Primary Recurrent Miscarriage Research Articles

Maternal Serum Amyloid a Level as a Novel Marker of Primary Unexplained Recurrent Early Pregnancy Loss

Background: Recurrent abortion affects 1-2% of women. Serum Amyloid A belongs to a family of apolipoproteins produced in response to cytokines released by activated monocytes and macrophages, isolated in the last 50 years. Our current study emphasizes human SAA protein as a sensitive biochemical marker for primary unexplained recurrent miscarriage. The aim of the current study is to examine the hypothesis that primary unexplained REPL might be associated with high maternal serum levels of SAA, which in turn could lead to defective trophoblastic invasion into the decidua, and subsequent pregnancy failure and miscarriage. Patients and Method: A prospective study (case control study) in Al-Zahraa Maternity Hospital, Najaf, Iraq, from first of January to the first of December of 2019. The study was conducted among 91 who were divided into two groups Group 1: women with missed miscarriage in the first trimester with at least two consecutive primary unexplained REPLs and no previous live births were enrolled. Group 2: A control group was formed of women with miscarriage no history of REPL who had at least one previous uneventful pregnancy with no adverse outcomes. Serum samples were collected to measure SAA levels. Result: The main outcome was the association between SAA and primary unexplained REPL. A total number of 91 participants. Mean SAA level was significantly higher among women with REPL than among women in the control group (P<0.001). The SAA level was dependent indicator of primary unexplained REPL, P<0.001 Elevated SAA levels found among women with primary unexplained REPL could represent biomarker for this complication of pregnancy. Conclusions: The present findings suggest that SAA is potentially a novel marker for primary unexplained REPL that warrants further investigation. For example, studies could be conducted to compare SAA levels among women with a history of primary unexplained REPL during the pregnant and non-pregnant states, as well as before and after miscarriage. In future, such studies might guide the timing for initiation of new treatments, such as gene therapy or the use of immune-receptor antagonists.

7378 Correction of Uterine Anomalies and Its Effect on Infertility and Recurrent Miscarriages in a Study Including 10000 Patients over 6 Years

<h3>Study Objective</h3> use of hysteroscopic metroplasty to enhance and promote the uterine receptivity in infertile women and those who had recurrent miscarriages. <h3>Design</h3> prospective study for 6 years from 2016 including 12000 cases of primary infertility and recurrent miscarriages. <h3>Setting</h3> operative hysteroscopy both 5mm and 9mm, patient on lithotomy position under either general or spinal anaesthesia. <h3>Patients or Participants</h3> cases were selected as primary infertility for more than 2 years, recurrent IVF or ICSI failure, recurrent miscarriages who had 3D transvaginal ultrasound assessment that revealed anomalies including Narrow T shaped, tubular, subseptated and septated cavities. <h3>Interventions</h3> hysteroscopic metroplasty to reach the normal cavity shape and dimensions. If excessive raw area levonorgestril triple dose for 21 days used post operative to enhance healing and putting Foleys catheter size 10 F for 3 days post operative. <h3>Measurements and Main Results</h3> 3D transvaginal ultrasound +or - saline sono hystrography done post hysteroscopic correction by one cycle to compare the shape and dimensions with the preoperative one and to ensure absence of intrauterine adhesions. 88% of cases had successfully got pregnant and continued their pregnancy beyond 36 weeks, 6 % had preterm labour between 30-36 weeks, 2% had preterm labour 28-30 weeks and 4 % still under follow up. <h3>Conclusion</h3> correction of uterine anomalies has a strong significance on success of implantation in cases of infertility, recurrent IVF and ICSI failure and recurrent miscarriages after prober 3D transvaginal ultrasound.

Reproductive outcomes following recurrent first-trimester miscarriage: a retrospective cohort study.

