Biochemical Pregnancy Loss Research Articles

Antithyroid antibodies may predict serum beta HCG levels and biochemical pregnancy losses in euthyroid women with IVF single embryo transfer

Objective To investigate the relationship between thyroid autoimmunity and early pregnancy serum β-HCG levels in intracytoplasmic sperm injection patients. Methods The study subjects were 85 female euthyroid patients undergoing intracytoplasmic sperm injection embryo transfer cycles with GnRH antagonist treatment. Patients who received transfer of more than one embryo, those with serum TSH levels of greater than 2.5 IU/ml and subjects using levothyroxine were excluded. Normal responder patients under the age of 40 years were randomly selected from the patient files retrospectively. Subjects were divided into two groups: those with autoimmune thyroid disease (thyroid autoimmunity group; n = 39) and those without the disease (control group; n = 46). Results The age, body mass index, trial number, total rFSH treatment dose, the number of cumulus oophorus complexes, number of metaphase II oocytes, and number of 2-pronuclei embryos were similar in the thyroid autoimmunity and control groups. Serum β-HCG levels measured on the 14th day after oocyte pickup were significantly lower in the thyroid autoimmunity group than in the control group (93.8 ± 35.8 versus 128.5 ± 55.8 mlU/ml, respectively; p < .001). The miscarriage rate was higher in the thyroid autoimmunity group than in the control group (34.4% versus 21.7%, respectively; p = .034). Conclusion We found that early-stage pregnancy serum β-HCG hormone levels among euthyroid patients undergoing intracytoplasmic sperm injection were lower in subjects with thyroid autoimmunity than in those without thyroid autoimmunity. This result, reported for the first time in the literature on euthyroid pregnant women with thyroid autoimmunity, may be predictor of early pregnancy losses in pregnant women with thyroid autoimmunity. Key message In intracytoplasmic sperm injection (ICSI)/IVF patients, due to lack of evidence-based data about the relationship between thyroid autoimmunity and pregnancy loss the current research was conducted. Early-stage pregnancy serum β-HCG hormone levels in euthyroid ICSI patients with thyroid autoimmunity are lower than those without autoimmunity which may be associated with early pregnancy losses.

Can embryo morphokinetic parameters predict euploid pregnancy loss?

To use time-lapse imaging to compare embryo morphokinetic parameters between embryos resulting in euploid pregnancy loss and euploid embryos resulting in live birth. Retrospective cohort study. Single academic fertility center. All euploid single embryo transfers between October 2015 and January2018. Collection and analysis of baseline characteristics, cycle parameters, and outcomes. Embryo morphokinetic measurements assessed with time-lapse imaging for time to syngamy (TPNf), time to two cells, time to three cells, time to four cells, time to eight cells, time to morula, and time to blastocyst. The study included 192 euploid single-embryo transfers. Of these, the pregnancy rate was 78% (150 of 193) and the live-birth rate was 63% (121 of 193). There were 43 transfers that did not result in pregnancy, 15 biochemical pregnancy losses, 13 clinical losses, and 121 live births. There was no statistically significant difference in age, body mass index, or number of oocytes retrieved between the groups. Unadjusted and adjusted models revealed no differences in the morphokinetics of embryos resulting in euploid miscarriage compared with those resulting in live birth. Embryos that resulted in a euploid miscarriage did not display evidence of abnormal morphokinetics on time-lapse imaging. Euploid pregnancy loss is likely multifactorial, including both embryo and endometrial factors. Further research is needed to identify factors that can predict and prevent euploid loss.

The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: a multicenter study.

The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: a multicenter study.

DYSREGULATED EMBRYONIC PLACENTATION IS MORE SIGNIFICANTLY ASSOCIATED WITH RISK OF EARLY SPONTANEOUS PREGNANCY LOSS THAN MATERNAL UTERINE SIGNALING

