Recurrent Pregnancy Loss Clinic Research Articles

Psychological changes among women with recurrent pregnancy loss during the COVID-19 period in northeastern China: a cross-sectional study

BackgroundIt aimed to investigate the prevalence of anxiety and depression in recurrent pregnancy loss (RPL) women and the related factors in Northeastern China during the Coronavirus disease 2019 (COVID-19) pandemic.MethodsFrom March to June 2021, we conducted an electronic questionnaire survey of 267 RPL women who attended the recurrent pregnancy loss clinic at Shengjing Hospital of China Medical University. The State–Trait Anxiety Inventory (STAI), Beck Depression Inventory-II (BDI-II), Perceived Stress Scale (PSS), and Medical Outcomes Study Social Support Survey (MOS-SSS-C) were used to screen for anxiety, depression, stress, and social support. Logistic regression was used to explore the related factors of anxiety and depression.ResultsRPL women had severe psychological problems during the pandemic: 56.6% showed state anxiety or trait anxiety, 26.6% showed high levels of stress, and 13.1% showed depression. Economic pressure caused by COVID-19, and high stress were common related factors for anxiety and depression. The interval since last miscarriage <6 months, worse mood changes due to COVID-19, and concerns about COVID-19 were associated with anxiety. A history of pregnancy loss >14 weeks was associated with depression. While adequate social support and actively seeking health help were protective factors for trait anxiety. And identifying the etiology was a protective factor for depression.ConclusionThe study revealed the prevalence of anxiety, depression, and the associated factors in RPL women during COVID-19. More attention should be paid to the psychology of RPL women and adequate social support should be provided.

P-488 Pregnancy loss rate in recurrent pregnancy loss patients according to gestational week: life tables for clinical guidance of patients during supportive care before week 24

Abstract Study question What is the hazard for a new pregnancy loss (PL) each gestational week (GW) reached in RPL patients and does it depend on baseline characteristics? Summary answer The PL rate declines for every GW passed during pregnancy and the hazard rate depends on age, BMI, conception method, and history of late PL. What is known already A few studies in healthy women have provided information about the risk of PL for each GW reached but were highly biased due to variable entry time. No similar study has been performed in recurrent pregnancy loss (RPL) patients who often ask their clinician about their pregnancy prognosis for each GW passed. No tool based on baseline characteristics have been provided to guide patients on the risk of a new PL at a specific GW Study design, size, duration In a prospective cohort study from January 2016 to January 2023, 517 RPL patients with ≥2 previous, consecutive PLs, no uterine or chromosomal abnormalities, and who during follow-up had ≥1 pregnancies after admission to the specialized RPL Clinic of Western Denmark were included. All patients were guided to contact the clinic immediately after a positive urine-hCG test to have an early ultrasound scan from GW 5. All registered pregnancies after admission were included (N = 639). Participants/materials, setting, methods Life table analyses on the risk of a PL according to GW from GW 4-24 were performed on the first and on all subsequent pregnancies after admission, respectively, and hazard ratios (HR) for age (</≥35 years), BMI (</≥30), smoking (no/yes), previous livebirth (no/yes), conception method (natural/IUI versus IVF/ICSI/FET), number of previous PLs (≥/<5), and previous late PL (no/yes) were calculated by univariate log-rank test for equality and a multivariate Cox proportional hazard model. Main results and the role of chance The median GW of PL after admission (n = 169) was 6 (IQR 4-7). In total, 32.1% of patients had ≥1 PL after admission with a cumulative hazard of 0.37 (95%CI 0.32-0.43). The cumulated hazard at GW 7 was 0.27 (0.23-0.32) and 0.34 (0.30-0.41) at GW 12 at which times 76.5% and 94.0% of PLs, respectively, had occurred. The life tables for first pregnancy outcome stratified by baseline characteristics showed that the risk of PL per GW was independent of smoking (HR = 1.14 [0.76-1.73], p = 0.514), prior livebirth (0.77 [0.59-1.01] p = 0.056) and number of previous PL (1.21 [0.84-1.75] p = 0.302), while significantly differing curves and hazard rates were found for maternal age >35 (1.36 [1.00-1.85], p = 0.043), BMI >30 (1.39 [1.00-1.97], p = 0.050), previous late PLs (1.80 [1.20-2.70], p = 0.005), and conception by ART (1.75 [1.39-2.56], p < 0.001), respectively, in comparison to their counterparts (BMI<35, no late PL, and natural conception). The results can be interpreted such as for each week the pregnancy has progressed intact, the risk of PL decreased significantly faster in recurrent PL patients with lower age and BMI, no prior late PL, and pregnancy after natural conceptioncompared with patients in the opposite groups[OBC1] . Comparable results were found when all pregnancies after admission were included. Limitations, reasons for caution For the stratified analyses, the size of each subgroup is small and therefore these life table analyses should be interpreted with caution. The risk of missing registration of early PLs is expectedly small, as patients are encouraged to take contact and have all PL registered to receive best supportive care. Wider implications of the findings The results illustrate that advice to RPL patients about expected pregnancy success at different GW of progressing pregnancy should be modified according to certain baseline characteristics. The time analysis graphs can help clinician inform their patients on the pregnancy prognosis and potentially alleviate the patient’s stress. Trial registration number no applicable as no human specimens were used. Database registered locally by: 2018-5