What are the subsequent reproductive outcomes (livebirths, miscarriages or other adverse pregnancy outcomes or no further pregnancy) of women with recurrent miscarriage (RM) attending a dedicated clinic? Of women with RM, 77% had a subsequent pregnancy, and among these pregnancies, the livebirth rate was 63%. RM affects ∼1-3% of women of reproductive age. RM has known associations with advanced maternal age, obesity, diabetes, inherited thrombophilias, thyroid dysfunction, endometriosis and parental balanced translocations. However, ∼ 50% of women or couples will be left without an explanation for their pregnancy loss, even after completing investigations. RM is also associated with secondary infertility and adverse pregnancy outcomes including preterm birth and perinatal death. We undertook a retrospective cohort study to identify subsequent pregnancy outcomes in women with RM, defined as three consecutive first-trimester miscarriages. Women attending the RM clinic at a tertiary university hospital in the Republic of Ireland over 12 years (2008-2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria. Women with non-consecutive first-trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information regarding medical history, investigation and management was gathered from paper and electronic medical records. Data were analysed using SPSS (Version 27). Associations between maternal characteristics and outcomes were explored using the χ2 test, with significance set at P < 0.05. Multinomial regression analysis was performed using a stepwise approach. There were 748 women who were included; 332 (44%) had primary RM and 416 (56%) had secondary RM. The median age was 36 years (range 19-47). Foetal aneuploidy was the most common investigative finding (15%; n = 111/748); 60% had unexplained RM. In addition to supportive care, most women were prescribed aspirin (96%) and folic acid (75%). Of the 748 women, 573 had a subsequent pregnancy (77%) and 359 (48% of all women; 63% of pregnancies) had a livebirth, while 208 had a further pregnancy loss (28% of all women; 36% of pregnancies) and 6 were still pregnant at the end of the study. Women aged 35-39 years were more likely to have a livebirth than no further pregnancy (relative risk ratio (RRR): 2.29 (95% CI: 1.51-5.30)). Women aged 30-34 years were more likely to have a livebirth (RRR: 3.74 (95% CI: 1.80-7.79)) or a miscarriage (RRR: 2.32 (95% CI: 1.07-4.96)) than no further pregnancy. Smokers were less likely to have a livebirth (RRR: 0.37 (95% CI: 0.20-0.69)) or a miscarriage (RRR: 0.45 (95% CI: 0.22-0.90)) than no further pregnancy. Couples with an abnormal parental karyotype were less likely to have a miscarriage than no further pregnancy (RRR: 0.09 (95% CI: 0.01-0.79)). Including successive pregnancies conceived over the study period, the overall livebirth rate was 63% (n = 466/742), but this was reduced to 44% in women aged ≥40 years and 54% in women with infertility. This work covers 13 years; however, those included in the later years have a shorter follow-up time. Although electronic health records have improved data availability, data collection in this cohort remains hampered by the absence of a formal booking visit for women presenting with miscarriage and a national miscarriage database or register. Our findings are largely reassuring as most women with RM and hoping to conceive achieved a livebirth. In addition to older age, smoking and parental balanced translocations were associated with a reduced likelihood of further pregnancy. No investigation or treatment was associated with pregnancy outcome, reiterating the importance of the supportive aspects of care for women and their partners after RM and counselling regarding individual risk factors. This contributes to the limited international data on the investigative findings and treatment of women with RM. The high rate of prescribed medications merits greater scrutiny, in conjunction with other pregnancy outcomes, and reiterates the need for a national guideline on RM. L.A.L. is a PhD scholar funded through the Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork. M.H. and C.F. are Postdoctoral Researchers on a project funded by the Health Research Board Ireland [ILP-HSR-2019-011] and led by K.O.D., titled: 'Study of the impact of dedicated recurrent miscarriage clinics in the Republic of Ireland'. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interests to declare. N/A.

Reproductive and ICSI outcomes after hysteroscopic metroplasty for T-shaped uterus, a prospective follow up study

BackgroundThe incidence of uterine anomalies is approximately 0.5–4.7%. In infertile women, this rises to 6.3%. T-shaped uterine anomalies have been associated with infertility, recurrent implantation failure (RIF), and recurrent miscarriage (RM). Hysteroscopic metroplasty (HM) may improve the reproductive outcomes of such cases. Study objectiveWe assessed the effects of hysteroscopic metroplasty on the reproductive and in vitro fertilization (IVF) outcomes in women with T-shaped uteri. DesignA prospective controlled study. SettingA teaching hospital. PatientsThe reproductive outcomes of 182 patients with primary infertility (PI), RIF, or RM who underwent hysteroscopic metroplasty to treat T-shaped uteri were prospectively analyzed. InterventionsBetween January 2017 and April 2021, hysteroscopic metroplasty was performed by a single experienced surgeon. The primary outcome was the live birth rate (either spontaneous or assisted). Measurements and principal resultsIn all, 182 patients who underwent bilateral, longitudinal, uterine-lateral wall incisions without complications were included. The clinical pregnancy rates after metroplasty were 50.9% (primary infertility group), 71.4% (RM group), and 39.5% (RIF group). During the 1-year follow-up, 25.5% of patients conceived spontaneously (all groups). ConclusionHysteroscopic metroplasty should be considered for women with primary infertility, RIF, and RM with T-shaped uteri.