Biochemical pregnancy loss (BPL) rates have remained persistent at 12-15% despite significant developments in in vitro fertilization including improved embryo culture, aneuploidy screening, and endometrial receptivity testing. In order to elucidate factors important for early pregnancy maintenance that could lead to BPL, we utilized a mouse model to investigate sites of implantation corresponding to viable embryos or spontaneous embryo resorption (miscarriage). Uterine and placental gene expression of implantation sites corresponding to either viable or spontaneously resorbing embryos from early murine pregnancy. Female wild-type, outbred CF-1 pregnant mice were identified on day 10.5 of embryonic development for collection of uterine implantation sites containing either viable embryos (controls) or embryos that were in the early stage of resorption and not yet hemorrhagic. Total RNA was isolated from embryonic placentas (n=6 per group) and maternal uterine tissue (n=5 per group). Quantitative real-time PCR was performed on the QuantStudio 5 (Applied Biosystems) for key implantation and early pregnancy genes including: Cd81, Glrx, Bdnf, Cox2, Ptgs2, Vegfa, and Icos. Gene expression data were analyzed by the REST software (Qiagen) and Student’s t-test, with significance at P<0.05. Embryonic placental expression of Cd81 was significantly increased in embryo resorption sites (P<0.001). Elevated Cd81 inhibits cytotrophoblast invasion, indicating that insufficient placentation may have contributed to early pregnancy loss. Expression of embryonic placental Glrx was decreased in resorption sites (P<0.01), suggesting that heightened oxidative stress hindered placentation and/or maternal-fetal communication resulting in fetal loss. On the maternal side, expression of the paracrine growth factor Bdnf was decreased in uterine tissue from embryo resorption sites (P<0.01). Previous studies have reported increased Bdnf in the pregnant uterus and reduced Bdnf in uterine flushings from repeat implantation failure patients. In contrast, genes involved in tissue remodeling, angiogenesis, and decidualization (Cox2, Ptgs2, Vegfa), immune balance (Icos), trophoblast invasion (Cd81), or pinopode formation (Glrx) were not differentially expressed in maternal uterine tissue between viable and resorbing implantation sites. The etiology of BPL is likely diverse and complex. Our preliminary data suggest that dysregulated embryonic placentation is more significantly associated with risk of early pregnancy loss than maternal uterine signaling. As lipid composition and amino acid metabolism are important for implantation, ongoing studies will utilize liquid chromatography mass spectrometry to identify metabolite changes that correlate with these observed significant embryonic placentation changes.

COVID-19 PANDEMIC EFFECT ON EARLY PREGNANCY – ARE MISCARRIAGE RATES ALTERED, IN ASYMPTOMATIC WOMEN?

To evaluate the effect of the COVID-19 pandemic state on early, 1st trimester pregnancies, in light of a link described between war-induced stress and adverse pregnancy outcomes. Retrospective cohort study conducted in a University fertility center. All 1ST trimester viability scans done since the COVID-19 shut down, March13-May 6, 2020 (Study group), and between March 1-May 17, 2019 (pre-pandemic Control), were reviewed. Early 1st trimester pregnancy outcomes (Viable pregnancy, Arrested pregnancy including biochemical pregnancy loss and miscarriage, and ectopic pregnancy (EP)) were measured. A multivariate analysis was performed to control for significant confounders. Power analysis revealed that a sample size of 58 patients per group has a 90% power with a 15% difference in outcomes and α=5%. The study group denied symptoms of COVID-19. 113 women were scanned in the study, and 172 in the control periods (5-11 weeks gestational age). The groups had similar demographics, gestational history, fertility diagnosis and treatment characteristics (Table). No significant differences were noted in the rate of recurrent pregnancy loss (RPL). Viable clinical pregnancy rates were not different between the groups (76.1% vs. 80.2% in the pandemic and pre-pandemic groups p= 0.41). No significant difference was seen in number of 1st trimester miscarriage (14.2% vs 12.8% p=0.76), biochemical pregnancies (3.5% vs 1.7% p=0.34), or in total miscarriage rate (22.1% vs 16.9% p=0.32), nor in EP rates (0.9% vs 2.3% p=0.36) Mean serum TSH levels were higher in the control but fell in the normal range for both groups. Use of donor sperm was higher in the control and may have favored lower miscarriage rates in that group. The COVID-19 pandemic environment does not seem to affect early first-trimester miscarriage rates in asymptomatic patients.Tabled 1CharacteristicStudy(n=113)Pre-pandemic Control (n=172)P-valueFemale Age, Years, mean±SD36.5 ± 4.537.2 ± 5.40.28RPL History, N(%)15 (13.3)15 (8.7)0.22Fertility diagnosis, N(%)Unexplained24 (21.4)32 (19.6)0.21Male Factor36 (32.1)58 (35.6)Tubal factor5 (4.5)11 (6.8)Polycystic ovarian syndrome21 (18.8)25 (15.3)Decreased ovarian reserve23 (20.5)20 (12.3)Endometriosis1 (0.9)4 (2.5)Base line testing, median(IQR)AMH ng/ml2.5 (1.0 – 4.4)2.5 (1.2 – 5.4)0.75TSH mIU/L1.3 (0.9 – 1.8)1.7 (1.2 – 2.3)0.001Antral follicular count (AFC)16 (9 – 29)14 (9 – 25)0.27Total motile sperm count, median(IQR)18 (6 – 43)12 (5 – 47)0.23Sperm donation, N (%)2 (1.8)17 (9.9)0.01Pregnancy, N (%)Spontaneous34 (30.1)54 (31.4)0.97IUI34 (30.1)51 (29.7)IVF45 (39.8)67 (38.9)ICSI (percentage of IVF patients)31 (79.5)52 (77.6)0.82Blastocyst transferred39 (86.7)56 (83.6)0.65 Open table in a new tab

