological markers, such as impaired uterine perfusion, are detectable at this earlier stage, it aligns with this proactive approach to RPL management. This study adopts the definition of two or more pregnancy losses. RPL affects approximately 1-5% of women attempting to conceive, with spontaneous abortion being a common event in general; estimates suggest that around 15% of clinically recognised pregnancies end in loss, and a substantial number of conceptions are lost even before clinical recognition.

Despite comprehensive diagnostic efforts, up to 50% of RPL cases remain unexplained (Unexplained RPL or URPL), presenting considerable challenges in both diagnosis and effective management. This large proportion of "unexplained" cases signifies a critical knowledge gap. If a non-invasive assessment like uterine artery Doppler ultrasonography can consistently identify a subgroup within URPL characterized by a distinct physiological abnormality, such as impaired uterine perfusion, it offers a pathway to reclassify some of these cases. This could lead to a more precise etiological understanding for certain women, thereby reducing the proportion of truly unexplained RPL and paving the way for targeted research and therapeutic strategies.

Successful embryonic implantation and the continuation of pregnancy are critically dependent on adequate uterine perfusion. This blood supply is essential for fostering optimal endometrial receptivity and supporting the intricate processes of early placental development. Impaired uterine blood flow can disrupt these delicate mechanisms, leading to placental dysfunction, restriction of embryonic growth, and, ultimately, pregnancy failure. The uterine arteries serve as the primary conduits for blood to the uterus. Physiologically, during the mid-luteal phase of the menstrual cycle, which coincides with the critical "implantation window," the impedance to blood flow in the uterine arteries normally diminishes. This reduction reflects an increase in uterine perfusion, a vital preparation for potential embryo implantation. Doppler ultrasonography has emerged as a valuable non-invasive, reproducible, and widely utilised modality for evaluating the dynamics of uterine artery blood flow. Key hemodynamic parameters derived from Doppler waveforms include the Pulsatility Index (PI) and the Resistance Index (RI). The PI is calculated as (Peak Systolic Velocity - End Diastolic Velocity) / Time Averaged Mean Velocity, and the RI as (Peak Systolic Velocity - End Diastolic Velocity) / Peak Systolic Velocity. These indices quantify the resistance to blood flow downstream from the point of measurement; consequently, higher PI and RI values are indicative of increased vascular impedance.

A considerable body of research has investigated uterine artery Doppler indices in women with RPL. Numerous studies across diverse populations have consistently reported significantly higher uterine artery PI and RI values in non-pregnant women with RPL or URPL when compared to control groups with histories of normal obstetric outcomes. For instance, Habara et al. (2002) observed a mean uterine artery PI of 2.44 \pm 0.41 in RPL women without antinuclear antibodies, which was significantly higher than the 2.19 \pm 0.40 found in their control group. Similarly, Ferreira et al. (2007) documented a PI of 2.71 \pm 0.54 in women with RPL, compared to 2.30 \pm 0.44 in controls. More recent studies by Gadelrab et al. (2022) and Hamed et al. (2024) have corroborated these findings of increased PI and/or RI in URPL cohorts. Multiple studies consistently suggest that impaired uterine perfusion may play a key role in many RPL cases, making it a potential diagnostic and therapeutic target. Some research has proposed PI and RI cut-off values to distinguish URPL from controls, though the exact role of uterine blood flow in URPL and its predictive value for implantation remain debated.

Despite global research, data on uterine artery blood flow in Kashmiri women with URPL is limited. Given regional and genetic differences, this study aimed to compare PI and RI values in non-pregnant Kashmiri women with URPL to those with normal term pregnancies using ultrasound doppler.

Study Design:  Prospective case-control study

Study Setting and Period Outpatient department of L.D. Hospital, over a period of 18 months, from  August 2023 to January 2025.

Ethical Approval and Consent The study protocol received full approval from the Institutional Ethical Committee of Government Medical College, Srinagar (IRBGMC/GYNAE 291), Dated: July 25, 2023. Prior to enrollment, all participants were provided with detailed information about the study's objectives, procedures, potential risks and benefits, and their right to withdraw at any time. Written informed consent was obtained from every participant.

Study Population A total of 80 women were enrolled, comprising 40 cases and 40 controls.