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6year-outcomes and to develop a framework for IVIg use in RPL. Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42years, body mass index (BMI)<35kg/m2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8g/kg was given prior to conception and monthly during pregnancy until 16-20weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n=111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p=0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR=3.27, CI 95% (1.15-10.2), p=0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n=31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p=0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p=0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p=0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL.

Prevalence, causes, and impact of non-visualized pregnancy losses in a recurrent pregnancy loss population.

Does the occurrence of non-visualized pregnancy loss (NVPL) affect future reproductive outcomes in patients with recurrent pregnancy loss (RPL)? The number of previous NVPLs is a significant predictor of subsequent live birth in patients with RPL. The number of preceding miscarriages is a strong indicator for future reproductive outcomes. However, NVPL particularly has been sparsely addressed in previous literature. We performed a retrospective cohort study of 1981 patients attending a specialized recurrent pregnancy loss clinic (RPL) from January 2012 to March 2021. A total of 1859 patients met the inclusion criteria of the study and were included in the analysis. Patients with a history of RPL, defined as ≥2 pregnancy losses before 20 weeks gestation, who attended a specialized RPL clinic in a tertiary care center were included. Patients' evaluation included parental karyotyping, antiphospholipid antibodies screening, uterine cavity assessment with hysterosalpingography (HSG) or hysteroscopy, maternal thyroid stimulating hormone (TSH) testing, and serum hemoglobin A1C testing. Other investigations were performed only when indicated such as testing for inherited thrombophilias, serum prolactin, oral glucose tolerance test, and endometrial biopsy. Patients were divided into three groups; patients who experienced NVPLs only (pure NVPLs group), patients with only visualized pregnancy losses (pure VPLs group), and patients with history of both NVPLs and VPLs (mixed group). Statistical analysis was performed using Wilcoxon rank-sum tests for continuous variables and Fisher's exact tests for categorical variables. Significance was detected when P values <0.05. A logistic regression model was used to determine the impact of NVPLs and VPLs numbers on any live birth subsequent to the initial RPL clinic visit. The prevalence of patients with pure NVPLs, pure VPLs, and mixed losses was 14.7% (274/1859), 31.8% (591/1859), and 53.5% (994/1859), respectively. The prevalence of acquired and congenital uterine anomalies diagnosed by HSG or hysteroscopy was significantly different between pure NVPLs, pure VPLs, and mixed groups (16.8% versus 23.7% versus. 20.7%, respectively P = 0.05). There were no significant differences in the results of other RPL investigations or baseline demographics between the three groups. A logistic regression model controlling for maternal age at the initial RPL clinic visit and the follow-up duration showed that the numbers of NVPLs (odds ratio (OR): 0.77, CI: 0.68-0.88) and VPLs (OR: 0.75, CI: 0.64-0.86) are strong predictors for subsequent live births after the initial RPL clinic visit (P < 0.001). The odds of having a live birth decreased by 23% and 25% with each additional NVPL and VPL, respectively. This study may be limited by its retrospective design. Some of our data, including home pregnancy tests and obstetric history, are based on patient self-reporting, which could have overstated the true prevalence of NVPLs. Another limitation is the lack of available live birth data for all patients at the time of the analysis. To our knowledge, this is the first study to examine and analyze the reproductive outcomes of patients with pure NVPLs in a substantial cohort of patients with RPL. NVPLs seem to affect future live births the same way as clinical miscarriages, which supports their inclusion in RPL definitions. This study was supported in part by Canadian Institute Heath Grant (CIHR): Reference Number/W11-179912 and Women's Health Research Institute (WHRI), Vancouver, BC, Canada. M.A.B: Research grants from Canadian Institute for Health Research (CIHR) and Ferring Pharmaceutical. M.A.B. is on the advisory board for AbbVie and Baxter. N/A.

Increased Live Birth Rate with Dydrogesterone among Patients with Recurrent Pregnancy Loss Regardless of Other Treatments.