The biochemical pregnancy loss rate remains stable up irrespective of age and differs in pattern from clinical miscarriages

Introduction As women age, the increasing rate of aneuploidy lead to an augmentation in the incidence of clinical miscarriages. It was anticipated that biochemical pregnancy rates would also rise with maternal age. However, no study has previously evaluated the effect of maternal age on biochemical pregnancy rates. Material and methods A retrospective cohort study of 2177 subjects who underwent single embryo transfer (SET) as part of a fresh or thawed IVF cycle were recruited from 2008 through 2012, resulting in 952 pregnancies. Data was stratified for age and compared using analysis of variance (continuous data) and chi-squared tests (categorical data). Results The likelihood of a clinical miscarriage increased with age (p < .001). Surprisingly, advancing age had no effect on the biochemical pregnancy loss rate (p = .72) (Age 21–30 y: 10.7%, Age 31–35 y:9.8%, Age 36–40y:11.5%, Age 41–42 y:13.6%). Conclusions Biochemical pregnancy loss rate did not increase as a function of age in women 21 to 42 years of age.

Prognostic value of blastocyst grade after frozen euploid embryo transfer in patients with recurrent pregnancy loss

ObjectiveTo determine whether trophectoderm (TE) grade or inner cell mass (ICM) grade have predictive value after euploid frozen embryo transfer (euFET) among recurrent pregnancy loss (RPL) patients.DesignRetrospective cohort study.SettingSingle fertility center.Patient(s)Women with ≥2 prior pregnancy losses with ≥1 euploid embryo for transfer undergoing preimplantation genetic testing for aneuploidy.Intervention(s)Intracytoplasmic sperm injection, TE biopsy, blastocyst grading and vitrification, and single euFET, with first transfer outcome recorded.Main Outcome Measure(s)Live birth and clinical miscarriage rates.Result(s)The study included 660 euFET cycles. In a binomial logistic regression analysis accounting for age, body mass index, antimüllerian hormone level, and day of blastocyst biopsy, or ICM grade C was not significantly associated with odds of live birth, miscarriage, or biochemical pregnancy loss. TE grade C was significantly associated with odds of live birth and was not associated with odds of miscarriage or biochemical pregnancy loss. Blastocyst grade CC had significantly lower live birth rate compared with all other blastocyst grades.Conclusion(s)Embryo grade CC and TE grade C are associated with decreased odds of live birth after euFET in RPL patients. Embryo grade is not associated with odds of clinical miscarriage in this cohort of RPL patients, suggesting that additional embryonic or uterine factors may influence the risk of pregnancy loss.

The live birth and neonatal outcomes in the subsequent pregnancy among patients with adverse pregnancy outcomes in first frozen embryo transfer cycles.

To explore whether the adverse pregnancy outcomes in first frozen embryo transfer (FET) cycles affect live birth and neonatal outcomes in the subsequent pregnancy? This was a retrospective study. Women with a history of adverse pregnancy outcomes in first FET cycles started their subsequent embryo transfer cycles. The adverse pregnancy outcomes included biochemical pregnancy, ectopic pregnancy, and first-trimester pregnancy loss. The main outcomes of present study were live birth rate and neonatal outcomes. Results showed patients with first-trimester pregnancy loss in first FET cycles had a 95 percent greater chance of live birth in subsequent FET cycles (OR 1.95, 95% CI 1.33-2.88). However, the biochemical pregnancy/ectopic pregnancy in initial FET cycles did not affect the chance of live birth in second cycles (biochemical pregnancy: OR 1.21, 95% CI 0.82-1.77; ectopic pregnancy: OR 1.06, 95% CI 0.55-2.05). The neonatal outcomes of singletons were not affected by the number of embryo transfer cycles. Patients with first-trimester pregnancy loss in first FET cycle had a greater chance of live birth in second FET cycles, but the biochemical pregnancy/ectopic pregnancy in first FET cycles did not significantly affect the live birth in second FET cycles. The three types of adverse pregnancy outcomes in first FET cycles did not affect neonatal outcomes in the second cycles.

Follicular-phase endometrial scratching: a truncated randomized controlled trial.