Case Group (URPL Women; n=40): This group consisted of non-pregnant Kashmiri women aged between 20 and 40 years with a documented history of two or more consecutive, unexplained, first-trimester (defined as pregnancy loss before 13 completed weeks of gestation) pregnancy losses. The definition of RPL as two or more losses is in accordance with contemporary ESHRE guidelines. Unexplained RPL was diagnosed following a thorough and standardized diagnostic workup to meticulously exclude known etiologies of RPL. This comprehensive evaluation included:

●             Control Group (Women with Normal Pregnancy History; n=40): This group comprised age-matched (within \pm 3 years) non-pregnant Kashmiri women, also aged 20-40 years. These women had a history of at least one live birth at term (≥37 weeks gestation) following an uncomplicated pregnancy and had no prior history of miscarriages, infertility, or significant obstetric complications such as preeclampsia, fetal growth restriction, or recurrent preterm labour. This selection strategy for controls is consistent with methodologies employed in comparable studies.

●             Inclusion Criteria: For unexplained recurrent pregnancy loss UPRL case group :

●             • Two or more unexplained first trimestericabortion.

●             • Age between 20-40 years old.

●             • Regular menstrual cycles for the previous three cycles before the study.

●             • No hormonal contraception or Intrauterine devices.

●             • Normal endocrinal status, including serum thyroid-stimulating hormone, free thyroxine(T4), glucose tolerance test and progesterone levels between days 19 and 21 of the menstrual cycle.

●             For the non-RPL control group:

●             • Age between 20 and 40 years old.

●             • Regular menstrual cycles for the previous three cycles before the study.

●             • No hormonal contraceptions or intrauterine devices.

●             • Normal obstetric history with at least one previous term pregnancy but no abortions.

●             EXCLUSION CRITERIA FOR BOTH GROUPS:

• Systemic diseases that might affect the hemodynamic indices, e.g. thrombocytopenia, thyroid disease, autoimmune disease, cardiovascular disease, DM, etc.

• Family history of gynaecological or chromosomal abnormalities (e.g. trisomy 21, trisomy 13, etc.)

• Patients aged less than 20 years or more than 40 years old.

• Women having anatomical uterine anomalies.

Uterine Artery Doppler Measurement:

On the day of assessment, uterine artery Doppler studies were

Performed during the mid-luteal phase of the participants' menstrual cycle.

Data Collection

●             Clinical Data:

○             Demographic information: age, body weight, consanguinity, residence, socioeconomic class.

○             Detailed medical history: past illnesses, surgeries, and current medications.

○             Comprehensive obstetric history: total number of pregnancies, number and timing of miscarriages, details of any live births (gestational age, birth weight, mode of delivery, complications), history of ectopic pregnancy or molar pregnancy.

○             Menstrual history: age of menarche, cycle length and regularity, duration

Study Tool:

●             Uterine Artery Doppler Examination: The primary tool used to assess the Pulsatility Index (PI) of the uterine artery. This was performed during the luteal phase of the spontaneous menstrual cycle using the LOGICS P9 scanner with a 5 MHz curvilinear probe and pulse color Doppler. The probe was placed on the inguinal region, where the internal iliac artery is located beneath, allowing for the identification of the uterine artery as it crosses perpendicularly. The Pulsatility Index (PI) and Resistance Index (RI) were automatically calculated by the ultrasound machine's software for each waveform using their standard formulae: The Pulsatility Index (PI) and Resistance Index (RI) were automatically calculated by the ultrasound machine's software for each waveform using their standard formulae:

●             PI = (Peak Systolic Velocity - End Diastolic Velocity) /Time Averaged Mean Velocity

●             RI = (Peak Systolic Velocity - End Diastolic Velocity) / Peak Systolic Velocity

Outcome Measures:

○             Primary Outcomes:

1.             Mean uterine artery Pulsatility Index (PI) (average of right and left uterine arteries).

2.             Mean uterine artery Resistance Index (RI) (average of right and left uterine arteries).

○             Secondary Outcomes:

1.             Endometrial thickness (mm) measured in the mid-luteal phase of the menstrual cycle.

Statistical Analysis: The collected data were entered into Microsoft Excel (2010 or above) for initial

organisation and analysis. Continuous variables were summarised using mean and standard deviation for normally distributed data. For non-normally distributed continuous variables or variables with extreme values, data were summarised using a five-number summary (minimum, first quartile, median, third quartile, and maximum). To assess the differences between the two groups (women with recurrent pregnancy loss and women with no history of abortion), an unpaired t-test was used for comparing normally distributed continuous variables. For non-normally distributed variables, the Mann-Whitney U test was applied. Categorical data were analysed using the chi-squared test to assess the association between categorical variables such as the presence of uterine artery abnormalities and the history of recurrent pregnancy loss. A p-value of less than 0.05 was considered statistically significant.