P-427 Pregnancy outcomes following recurrent first-trimester miscarriage: a retrospective cohort study

Abstract Study question What are the subsequent pregnancy outcomes (livebirths, miscarriages or other adverse pregnancy outcomes) in a cohort of women with recurrent miscarriage (RM)? Summary answer The overall live birth rate in women with RM was 62% (466/748), falling to 44% in women aged &amp;gt;40 and 54% in women with infertility. What is known already RM affects approximately 1% of women of reproductive age. RM is recognized as a prognostic indicator for subsequent pregnancies and adverse pregnancy outcomes including ante-partum hemorrhage, diabetes, preterm birth, small for gestational age and perinatal death. While RM has known associations with advanced maternal age, obesity, diabetes, thyroid dysfunction and endometriosis, approximately 50% of women/couples will be left without an explanation for their pregnancy loss, even after completing investigations. Study design, size, duration A retrospective cohort study was undertaken to identify subsequent pregnancy outcomes in women with RM, where RM referral criteria are 3 consecutive first-trimester miscarriages. Women attending the pregnancy loss clinic at a tertiary university hospital in the Republic of Ireland over a 12-year period (2008 - 2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria. Participants/materials, setting, methods Women with non-consecutive first trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information was gathered from paper and electronic medical records. Data were analysed descriptively using SPSS (Version 27). Main results and the role of chance Of 748 women identified, 332(44%) had primary RM, 416(56%) had secondary RM. The median age was 36(range 19-47) years with 12% aged under 29 and 64% of women aged ≥35. 142(19%) had a history of infertility with 43(5.7%) attending for ART. 12% of women had anti-nuclear antibodies(89/742), 8% had abnormal thyroid function tests(60/742), 4.7% were heterozygous carriers of the Factor V Leiden gene mutation(35/737), 1.5% had positive anti-cardiolipin antibodies(11/733), 2% were carriers of a Prothrombin gene mutation(7/343) and 1% had elevated HbA1c levels(7/742). Fetal karyotype was recorded in 141 pregnancies, with 111 abnormal results(78%;111/141). Trisomy(T) 16 was most common(17/111; 15%) followed by T21 and T22(n = 14; 13%). Parental karyotyping of 697 sets of parents identified 28 balanced translocations(4%; 28/697). Prescribed pharmacological treatments included high dose folic acid(75%; n = 548/728), aspirin(96%; 696/726), progesterone (52%; 389/728), tinzaparin(24%; 175/727), prednisolone(4%; 28/726), metformin(2%; 12/727) and hydroxychloroquine(1%; 7/727). 573 women had a subsequent pregnancy (76.6%); 359(62%; 359/573) had a live birth, 190 had a miscarriage(33%) and 18(3%) had an adverse pregnancy outcome such as ectopic pregnancy, stillbirth or second-trimester miscarriage. Including successive pregnancies over the study period, the overall live birth rate was 62%(466/748), falling to 44% in women aged &amp;gt;40 and 54% in women with infertility. Limitations, reasons for caution This work covers a 12-year period, and while the RM clinic staffing is largely unchanged, some changes in management of RM patients has occurred in this time, reflecting up-to-date evidence and greater public awareness. Furthermore, the adoption of an electronic health chart in 2017 may have affected data availability. Wider implications of the findings Our findings confirm RM occurs more frequently in women aged &amp;gt;35. Aneuploidy remains a leading cause of miscarriage. Age is a prognostic indicator for livebirth after RM. These findings will facilitate counselling in this cohort. The substantial rates of prescribed medications and infertility in women with RM merit further exploration. Trial registration number N/A

P–426 Uterine Natural Killer Cells in Recurrent Miscarriage and Implantation Failure: An Updated Systematic Review and Meta-analysis