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies. Several treatment options are available, including progesterone, which is one of the few treatments that improve live birth rates in RPL patients. To compare the live birth rates, medical and obstetric characteristics, and RPL evaluation results of women with and without progesterone treatment. These women attended the RPL clinic at Soroka University Medical Center. A retrospective cohort study based on 866 patients was conducted. The patients were divided into two groups and examined: the dydrogesterone treatment group consisting of 509 women and a group of 357 patients who did not receive the treatment. All the patients had a subsequent (index) pregnancy. The two groups were not statistically different in terms of their demographic and clinical characteristics or evaluation results. In a univariate analysis, no statistically significant differences were found between the groups in terms of live birth rates (80.6% vs. 84%; p-value = 0.209). In a multivariate logistic analysis adjusted for maternal age, the ratio of pregnancy losses to the number of pregnancies, other administered treatments, antiphospholipid syndrome, and body mass index, dydrogesterone treatment was found to be independently associated with a higher rate of live births than the control group (adjusted OR = 1.592; CI 95% 1.051-2.413; p-value = 0.028). Progesterone treatment is associated with an increased live birth rate in RPL patients. Studies with larger sample sizes are recommended to strengthen these results.

Temporal trends in thyroid-stimulating hormone and live birth rate in subclinical hypothyroid patients in a recurrent pregnancy loss population

ObjectivesThe purpose of this study was to explore if thyroperoxidase antibody positivity impacts thyroid stimulating hormone levels during pregnancies following the index visit and how live birth rate is impacted when treated subclinical hypothyroidism is treated with levothyroxine or not. Study designA retrospective chart review of 1443 recurrent pregnancy loss patients from BC Women’s Hospital recurrent pregnancy loss clinic was conducted. Thyroid stimulating hormone in pregnancies after the index visit across thyroperoxidase antibody status was analyzed using mixed-effects linear regression. Live birth rate in patients with subclinical hypothyroidism (thyroid stimulating hormone 2.5–10 mIU/L) with levothyroxine treatment was compared to those without relative to euthyroid patients using logistic regression. Results and conclusionsThere was no significant difference in patient demographics including age, body mass index, or number of previous live births or pregnancy losses between groups. The distribution of recurrent pregnancy loss causes between groups revealed no difference in proportion of patients with anti-phospholipid antibody syndrome, hereditary thrombophilia, hyperprolactinemia, or anatomic causes. There was no significant change in thyroid stimulating hormone across thyroperoxidase antibody or treatment status (p = 0.24) for up to four subsequent pregnancies. An increased live birth rate in subclinical hypothyroidism when treated with levothyroxine relative to untreated (OR = 2.25, p < 0.001) was seen.Thyroid stimulating hormone values do not change over time following the index visit for up to 4 subsequent pregnancies irrespective of the thyroxperoxidase antibody status. An increase in live birth rate was found in patients with borderline subclinical hypothyroidism when treated with levothyroxine.

Live Birth Rate in Women with Recurrent Pregnancy Loss after In Vitro Fertilization with Concomitant Intravenous Immunoglobulin and Prednisone.

Pregnancy loss after in vitro fertilization (IVF) is at least as common as after spontaneous conception. Recurrent pregnancy loss (RPL) may often have an immunological background, and it is therefore relevant to test immune-based interventions in these patients. The objective was to investigate the effect of immunotherapy with intravenous immunoglobulin (IvIg) and prednisone (PRS) as concomitant therapy to IVF in women with RPL after earlier IVF treatments. In a cohort study conducted at The Danish RPL Clinic, 41 women with three or more consecutive pregnancy losses after IVF underwent at least one further IVF cycle with concomitant immunotherapy from 2012 to 2017. The immunotherapy with IvIg and PRS was given before embryo transfer and repeatedly in the first trimester when pregnancy was achieved. Fourteen women (34.2%) achieved a live birth after the first embryo transfer with immunotherapy, and a total of 32/41 (78%) achieved a live birth after up to 4 embryo transfers. Baseline characteristics and the presence of autoantibodies were not significantly different among women achieving live birth or not. The observed 34% birth rate in women with RPL after IVF receiving immunotherapy appears higher than the expected 16–19% birth rate without immunotherapy and is similar to findings in a previous cohort from our clinic. Concomitant immunotherapy as described may be a promising intervention for women with RPL after IVF; however, the effect must be tested in a randomized controlled trial.

The effect of low-molecular-weight heparin on live birth rate of patients with unexplained early recurrent pregnancy loss: A two-arm randomized clinical trial.