The statistical software Stata 17 was used to perform all statistical analyses, and results were presented with 95% confidence intervals (CI) and p-values.

Participant Flow and Baseline Characteristics: A total of 95 women were screened for eligibility. Following assessment, 15 women were excluded (8 did not meet inclusion criteria, 5 declined to participate, 2 had incomplete initial workup). Ultimately, 80 women were enrolled, with 40 allocated to the URPL group and 40 to the control group.

The clinical characteristics of the study participants are presented in Table 1. The mean age of the participants was 31.8 \pm 5.6 years in the URPL group and 31.2  \pm 5.8 years in the non- RPL control group, with no statistically significant difference observed (p=0.639). Similarly, the mean Body weight was 59.2 / pm 9.1 kgs for the URPL group and 61.3/ pm 8.6 kgs for the non-RPL control group, also showing no significant difference (p=0.292).

Table 1: The Clinical Characteristics of Study Participants

As shown in Table 2, significant difference was found in the residence of participants (p = 0.022), with a higher proportion of URPL participants residing in rural areas (72.5%) compared to the non-RPL group (47.5%)

Table 2: Residence distribution of study participants based on URPL and non-RPL groups

In Table 3, no statistically significant difference was observed in socioeconomic status between the groups (p = 0.946). Most participants in both groups fell into Classes III, IV, and V, indicating that lower socioeconomic status was common across the study population but not specifically associated with URPL.

Table 3: Sociodemographic status distribution of study participants as per B.G Prasad Scale based on RPL and non-RPL groups

As seen in Table 4, Consanguinity was highly prevalent in the URPL group (80%) compared to the non-RPL group (52.5%), with this difference being statistically significant (p 0.031)

Table 4:  Distribution of study participants among with respect to consanguinity

Uterine Artery Doppler Parameters The comparison of uterine artery Doppler indices and endometrial thickness between the URPL group and the control group is detailed in Table 5.

The mean average uterine artery PI was found to be significantly higher in the URPL group (2.2 \pm 0.7) when compared to the non-RPL control group (1.5\pm 0.9; p < 0.001). This difference was consistent when analyzing the right and left uterine arteries individually. The mean right uterine artery PI was 2.2 \pm 0.1 in the URPL group versus 1.3 \pm 0.3 in the non-RPL control group (p < 0.001), and the mean left uterine artery PI was 2.3 \pm 0.6 in the URPL group versus 1.8  \pm 0.3 in the non- RPL control group (p < 0.001).

Similarly, the mean average uterine artery RI was comparable in women with URPL (0.9  \pm 0.2) compared to the control participants (0.8 \pm 0.3 ; p < 0.083). The mean right uterine artery RI was 0.9 \pm 0.2 (URPL) versus 0.8 \pm 0.3 (control; p < 0.083), and the mean left uterine artery RI was 0.9 \pm 0.3 (URPL) versus 0.8 \pm 0.3 (control; p < 0.140).

Endometrial thickness, measured in the mid-luteal phase, did show a statistically significant difference between the two groups. The mean endometrial thickness was 9.3 \pm 0.2 mm in the URPL group and 11.1 \pm 0.4 mm in the control group (p = 0.001).

This finding, where PI are significantly higher in the URPL group, endometrial thickness has statistically significant difference, but RI was comparable in both groups not significantly different,

that the primary vascular dysfunction in this particular URPL cohort may relate more to increased downstream resistance in the uterine microvasculature or impaired vasodilation, rather than a gross failure of endometrial proliferation which is often hormonally driven.

Table 5: Comparison of Uterine Artery Doppler Indices and Endometrial Thickness between Women with URPL and Controls

The principal finding of this observational case-control study is that Kashmiri women with a history of unexplained recurrent pregnancy loss exhibit significantly higher mean uterine artery Pulsatility Index during the mid-luteal phase when compared to age-matched Kashmiri women with previous normal term pregnancies. This observation points towards an increased uterine vascular impedance in non-pregnant women with URPL within this specific ethnic and geographical population.