Abstract Study question Do women with recurrent miscarriage (RM) or implantation failure (RIF) have different levels of uterine Natural Killer (NK) cells compared to fertile controls? Summary answer Women with RIF but not RM are associated with significantly higher levels of CD56+ uterine NK cells compared to controls. What is known already Uterine NK cells (uNK) are different from peripheral NK cells (pNK) and are important in early pregnancy for development of the placenta. The association between uNK and RM/RIF is less clear, but dysfunction of uNK is believed to result in early pregnancy failure. Previous systematic reviews by Seshadri (2014) and Tang (2013) on infertile and RM patients showed no significant difference in uNK levels and highlighted need for further studies. Since, many prospective studies have been published and therefore warrant an updated systematic review. On the other hand, evidence for correlation between uNK and pNK is sparse and needs clarification. Study design, size, duration We have conducted a systematic review and meta-analysis to evaluate three outcomes. The primary outcome was the difference of uNK level in RM/RIF compared to controls. The secondary outcome was livebirth rate in women with RM/RIF with high compared to normal uNK level, and the tertiary outcome was correlation between uNK and pNK in RM/RIF. Participants/materials, setting, methods The electronic database search included MEDLINE, EMBASE, Web of Science and bibliographies from included articles from inception to December 2020 using a combination of MESH and keywords. Search, screen, and data extraction were performed by two reviewers independently. Quality assessment was conducted with ROBINS-I and meta-analysis with Revman 5.3. Out of 4636 studies screened, 43 studies (2539 women) and 3 studies each (598 and 77 women) were analysed for primary, secondary and tertiary outcomes respectively. Main results and the role of chance Our meta-analysis showed that CD56+ uNK were significantly higher in women with RIF but not RM compared to controls (SMD 0.60; 95% CI 0.12–1.08]. Subgroup analysis in RM patients showed no significant difference whether definition of 2 or 3 previous RM was used, in primary/secondary RM compared to controls, or in primary versus secondary RM. CD56+ uNK were significantly higher in RM/RIF when sampled during mid-luteal phase [SMD 0.56; 95% CI 0.19–0.93] but not in the early pregnancy decidua. Interestingly, there was significant difference in CD56+ uNK when analysed by immunohistochemistry [SMD 0.50; CI 0.05–0.94] but not by flow cytometry, and when CD56+ uNK were reported as percentage over total endometrial cells [SMD 0.58; 95% CI 0.10–1.07]. Further subgroup analysis showed significant difference in CD16 + [SMD 0.54; 95% CI 0.18–0.89] but not in CD56+CD16-, CD56+CD16+ or CD57. For pregnancy outcome, there was no significant difference in livebirth rate in RM/RIF patients with high uNK compared to normal uNK [RR 1.06, 95% CI 0.86–1.30]. Mean uNK level in RM patients with subsequent miscarriage was not significantly higher than subsequent livebirth. Finally, the pooled correlation between CD56 pNK and CD56 uNK (r = 0.42; 95% CI –0.04–0.73] was not significant in RM/RIF patients. Limitations, reasons for caution The meta-analysis is limited by quality of some of the studies. Some data were presented in median that was transformed to mean which may result in data skew. Other confounding factors e.g. maternal age, fetal karyotype, number of previous miscarriages and variable definition of controls may contribute to bias. Wider implications of the findings: Clinical interpretation of uNK level needs to be treated with caution because there is significant heterogeneity in method of analysis. There may be a role for uNK measurement in RIF patients however further studies to understand pathophysiology underlying elevated uNK is warranted before recommending it as a diagnostic tool. Trial registration number N/A

Office hysteroscopic metroplasty with diode laser for septate uterus: a multicenter cohort study

Objective To investigate the effectiveness and safety of office hysteroscopic metroplasty by diode laser for the treatment of septate uteri. Study design We performed a prospective cohort study including 41 nulliparous women diagnosed with septate uterus and a history of primary infertility or recurrent miscarriage. All patients underwent hysteroscopic metroplasty for the treatment of the uterine septum, which was performed in-office setting using a 4.3 mm continuous-flow hysteroscope and a 15-watt diode laser at 1470 nm. Surgical and reproductive outcomes after 2 years of follow-up are reported. Results The procedure was well tolerated by 93% of patients. No surgical complications were reported. Thirty women out of 38 (78.9%) became pregnant: 17 (56.7%) pregnancies were spontaneously conceived, and 13 (43.3%) were obtained with assisted reproductive techniques. Twenty-four (80%) of the 30 pregnant women had a live birth, with a cumulative live birth of 63.2% among the 38 women (95% CI: 45.9–78.2%). There were no cases of post-partum hemorrhage or uterine rupture among 14 (58.3%) women who had vaginal deliveries. Conclusion Office hysteroscopic metroplasty for septate uterus using diode laser appears to be a feasible and safe alternative to other available techniques and has sufficient efficacy in terms of reproductive outcomes to be considered for further investigations.