The effect of anticoagulant medication in unexplained early recurrent pregnancy loss (RPL) patients is controversial. This clinical trial evaluated the effect of low-molecular-weight heparin (LMWH) on pregnancy outcomes in these patients. The study was performed as a single-blind randomized clinical trial between 2016 and 2018. Samples were selected from patients who were referred to Avicenna RPL clinic with a history of at least two previously happened early unexplained miscarriages. The eligibility was defined strictly to select unexplained RPL patients homogenously. One hundred and seventy-three patients who got pregnant recently were allocated randomly into two groups LMWH plus low-dose aspirin treatment (Group A = 85) and low-dose aspirin treatment only (Group B = 88)) and were followed up till their pregnancy termination (delivery/abortion). A per-protocol analysis was carried out and all statistical tests were two-sided with a P < 0.05 significance level. The live birth rates (LBRs) in Groups A and B were 78% and 77.1%, respectively, which did not show any statistically significant difference between the two groups, neither in rates nor in time of abortion. In subgroup analysis for polycystic ovary syndrome (PCOS) patients, the odds ratio for study outcome (intervention/control) was 2.25 (95% confidence interval: 0.65-7.73). There was no major adverse event whereas minor bleeding was observed in 18% of patients in Group A. LMWH does not improve the LBR in unexplained RPL patients, however, it is recommended to evaluate its effect separately in PCOS patients.

External validation of a frequently used prediction model for ongoing pregnancy in couples with unexplained recurrent pregnancy loss.

What is the predictive performance of a currently recommended prediction model in an external Dutch cohort of couples with unexplained recurrent pregnancy loss (RPL)? The model shows poor predictive performance on a new population; it overestimates, predicts too extremely and has a poor discriminative ability. In 50-75% of couples with RPL, no risk factor or cause can be determined and RPL remains unexplained. Clinical management in RPL is primarily focused on providing supportive care, in which counselling on prognosis is a main pillar. A frequently used prediction model for unexplained RPL, developed by Brigham et al. in 1999, estimates the chance of a successful pregnancy based on number of previous pregnancy losses and maternal age. This prediction model has never been externally validated. This retrospective cohort study consisted of 739 couples with unexplained RPL who visited the RPL clinic of the Leiden University Medical Centre between 2004 and 2019. Unexplained RPL was defined as the loss of two or more pregnancies before 24 weeks, without the presence of an identifiable cause for the pregnancy losses, according to the ESHRE guideline. Obstetrical history and maternal age were noted at intake at the RPL clinic. The outcome of the first pregnancy after intake was documented. The performance of Brigham's model was evaluated through calibration and discrimination, in which the predicted pregnancy rates were compared to the observed pregnancy rates. The cohort included 739 women with a mean age of 33.1 years (±4.7 years) and with a median of three pregnancy losses at intake (range 2-10). The mean predicted pregnancy success rate was 9.8 percentage points higher in the Brigham model than the observed pregnancy success rate in the dataset (73.9% vs 64.0% (95% CI for the 9.8% difference 6.3-13.3%)). Calibration showed overestimation of the model and too extreme predictions, with a negative calibration intercept of -0.46 (95% CI -0.62 to -0.31) and a calibration slope of 0.42 (95% CI 0.11-0.73). The discriminative ability of the model was very low with a concordance statistic of 0.55 (95% CI 0.51-0.59). Recalibration of the Brigham model hardly improved the c-statistic (0.57; 95% CI 0.53-0.62). This is a retrospective study in which only the first pregnancy after intake was registered. There was no time frame as inclusion criterium, which is of importance in the counselling of couples with unexplained RPL. Only cases with a known pregnancy outcome were included. This is the first study externally validating the Brigham prognostic model that estimates the chance of a successful pregnancy in couples with unexplained RPL. The results show that the frequently used model overestimates the chances of a successful pregnancy, that predictions are too extreme on both the high and low ends and that they are not much more discriminative than random luck. There is a need for revising the prediction model to estimate the chance of a successful pregnancy in couples with unexplained RPL more accurately. No external funding was used and no competing interests were declared. N/A.

Exploring gender differences among couples with unexplained recurrent pregnancy loss regarding preferences for supportive care

BackgroundInternational guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for supportive care have been identified and women’s preferences have been quantified. Although it is known that RPL impacts the mental health of both partners, male preferences for supportive care have hardly been explored.MethodsA cross-sectional study was conducted in couples who visited a specialized RPL clinic in the Netherlands between November 2018 and December 2019. Both members of the couples received a questionnaire that quantified their preferences for supportive care in a next pregnancy and they were asked to complete this independently from each other. Preferences for each supportive care option were analysed on a group level (by gender) and on a couple level, by comparing preferences of both partners.ResultsNinety-two questionnaires (completed by 46 couples) were analysed. The overall need for supportive care indicated on a scale from 1 to 10 was 6.8 for men and 7.9 for women (P = 0.002). Both genders preferred to regularly see the same doctor with knowledge of their obstetric history, to make a plan for the first trimester and to have frequent ultrasound examinations. A lower proportion of men preferred a doctor that shows understanding (80% of men vs. 100% of women, P = 0.004) and a doctor that informs on wellbeing (72% vs. 100%, P = ≤0.000). Fewer men preferred support from friends (48% vs. 74%, P = 0.017). Thirty-seven percent of men requested more involvement of the male partner at the outpatient clinic, compared to 70% of women (P = 0.007). In 28% of couples, partners had opposing preferences regarding peer support.ConclusionsWhile both women and men affected by RPL are in need of supportive care, their preferences may differ. Current supportive care services may not entirely address the needs of men. Health care professionals should focus on both partners and development of novel supportive care programs with specific attention for men should be considered.