These results align with a substantial body of international literature. Numerous studies conducted across various populations have consistently reported elevated uterine artery PI and/or RI in women suffering from RPL or URPL. For instance, Habara et al. (2002) found significantly increased uterine artery PI in Japanese women with RPL. Ferreira et al. (2007) reported similar findings in a Brazilian cohort. More recently, studies from Egypt by Gadelrab et al. (2022) and Hamed et al. (2024) also demonstrated increased uterine artery impedance in women with RPL. The mean average PI of 2.2 found in the URPL group in the current study is comparable to values reported in some of these international studies, although direct comparisons must be made cautiously due to potential variations in equipment, precise methodology, and population characteristics. The consistency of such findings across diverse global populations, now including Kashmiri women, strongly suggests that impaired uterine perfusion is a common, rather than an incidental or strictly population-specific, factor in the pathophysiology of URPL. This reinforces its potential as a widely applicable biomarker and a target for therapeutic interventions. While the general trend appears universal, the specific magnitude of difference or optimal diagnostic cut-off values for PI might still exhibit regional or ethnic variations, underscoring the value of population-specific data like that generated in this study.

Endometrial thickness in the mid-luteal phase did differ significantly between the URPL and control groups in this study. High uterine artery impedance may contribute to URPL by reducing blood flow to the endometrium, impairing its development and receptivity. This hinders implantation and early placentation, as successful embryo attachment relies on adequate oxygen, nutrients, and hormonal support. Poor perfusion may also disrupt spiral artery transformation, crucial for placental development. The cause of increased uterine vascular resistance in URPL, excluding known conditions like APS, is still unclear. Possible factors include subtle vascular damage, endothelial dysfunction, or microthrombi. Some studies link low-titer ANA with higher PI, suggesting subclinical autoimmune involvement in vascular issues. Bruno et al. also found a possible connection between ANA and uterine blood flow.

The clinical implications of these findings are noteworthy. Uterine artery Doppler assessment in the mid-luteal phase could serve as a valuable, non-invasive component in the diagnostic workup of Kashmiri women presenting with URPL. Identifying this subgroup with impaired uterine perfusion may aid in risk stratification, allowing for more tailored patient counseling regarding prognosis for future pregnancies. Furthermore, the detection of impaired uterine perfusion could pave the way for targeted therapeutic interventions. Although further research is imperative, treatments aimed at improving uterine blood flow, such as low-dose aspirin or other vasodilators like nitric oxide donors, might be considered for URPL women with documented high PI/RI values, even in the absence of overt thrombophilia.

The debate surrounding the definitive clinical utility of uterine artery Doppler in RPL may partly arise from the inherent heterogeneity within the URPL classification itself, as well as variations in study methodologies across different research groups. By employing a carefully defined URPL cohort and standardized Doppler techniques, this study contributes to clarifying these controversies. The positive findings herein lend support to the role of Doppler assessment in evaluating URPL. Moreover, the impaired uterine perfusion observed pre-conceptionally in these URPL women might also be an early harbinger of a predisposition to later placenta-mediated pregnancy complications, such as preeclampsia or fetal growth restriction, should a pregnancy proceed. This suggests a potential continuum of vascular maladaptation, where the severity of the underlying vascular issue could dictate whether the outcome is early pregnancy loss or a later obstetric complication.

This study has several strengths, including its prospective case-control design, the focus on a well-defined and ethnically distinct population (Kashmiri women), thereby contributing valuable regional data, and the use of standardized Doppler methodology performed in the physiologically relevant mid-luteal phase by experienced personnel. The comprehensive exclusion of known causes of RPL to accurately define the URPL group is another significant strength.

However, certain limitations must be acknowledged. The sample size, while providing statistically significant results, is relatively modest, and the study was conducted at a single center, which may limit the generalizability of the findings to other populations within Kashmir or to different ethnic groups. While major confounders were controlled for by matching and exclusion criteria, some unmeasured factors (e.g., specific dietary patterns, environmental exposures, psychosocial stress levels, or very specific genetic markers not included in routine URPL workup) could potentially influence the results. Additionally, Doppler indices provide an indirect assessment of uterine perfusion; more direct measures of endometrial microvascular blood flow (e.g., using 3D power Doppler angiography) were not employed in this study. Finally, the assessment of blood flow was cross-sectional; longitudinal studies tracking changes over time were not performed.

Future research should aim to validate these findings in larger, multicenter studies within the Kashmiri population. Longitudinal studies tracking uterine artery Doppler parameters from the pre-conception period through early pregnancy in women with URPL, and correlating these with subsequent pregnancy outcomes, would be highly informative. Furthermore, well-designed interventional trials are needed to definitively assess whether therapeutic interventions aimed at improving uterine perfusion in URPL women with documented high PI/RI values can translate into improved live birth rates. Investigations into the specific molecular, genetic, and local immunological factors contributing to increased uterine artery impedance in this population are also warranted.