Evaluation of etiology and pregnancy outcome in recurrent miscarriage patients.

The purpose of this study was to evaluate etiology and pregnancy outcome of recurrent miscarriage women. The enrolled patients (280) were evaluated for Triiodothyronine, Thyroxine, Thyroid stimulating hormone, prolactin, chromosomal analysis, Haemoglobin A1C, blood sugar, Magnetic resonance imaging, 3D-ultrasound, auto-antibodies profile (antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, antinuclear antibodies, anti-thyroid antibodies and β2 glycoprotein1), torch profile (Toxoplasmo gondii, rubella, cytomegalo virus and herpes simplex virus), blood vitamin D3 levels, psychological factors, Body mass index and thrombotic factors (protein S and C deficiency, Prothrombin G20210A mutation, anti-thrombin III, Factor V Leiden and Methylenetetrahydrofolate reductase mutation), uterosalpingography (hysteronsalpingography) and hysteroscopy. The therapeutic regimens either singly or combined were employed for the treatment of recurrent miscarriage patients on the basis of etiology (single or multiple) and include intravenous immunoglobulin, low molecular weight heparin, low dose aspirin, levothyroxine, progesterone, folic acid, human chorionic gonadotrophin, vitamin D3, psychotherapy, genetic counselling. However, patients with idiopathic recurrent miscarriage were treated with progesterone supplementation, anticoagulation and/or immune modulatory agents. The incidence of primary recurrent miscarriage was highest and most of the women experienced recurrent miscarriage during first trimester. Endocrinological disorders (39%) were found as the major pathological factor for recurrent miscarriage. Other factors include uterine abnormalities (5.7%), vitamin D3 deficiency (3.5%), psychological factors (3.2%) infection (3.6%), autoimmune abnormalities (1.8%) and protein S deficiency (1.8%). However, 40% cases were idiopathic. The overall live birth rate achieved after the management of recurrent miscarriage patients was 75.7%. Enocrinopathy was the major cause of recurrent miscarriage. The overall live birth rate achieved was 75.7% with highest pregnancy outcome in secondary recurrent miscarriage patients after the management.

Hysteroscopic Metroplasty for T-Shaped Uterus: A Systematic Review and Meta-analysis of Reproductive Outcomes.

To date, a comprehensive review on the safety and effectiveness of hysteroscopic metroplasty for T-shaped uterus is still missing. To provide a robust synthesis of the available studies investigating reproductive outcomes after hysteroscopic metroplasty for T-shaped uterus. We performed a systematic review and meta-analysis (CRD42019143291), using the proportion method with 95% confidence interval (CI). Statistical heterogeneity was assessed by Higgins test (I2). We included 11 cohort studies embedding 937 women who underwent hysteroscopic metroplasty. After surgery, the pooled percentage of live birth was 44.54% (95% CI, 36.12%-53.12%; I2 = 46.22%) and 56.88% (95% CI, 46.48%-66.98%; I2 = 36.38%) in women with primary infertility and recurrent miscarriage, respectively. In women with recurrent miscarriage, the pooled proportion of miscarriage was 21.46% (95% CI, 15.09%-28.61%; I2 = 30.18%). The pooled clinical pregnancy proportion in women with primary infertility was 57.19% (95% CI, 43.83%-70.03%; I2 = 77.81%). The pooled rate of surgical complications was 0.65% (95% CI, 0.20%-1.33%; I2 = 11.44%). The hysteroscopic correction of T-shaped uteri was associated with high live birth rate and low miscarriage rate, both in case of primary infertility and recurrent miscarriage. Hysteroscopic metroplasty can be considered a safe and effective strategy to improve reproductive outcomes in case of T-shaped uterus.

IgG4 deficiency can be a new entity for primary recurrent miscarriage: Successful pregnancy in two cases after treatment with intravenous immunoglobulin

IgG4 deficiency can be a new entity for primary recurrent miscarriage: Successful pregnancy in two cases after treatment with intravenous immunoglobulin

The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage

BackgroundPeripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study.MethodsIn total, n = 575 RM patients (n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45+CD3−CD56+CD16+ NK cells were determined by flow cytometry and uterine CD56+ NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)).ResultsPatients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /μl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044).ConclusionsThe demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.

Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTIONDoes administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss?SUMMARY ANSWERrhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.WHAT IS KNOWN ALREADYThe only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATIONA randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK.PARTICIPANTS/MATERIALS, SETTING, METHODSOne hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat.MAIN RESULTS AND THE ROLE OF CHANCEA total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29–34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26–33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7–1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1–13.4; P = 0.93).LIMITATIONS, REASONS FOR CAUTIONThis trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy.STUDY FUNDING/COMPETING INTEREST(S)This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.TRIAL REGISTRATION NUMBEREUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063TRIAL REGISTRATION DATE31 Mar 2014DATE OF FIRST PATIENT’S ENROLMENT23 Jun 2014

Lymphocyte active immunotherapy for unexplained recurrent spontaneous abortion

This study is to evaluate the curative effect of lymphocyte active immune treatment for unexplained recurrent spontaneous abortion. Fourteen randomized controlled trials of 994 subjects were included. Blocking antibody positive rate of patients who experienced a new pregnancy showed significant differences between immunotherapy and placebo. Moreover, live birth rate among paternal or third-party donor lymphocytes and placebo groups had significant difference [RR= 1.63, 95% CI (1.38-1.92), p＜0.05]. Trial sequential analysis showed that the Z-curve crosses the trial sequential monitoring boundaries, confirming that the clinical benefit of active immunotherapy was significant. Subgroup analysis suggests that immunotherapy with lymphocytes might be more effective for primary recurrent spontaneous abortion than for secondary recurrent miscarriage. Taken together, women with primary recurrent spontaneous abortion who are negative for blocking antibody prior to treatment seemed most likely to obtain a potential beneficial effect of lymphocyte active immunotherapy, but not secondary recurrent spontaneous abortion.

Cytogenetic abnormalities in couples with a history of primary and secondary recurrent miscarriage: a Brazilian Multicentric Study

Objective: To evaluate the difference between chromosomal abnormalities between the gender of couples affected by Recurrent miscarriage (RM) and if there is an association between previous obstetric history and chromosomal abnormalities of the parents.Methods: Multicenter, retrospective, observational study from seven different RM clinics between 2006 and 2016. We enrolled 707 couples (1014 participants) with a history of RM. We compared the frequency of chromosomal abnormalities between groups of couples with primary and secondary RM and separated between women and their partners. Furthermore, we compared the prevalence of chromosomal abnormalities between groups based on the number of previous spontaneous abortions.Results: The overall prevalence of all cytogenetic abnormalities was 5.59% (n = 1414, women and their partners). Excluding cases of polymorphism and inversion of chromosome 9, which are considered variants of normality, the prevalence in all individuals was 2.26% (n = 32/1414). The comparative analysis of cases of chromosomal abnormalities among couples with primary and secondary RM based on the number of previous miscarriages (PM) revealed a similar frequency between groups. The statistical analysis of the total cases (primary PM + secondary PM) in these three groups were as follows: (a) couple, 2 pm versus 3 pm vs. ≥4 PM, p = .514; (b) women, 2 pm versus 3 pm vs. ≥4 PM, p = .347; and (3) partner, 2 pm versus 3 pm vs. ≥4 PM, p = .959. Chromosomal abnormalities were significantly more prevalent among women than among their partners (6.9 versus 4.2%; p = .027). Moreover, the distribution of leading chromosomal abnormalities among women was different compared with their partners. Among women, we observed these abnormalities in the following frequency order: mosaicism (38.8%), polymorphism (32.6%), translocation (16.3%), and inversion (12.3%). Among their partners, these abnormalities were polymorphism (73.3%), inversion (13.3%), mosaicism (6.7%), and translocation (6.7%).Conclusion: The number of PM and the history of full-term pregnancy does not correlate with an increase or decrease in the prevalence of cytogenetic abnormalities in couples with RM.

The Reproductive Outcome in patients having Primary Infertility or Recurrent Miscarriages after performing Hysteroscopic Septal Resection

The Reproductive Outcome in patients having Primary Infertility or Recurrent Miscarriages after performing Hysteroscopic Septal Resection

Ectopic pregnancy in women with recurrent miscarriage.