Cancer diagnosis among women with recurrent pregnancy loss: a retrospective cohort study

Research questionWhat is relationship between unexplained recurrent pregnancy loss (RPL) and risk of cancer morbidity? DesignA retrospective observational cohort study was conducted, based on data from a tertiary medical centre. RPL cases (exposed) were defined as women presenting with three or more unexplained confirmed pregnancy losses at 5–24 weeks, whose first visit to the RPL clinic was between 1990 and 2010. The unexposed group included women giving birth who were not RPL patients; these were matched by age and year of giving birth/admission (1:5 ratio). Data from the RPL and the live birth registries were cross-linked to the Israeli national cancer registry according to the unique ID number and merged into one database. ResultsThe study group comprised 937 RPL patients who were matched by maternal age (P = 1.0) and admission date (P = 0.84) to 4685 women achieving a live birth. There was no difference in overall cancer incidence between groups (adjusted odds ratio [OR] 0.76, 95% confidence interval [CI] 0.55–1.03; P = 0.08). The secondary RPL group showed a trend towards decreased cancer morbidity incidence compared with primary RPL (adjusted OR 0.65, 95% CI 0.41–1.03; P = 0.07). Analysis by cancer type showed a similar risk for breast cancer among women with RPL compared with live birth, but a significantly lower risk for gynaecological cancers among women with RPL (adjusted OR 0.25, 95% CI 0.08–0.79; P = 0.018). ConclusionsUnexplained RPL may be related to a lower risk of gynaecological cancers, possibly explained by hyper-responsive immunological mechanisms involving uterine natural killer cells.

P–355 Cancer diagnosis among patients with recurrent pregnancy loss: a cohort study

Abstract Study question Is unexplained recurrent pregnancy loss (RPL) related to long term cancer morbidity? Summary answer Recurrent unexplained pregnancy loss patients showed lower cancer morbidity. This trend was significant in the secondary aborters and in a sub-analysis for gynecological cancers. What is known already The association between infertility and cancer was studied, but has scarcely been studied in RPL; One study reported a higher incidence of breast and uterine cancers, while another found no association. Immune dysfunction is a possible cause of ‘unexplained RPL’; RPL patients have an increased number of toxic natural killer cells (NKs) in both peripheral blood and decidua. The immune system is also involved in the recognition of cancer cells, potentially leading to effective killing. It is possible that the NK populations in RPL are capable of a better response towards cancer cells in the uterine environment and related organs. Study design, size, duration A retrospective cohort study comparing RPL patients and patients with normal deliveries presenting between 1990 –2010 and followed up until 2018. Participants/materials, setting, methods The RPL (exposed) group consisted of patients with 3 or more losses between 5–24 weeks. The comparison (unexposed) group included women who gave birth, and were not listed in the registry of RPL patients. Matching was based on maternal age and year of delivery, which was matched to the date of admission to the RPL clinic. Patients’ data were cross-linked to the national cancer registry. Kaplan-Meier survival curves were used to compare cancer incidence. Main results and the role of chance The RPL group comprised of 937 RPL patients, compared to 4685 patients with a live birth. The mean follow up time was 16.3 ±5.3 years for RPL cases and 15.9 ± 4.9 for the comparison group. Groups were compared in terms of lifetime risk, post-admission risk and according to cancer type. In a Univariate analysis, the life time risk for cancer was 5.3% (49/937) among RPL patients and 6.8% (317/4685) in the comparison group (p = 0.08). Survival analysis showed the same trend - a lower cancer morbidity in RPL patients (p = 0.06). The low cancer morbidity was more prominent, reaching statistical significance in secondary RPL patients (p = 0.05) , but not in primary RPL (p = 0.4). Breast cancer was the most common tumor, but was neither more nor less common in RPL than in the comparison group. Gynecological cancers, however, were significantly less common in RPL patients: 0.3% (3/937) compared to 1.3% (60/4685) in the comparison group (p = 0.01). After adjustment for maternal age the odds ratio for gynecological cancer was 0.247 (p = 0.018, 95% CI 0.077–0.791) and significantly represented in the survival analysis (p = 0.01). Limitations, reasons for caution There was no access to BMI and smoking status. Patients were followed for a mean period of 16 years; cancer may present later than 16 years. Wider implications of the findings: Unexplained RPL is assumed to have an immunological basis. Our study may provide an indirect support for hyper-responsive immunological mechanisms in RPL patients. Further research is needed to deepen our understanding of the underlying mechanisms and possibly to facilitate treatment options. Trial registration number Not applicable