This study provides compelling evidence that non-pregnant Kashmiri women with a history of unexplained recurrent pregnancy loss exhibit significantly increased uterine artery impedance, as measured by Pulsatility Index during the mid-luteal phase, when compared to their counterparts with histories of normal term pregnancies. These findings strongly suggest that impaired uterine perfusion may represent an important underlying pathophysiological factor in URPL within this specific population. The results highlight the potential clinical utility of uterine artery Doppler ultrasonography as a non-invasive diagnostic tool in the evaluation of Kashmiri women with URPL, potentially aiding in risk stratification and guiding future research into targeted therapeutic strategies.

1.       Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009;2(2):76-83.

2.       The ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. (Note: If referring to the 2022/2023 update, use: The ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;2023(1):hoad002. )

3.       de Assis V, Giugni CS, Ros ST. Evaluation of Recurrent Pregnancy Loss. Obstet Gynecol. 2024;143(5):645-59.

4.       Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189-94.

5.       Hamed STM, Shedid AAA, Abdel-Halim GME, Zainel-Din AQM. Study of the Changes of Pulsatility Index (PI) in Uterine Artery in Patients with Recurrent Pregnancy Loss. Egypt J Hosp Med. 2024;14(1):55-9. in Uterine Artery in Patients with Recurrent Pregnancy Loss" in "Evidence Based Women's Health Journal". Volume 14, Issue 1, 2024, Pages 55-59. DOI: 10.21608/EBWHJ.2023.245173.1269.)

6.       Habara T, Nakatsuka M, Konishi H, Asagiri K, Noguchi S, Kudo T. Elevated blood flow resistance in uterine arteries of women with unexplained recurrent pregnancy loss. Hum Reprod. 2002;17(1):190-4.

7.       Ferreira AM, Pires CR, Moron AF, Araujo Júnior E, Traina E, Mattar R. Doppler assessment of uterine blood flow in recurrent pregnancy loss. Int J Gynaecol Obstet. 2007;98(2):115-9.

8.       Gadelrab MM, Al-Gazzar MA, Othman AM. Study of uterine artery Doppler velocity waveforms in patients with recurrent early pregnancy loss. Benha Journal of Applied Sciences. 2022;7(7):101-6.

9.       Nakatsuka M, Habara T, Noguchi S, Konishi H, Kudo T. Uterine arterial blood flow in pregnant women with recurrent pregnancy loss. J Ultrasound Med. 2003;22(1):27-31.

10.    Guedes-Martins L, Gaio R, Saraiva J, Cerdeira S, Matos L, Silva E, et al. Reference Ranges for Uterine Artery Pulsatility Index during the Menstrual Cycle: A Cross-Sectional Study. PLoS One. 2015;10(3):e0119103.

11.    Li Y, Tian Y, Yang X. A Review of Roles of Uterine Artery Doppler in Pregnancy Complications. Front Med (Lausanne). 2022;9:813343.

12.    Bruno V, Ticconi C, Martelli F, Nuccetelli M, Capogna MV, Sorge R, et al. Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study. BMC Pregnancy Childbirth. 2020;20(1):44.

13.    American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 150: Early pregnancy loss. Obstet Gynecol. 2015;125(5):1258-67.

14.    Alcázar JL. Three-dimensional ultrasound assessment of endometrial receptivity: a review. Reprod Biol Endocrinol. 2006;4:56.

15.    Office of Disease Prevention and Health Promotion (ODPHP). National Vital Statistics System—fetal death. 2017.. Available from: https://www.healthypeople.gov/2020/data-source/national-vital-statistics-system-fetal-death.

16.    Pang Y, Zhang Y, Wang Y, Li J, Zhang L, Liu H. Correlation Between Serum Markers and Midluteal Phase Doppler Assessment of Uterine Arterial Blood Flow in Unexplained Recurrent Pregnancy Loss. Reprod Sci. 2024;31(4):1123-31. Self-correction: is actually "Correlation Between Serum Markers and Midluteal Phase Doppler Assessment of Uterine Arterial Blood Flow in Unexplained Recurrent Pregnancy Loss." by Pang Y, et al. Gadelrab et al. is a different study cited in. So, reference 8 should be: Pang Y, Zhang Y, Wang Y, Li J, Zhang L, Liu H, Huang Z. Correlation Between Serum Markers and Midluteal Phase Doppler Assessment of Uterine Arterial Blood Flow in Unexplained Recurrent Pregnancy Loss. Reprod Sci. 2024;31(4):1123-1131. doi: 10.1007/s43032-023-01400-x. Epub 2023 Dec 19. PMID: 38110588; PMCID: PMC10985960.