The aim of this study was to investigate the possible association between recurrent miscarriage (RM) and ectopic pregnancy (EP). In this case-control retrospective study, the clinical cards of women followed as outpatients in the RM and low-risk pregnancy offices of the Obstetrics and Gynecology Unit at the Policlinico Tor Vergata University Hospital were carefully reviewed for the occurrence of EP. Overall, 598 women with RM and 2043 normal women without RM (controls) were included in the study. Among these women, 4974 pregnancies were analyzed, in which 2028 miscarriages occurred. The EP rate (3.51%) was significantly higher in RM than in control women (1.51%) [odds ratio = 2.31 (95% confidence interval: 2.3-2.4)]; it was particularly high in women with primary RM (5.11%). However, when EP rates were calculated not by women but by overall pregnancies, no differences could be found between RM and control women. In control women, the absence of a miscarriage in the reproductive history was associated with a lower rate of EP. Women with RM, particularly primary RM, are at increased risk of EP. This increased risk seems to be dependent on the high number of pregnancies occurring in women with RM rather than to specific characteristics of these women.

Undiagnosed Primary Hyperparathyroidism and Recurrent Miscarriage: The First Prospective Pilot Study

BackgroundPrimary hyperparathyroidism (pHPT) in pregnancy is reported to be associated with significant maternal and foetal complications and an up to threefold increase in the risk of miscarriage. However, the true incidence of pHPT in pregnancy, complete and miscarried, is unknown and there are no data on the prevalence of undiagnosed pHPT in recurrent miscarriage (RM) (≥3 consecutive miscarriages under 24-week gestation). This is the first prospective study aiming to establish the prevalence of undiagnosed pHPT in RM.MethodsFollowing UK National ethics committee approval, women who had experienced 3 or more consecutive miscarriages were recruited from a nationwide RM clinic. Serum corrected calcium, phosphate, PTH and vitamin D were evaluated. Patients with raised serum calcium and/or PTH were recalled for confirmatory tests. Power calculations suggested that a minimum of 272 patients were required to demonstrate a clinically significant incidence of pHPT.ResultsThree hundred women were recruited, median age 35 years (range 19–42). Eleven patients had incomplete data, leaving 289 patients suitable for analysis; 50/289 patients (17%) with abnormal tests were recalled. The prevalence of vitamin D deficiency (<25 nmol/l) and insufficiency (25–75 nmol/l) was 8.7 and 67.8%, respectively. One patient was diagnosed with pHPT (0.34%) and underwent successful parathyroidectomy.ConclusionsThe prevalence of undiagnosed pHPT (0.34%) in RM in this study appears to be many times greater than the 0.05% expected in this age group. The findings of this pilot study merit follow-up with a larger-scale study. Routine serum calcium estimation is not currently undertaken in RM and should be considered.

The Reproductive Outcome in Patients Having Primary Infertility or Recurrent Miscarriages after Performing Hysteroscopic Septal Resection

Objective: To assess the reproductive outcome after hysteroscopic septal resection in women with unexplained infertility or recurrent miscarriage. Design: Prospective clinical trial. Setting: Zagazig university hospitals, Egypt.

Undiagnosed primary hyperparathyroidism and recurrent miscarriage: A clinically significant risk? A pilot study

Undiagnosed primary hyperparathyroidism and recurrent miscarriage: A clinically significant risk? A pilot study

Vitamin D deficiency in an Italian cohort of infertile women

The purpose of this study was to explore whether vitamin D might be a marker of female primary infertility in association with the presence of autoimmune diseases (ADs). The study was a cross-sectional descriptive study in consecutive outpatients of the Polymedical Center for Prevention of Recurrent Spontaneous Abortion (RSA), in Rome, Italy. Women were eligible if they received a diagnosis of primary infertility or RSA. Serum vitamin D, calcium, and PTH were analyzed. Women with primary infertility (n=70) or RSA/non-infertile (n=105) were enrolled; controls (n=250) were included. Infertile women presented lower vitamin D (P=0.03) and higher prevalence of AD (P=0.007) than non-infertile women. In the multivariate analysis, the presence of ADs is associated with higher odds of infertility (OR=2.2), while normal vitamin D was a protective factor (OR=0.9). We described that having vitamin D deficiency and suffering from an AD are independent risk factors for women primary infertility. Supplementation of vitamin D might be useful for pregnancy outcome.