Identification of distinct seminal plasma cytokine profiles associated with male age and lifestyle characteristics in unexplained recurrent pregnancy loss

BackgroundSeminal plasma contains a wide range of cytokines, chemokines and growth factors. Part of these signalling molecules assist in inducing a state of active maternal immune tolerance towards the fetus. Disbalances in seminal plasma content may contribute to pregnancy loss. This study investigated cytokine expression profiles in seminal plasma of male partners of couples with unexplained recurrent pregnancy loss (RPL) and the association with clinical and lifestyle characteristics, including smoking, alcohol consumption and body mass index (BMI). MethodsIn the seminal plasma of 52 men who visited a specialised RPL clinic the levels of 25 pre-selected cytokines, chemokines and growth factors were measured by Bio-Plex assay or ELISA. Two-way hierarchical cluster analysis was performed. Identified patient clusters were compared on clinical and lifestyle characteristics. ResultsTwo distinct cytokine expression profiles in the seminal plasma were revealed by cluster analysis. Patient cluster I showed relatively higher levels of pro-inflammatory cytokines, including IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18 and TNF-α, compared to Patient cluster II. Men belonging to Patient cluster I were significantly older and had significantly more lifestyle risk factors compared to men in Patient cluster II. ConclusionCluster analysis suggested the existence of a less favourable pro-inflammatory cytokine expression profile, being present in part of men affected by RPL and associated with advanced male age and lifestyle risk factors. These findings may serve as a starting point for further research into underlying mechanisms and ultimately lead to novel diagnostic and therapeutic approaches for couples with RPL.

Defining recurrent pregnancy loss: associated factors and prognosis in couples with two versus three or more pregnancy losses

Research questionThe definition of recurrent pregnancy loss (RPL) differs internationally. The European Society of Human Reproduction and Embryology (ESHRE) defines RPL as two or more pregnancy losses. Different definitions lead, however, to different approaches to care for couples with RPL. This study aimed to determine whether the distribution of RPL-associated factors was different in couples with two versus three or more pregnancy losses. If a similar distribution were found, couples with two pregnancy losses should be eligible for the same care pathway as couples with three pregnancy losses. DesignThis single-centre, retrospective cohort study investigated 383 couples included from 2012 to 2016 at the Leiden University Medical Center RPL clinic. Details on age, body mass index, smoking status, number of pregnancy losses, mean time to pregnancy loss and performed investigations were collected. The prevalence of uterine anomalies, antiphospholipid syndrome, hereditary thrombophilia, hyperhomocysteinaemia, chromosomal abnormalities and positive thyroid peroxidase antibodies were compared in couples with two versus three or more pregnancy losses. ResultsNo associated factor was found in 71.5% of couples with RPL. This did not differ statistically between couples with two versus three or more pregnancy losses (73.6% versus 70.6%; P = 0.569). The distribution of investigated causes did not differ between the two groups. ConclusionsAs the distribution of associated factors in couples with two versus three or more pregnancy losses is equal, couples with two pregnancy losses should be eligible for the same care pathway as couples with three. This study supports ESHRE's suggestion of including two pregnancy losses in the definition of RPL.

Comparison between sperm parameters and chromatin in recurrent pregnancy loss couples after antioxidant therapy.

Background and Aims:Recurrent Pregnancy loss (RPL) is a heterogeneous disease. The role of maternal factor is clear but the relationship between the paternal factors remains uncertain. It has been shown that increase the level of Reactive Oxygen Species (ROS) and decrease the antioxidant levels in men can lead to RPL. New researches show treatment with antioxidant can improved sperm parameter. The aim of the present study was to assess the effect of vitamin E plus Zinc therapy on sperm parameters and chromatin quality in couples with RPL.Methods:In this clinical trial study, 60 RPL patients were selected from RPL clinic. Standard sperm parameters were analyzed and then male partners were intake vitamin E and Zinc in antioxidant therapy plan for 90 days. After that, sperm parameters were analyzed again. Sperm chromatin assay was reviewed before and after vitamin E and Zinc therapy by cytochemical assay including aniline blue (AB), chromomycin A3 (CMA3), toluidine blue (TB). To assess DNA fragmentation index, TUNEL test was used. Data were analyzed and compared before and after treatment.Results:data analysis showed all sperm parameters significantly improved after treatment (P < 0.001). The number of AB+ and TB+ sperms were decreased significantly after vitamin E and Zinc therapy (P = 0.0001). Decrease in DNA fragmentation in post treatment group in comparison to pre-treatment was statistically significant.Conclusion:Supplemental of vitamin E plus Zinc may improve sperm parameters chromatin quality and decrease sperm DNA fragmentation in RPL patients.

Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients.

Will the addition of 24-chromosome microarray analysis on miscarriage tissue combined with the standard American Society for Reproductive Medicine (ASRM) evaluation for recurrent miscarriage explain most losses? Over 90% of patients with recurrent pregnancy loss (RPL) will have a probable or definitive cause identified when combining genetic testing on miscarriage tissue with the standard ASRM evaluation for recurrent miscarriage. RPL is estimated to occur in 2-4% of reproductive age couples. A probable cause can be identified in approximately 50% of patients after an ASRM recommended workup including an evaluation for parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances and autoimmune factors including antiphospholipid syndrome. Single-center, prospective cohort study that included 100 patients seen in a private RPL clinic from 2014 to 2017. All 100 women had two or more pregnancy losses, a complete evaluation for RPL as defined by the ASRM, and miscarriage tissue evaluated by 24-chromosome microarray analysis after their second or subsequent miscarriage. Frequencies of abnormal results for evidence-based diagnostic tests considered definite or probable causes of RPL (karyotyping for parental chromosomal abnormalities, and 24-chromosome microarray evaluation for products of conception (POC); pelvic sonohysterography, hysterosalpingogram, or hysteroscopy for uterine anomalies; immunological tests for lupus anticoagulant and anticardiolipin antibodies; and blood tests for thyroid stimulating hormone (TSH), prolactin and hemoglobin A1c) were evaluated. We excluded cases where there was maternal cell contamination of the miscarriage tissue or if the ASRM evaluation was incomplete. A cost analysis for the evaluation of RPL was conducted to determine whether a proposed procedure of 24-chromome microarray evaluation followed by an ASRM RPL workup (for those RPL patients who had a normal 24-chromosome microarray evaluation) was more cost-efficient than conducting ASRM RPL workups on RPL patients followed by 24-chromosome microarray analysis (for those RPL patients who had a normal RPL workup). A definite or probable cause of pregnancy loss was identified in the vast majority (95/100; 95%) of RPL patients when a 24-chromosome pair microarray evaluation of POC testing is combined with the standard ASRM RPL workup evaluation at the time of the second or subsequent loss. The ASRM RPL workup identified an abnormality and a probable explanation for pregnancy loss in only 45/100 or 45% of all patients. A definite abnormality was identified in 67/100 patients or 67% when initial testing was performed using 24-chromosome microarray analyses on the miscarriage tissue. Only 5/100 (5%) patients, who had a euploid loss and a normal ASRM RPL workup, had a pregnancy loss without a probable or definitive cause identified. All other losses were explained by an abnormal 24-chromosome microarray analysis of the miscarriage tissue, an abnormal finding of the RPL workup, or a combination of both. Results from the cost analysis indicated that an initial approach of using a 24-chromosome microarray analysis on miscarriage tissue resulted in a 50% savings in cost to the health care system and to the patient. This is a single-center study on a small group of well-characterized women with RPL. There was an incomplete follow-up on subsequent pregnancy outcomes after evaluation, however this should not affect our principal results. The maternal age of patients varied from 26 to 45 years old. More aneuploid pregnancy losses would be expected in older women, particularly over the age of 35 years old. Evaluation of POC using 24-chromosome microarray analysis adds significantly to the ASRM recommended evaluation of RPL. Genetic evaluation on miscarriage tissue obtained at the time of the second and subsequent pregnancy losses should be offered to all couples with two or more consecutive pregnancy losses. The combination of a genetic evaluation on miscarriage tissue with an evidence-based evaluation for RPL will identify a probable or definitive cause in over 90% of miscarriages. No funding was received for this study and there are no conflicts of interest to declare. Not applicable.

Description of cytogenetic abnormalities and the pregnancy outcomes of couples with recurrent pregnancy loss in a tertiary-care center in Saudi Arabia.