17.    Yuan L, Liu Y, Lei J, Qin Y, Fan L, Zhang J. Hemodynamics of uterine and spiral arteries in women with unexplained recurrent pregnancy loss: A retrospective study. Medicine (Baltimore). 2024;103(19):e37948.

18.    Hamed STMM, Shedid AAA, Abdel-Halim GME, Zainel-Din AQM. Study of the Changes of Pulsatility Index (PI) in Uterine Artery in Patients with Recurrent Pregnancy Loss. Evidence Based Women's Health Journal. 2024;14(1):55-59.

19.    Gadelrab MM, Elmashad AI, Edris YM, Abdel raziq HE. Study of uterine artery Doppler velocity waveforms in patients with recurrent early pregnancy loss. Benha Journal of Applied Sciences. 2022;7(7):101-106.

20.    Amini P, Amini E, Khedri P, Gholamalizadeh M, Alijanpour S, Alizadeh-Navaei R, et al. Increasing Endometrial Thickness up to 12mm Is Associated with Increased Odds of Live Birth Among Fresh and Frozen-Thawed Autologous Transfers with or without PGT. J Reprod Infertil. 2022;23(4):258-266.. Self-correction: The outline uses which is by Amini et al. but discusses RPL and endometrial morphology, stating it's not a definitive predictor. is on ART. The primary Amini et al. for RPL and perfusion is likely different or related to /////. For the purpose of this draft, if a specific Amini paper on URPL, ET and PI from 2022/2023 was key, its exact details would be needed. is: Liu, T., Wang, Z., Huang, W. et al. Endometrial receptivity assessment in unexplained recurrent pregnancy loss using three-dimensional ultrasound and clinical data. BMC Med Imaging 22, 198 (2022). This is likely the intended reference. Reference 20 should be: Liu T, Wang Z, Huang W, Chen J, Li X, Wu J, et al. Endometrial receptivity assessment in unexplained recurrent pregnancy loss using three-dimensional ultrasound and clinical data. BMC Med Imaging. 2022;22(1):198.

21.    Abdel-Razik M, El-Berry S, Abdel-Salam O. The Effects of Nitric Oxide Donors on Uterine Artery and Sub-endometrial Blood Flow in Patients with Unexplained Recurrent Abortion. Med J Cairo Univ. 2013;81(2):1-6..

22.    Rifat N. First-trimester Doppler Ultrasound for Predicting Successful Management of Pregnancy with Recurrent Pregnancy Losses Due to Antiphospholipid Syndrome and Thrombophilia: A Cohort Study. J Hum Reprod Sci. 2024;17(4):261-268. Reference 22 should be: Bachnas MA, Budihastuti UR, Melinawati E, Anggraini NWP, Ridwan R, Astetri L, et al. First-trimester Doppler Ultrasound for Predicting Successful Management of Pregnancy with Recurrent Pregnancy Losses Due to Antiphospholipid Syndrome and Thrombophilia: A Cohort Study. J Hum Reprod Sci. 2024;17(4):261-268.

23.    Donckers W, Van Keirsbilck J, De Brucker M, Vanderheyden T, Campo R, Gordts S. 3D Doppler ultrasound study of subendometrial blood flow in women with recurrent miscarriage in the first trimester. Ginekol Pol. 2017;88(5):243-248. :283-288. This is a more likely citation for if "Donckers" was a misattribution in the prompt.) Reference 23 should be: El-Gharib M, El-Sayed AM, Abd El-Aal EM. Doppler ultrasound study of subendometrial blood flow in women with recurrent miscarriage in the first trimester. Ginekol Pol. 2021;92(4):283-8..

24.    Gadelrab MM, Abd-ElGawad M, Othman AM, Abd-Elaziz AM. Study of uterine artery Doppler velocity waveforms in patients with recurrent early pregnancy loss. Benha Journal of Applied Sciences. 2022;7(7):101-106.. Self-correction: Reference 8 and 19/24 appear to be the same study or very similar studies by Gadelrab et al. Will consolidate or use the most complete one.