Objectives:To determine the prevalence of chromosomal abnormalities in couples with recurrent pregnancy loss (RPL), to determine other factors that may be associated with the chromosomal abnormalities, and to assess the outcomes of couples who had undergone multidisciplinary interventions according to associated etiological factors.Methods:This retrospective cohort study involved 1074 couples who attended RPL clinic during an 11-year period from January 2006 to December 2016 at a single center, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. All of the couples had undergone complete RPL evaluations and were closely monitored and managed during pregnancy.Results:Out of the 1074 couples, 77 (7.2%) carried some form of chromosomal abnormality, and the female (48, 62.3%) patients were affected more frequently than the male (29, 37.3%) patients. Out of the 77 cases with chromosomal abnormalities, 46.8% had reciprocal translocations, 10.3% had Robertsonian translocations, and 3.9% had complex structural abnormalities. Inversions had occurred in 14.3% and chromosomal additions had occurred in 2.6% of the patients. Isolated chromosomal abnormalities were detected in 25 out of 77 (32.5%) couples. The couples were closely followed, and 67% of the subsequent pregnancies resulted in live births.Conclusion:This study’s findings provide an insight into the prevalence of chromosomal abnormalities in couples with RPL in our region and the factors that may be associated with RPL. This information will help to ensure the required resources are provided to care for these patients.

Prevalence and Treatment Choices for Couples with Recurrent Pregnancy Loss Due to Structural Chromosomal Anomalies.

Parental carriers of balanced structural chromosomal rearrangements such as reciprocal or Robertsonian translocations are at increased risk of recurrent pregnancy loss (RPL) due to the production of gametes with unbalanced non-viable chromosome variants. As a purported means of improving reproductive outcomes in this population, IVF and preimplantation genetic diagnosis (PGD) have been introduced as an alternative to natural conception and prenatal diagnosis. In this study, we evaluate the prevalence and treatment choices of couples with structural chromosomal rearrangement referred to a tertiary care RPL clinic. In addition, we compare the two methods of management in terms of live birth rate. This is a retrospective chart review of 2321 couples who were referred to a highly specialized RPL clinic for ongoing clinical management between January 2005 and December 2013 (n = 23). Couples who pursued PGD through local fertility centres during this time were also included (n = 13). Thirty-six couples (1.6%) were found to be parental carriers of a structural chromosomal rearrangement. In this cohort, couples were twice as likely to pursue natural conception compared with IVF with PGD. No significant differences were observed in live birth rate between PGD and clinical management (66.6% vs. 53.3%, P = 0.717). With PGD management, six live birth outcomes were observed, with an incidence of one birth in 5.63 years of follow-up. With clinical management, 24 live birth outcomes were observed, with an incidence of one birth in 4.09 years of follow-up. Mean time to live birth was 17.5 months and 23.3 months in clinical management and PGD, respectively. Among couples presenting to a tertiary RPL clinic, parental carriers of structural chromosomal rearrangement and history of RPL are more likely to pursue natural conception over IVF and PGD. With regards to reproductive outcomes, no significant difference in miscarriage rate, time to live birth, or live birth rate was observed between couples who pursued PGD compared with expectant clinical management.

The distribution of etiology and therapy outcomes of recurrent pregnancy loss at Kobe University recurrent pregnancy loss clinic

The distribution of etiology and therapy outcomes of recurrent pregnancy loss at Kobe University recurrent pregnancy loss clinic

Pregnancy outcomes among patients with recurrent pregnancy loss and uterine anatomic abnormalities.

Abstract Background: Different etiologies for recurrent pregnancy loss have been identified, among them are: anatomical, endocrine, genetic, chromosomal and thrombophilia pathologies. Aims: To assess medical and obstetric characteristics, and pregnancy outcomes, among women with uterine abnormalities and recurrent pregnancy loss (RPL). This study also aims to assess the impact of uterine anatomic surgical correction on pregnancy outcomes. Methods: A retrospective case control study of 313 patients with two or more consecutive pregnancy losses followed by a subsequent (index) pregnancy. Anatomic abnormalities were detected in 80 patients. All patients were evaluated and treated in the RPL clinic at Soroka University Medical Center. Out of 80 patients with uterine anatomic abnormalities, 19 underwent surgical correction, 32 did not and 29 had no clear record of surgical intervention, and thus were excluded from this study. Results: Women with anatomic abnormalities had a higher rate of previous cesarean section (18.8% vs. 8.6%, P=0.022), tended to have a lower number of previous live births (1.05 vs. 1.37, P=0.07), and a higher rate of preterm delivery (22.9% vs. 10%, P=0.037). Using multivariate logistic regression analysis, anatomic abnormality was identified as an independent risk factor for RPL in patients with previous cesarean section after controlling for place of residence, positive genetic/autoimmune/endocrine workup, and fertility problems (OR 7.22; 95% CI 1.17–44.54, P=0.03). Women suffering from anatomic abnormalities tended to have a higher rate of pregnancy loss compared to those without anatomic abnormalities (40% vs. 30.9%, P=0.2). The difference in pregnancy loss rate among women who underwent surgical correction compared to those who did not was not statistically significant. Conclusion: In patients with previous cesarean section, uterine abnormality is an independent risk factor for pregnancy loss. Surgical correction of uterine abnormalities among RPL patients might have the potential to improve live birth rate.