Does intentional endometrial injury (scratching) during the follicular phase of ovarian stimulation (OS) increase the clinical pregnancy rate (CPR) in ART? CPR did not vary between the endometrial injury and the control group, but the trial was underpowered due to early termination because of a higher clinical miscarriage rate observed in the endometrial injury arm after a prespecified interim analysis. Intentional endometrial injury has been put forward as an inexpensive clinical tool capable of enhancing endometrial receptivity. However, despite its widespread use, the benefit of endometrial scratching remains controversial, with several recent randomized controlled trials (RCTs) being unable to confirm its added value. So far, most research has focused on endometrial scratching during the luteal phase of the cycle preceding the one with embryo transfer (ET), while only a few studies investigated in-cycle injury during the follicular phase of OS. Also, the persistence of a scratch effect in subsequent treatment cycles remains unclear and possible harms have been insufficiently studied. This RCT was performed in a tertiary hospital setting between 3 April 2014 and 8 October 2017. A total of 200 women (100 per study arm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle followed by fresh ET were included. Participants were randomized with a 1:1 allocation ratio to either undergo a pipelle endometrial biopsy between Days 6 and 8 of OS or to be in the control group.The primary outcome was CPR. Secondary outcomes included biochemical pregnancy rate, live birth rate (LBR), early pregnancy loss (biochemical pregnancy losses and clinical miscarriages), excessive procedure pain/bleeding and cumulative reproductive outcomes within 6months of the study cycle. The RCT was stopped prematurely by the trial team after the second prespecified interim analysis raised safety concerns, namely a higher clinical miscarriage rate in the intervention group. The intention-to-treat CPR was similar between the biopsy and the control arm (respectively, 44 versus 40%, P = 0.61, risk difference = 3.6 with 95% confidence interval = -10.1;17.3), as was the LBR (respectively, 32 versus 36%, P = 0.52). The incidence of a biochemical pregnancy loss was comparable between both groups (10% in the intervention group versus 15% in the control, P = 0.49), but clinical miscarriages occurred significantly more frequent in the biopsy group (25% versus 8%, P = 0.032). In the intervention group, 3% of the patients experienced excessive procedure pain and 5% bleeding. The cumulative LBR taking into account all conceptions (spontaneous or following ART) within 6months of randomization was not significantly different between the biopsy and the control group (54% versus 60%, respectively, P = 0.43). The trial was stopped prematurely due to safety concerns after the inclusion of 200 of the required 360 patients. Not reaching the predefined sample size implies that definite conclusions on the outcome parameters cannot be drawn. Furthermore, the pragmatic design of the study may have limited the detection of specific subgroups of women who may benefit from endometrial scratching. Intentional endometrial injury during the follicular phase of OS warrants further attention in future research, as it may be harmful. These findings should be taken in consideration together with the growing evidence from other RCTs that scratching may not be beneficial. This study was supported by 'Fonds Wetenschappelijk Onderzoek' (FWO, Flanders, Belgium, 11M9415N, 1524417N). None of the authors have a conflict of interest to declare with regard to this study.

Pregnancy and perinatal outcomes in pregnancies resulting from time interval between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer

BackgroundAdverse obstetric outcomes are correlated with altered circulating hormone levels at the time implantation by the trophectoderm. What’ more, embryo freezing process may also have adverse effect on perinatal outcomes. This study aims to evaluate whether increasing interval time between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer could have any effect on pregnancy and perinatal outcomes.MethodsThis was a retrospective cohort study included the first single blastocyst transfer in artificially cycles of all patients who underwent a freeze-all cycle between January 1st, 2016 and September 30th, 2018. All patients were divided into two groups according to the time interval between oocyte retrieval and the day of first frozen-thawed embryo transferred (FET): Group 1 (immediate FET cycles) and Group 2 (delayed FET cycles).ResultsNo significant differences were reported between the two groups regarding the rates of clinical pregnancy, live birth, biochemical pregnancy and pregnancy loss even after adjusting for measured confounding. When accounting for perinatal outcomes, gestational age, birth weight, delivery mode, fetus gender, preterm birth, gestational hypertension, GDM, placenta previa, fetal malformation and low birthweight also did not vary significantly between the two groups. Only the incidence of macrosomia was more frequently in the Group 2 compared with the Group 1 (AOR 3.886, 95%CI 1.153–13.103, P = 0.029) after adjusting with a multiple logistic regression model.ConclusionsWe found delayed FET cycles for blastocyst transfer following freeze-all cycles may not improve the pregnancy outcomes. On the contrary, postponement of FET cycles may increase the risk of macrosomia. Therefore, FET cycles for blastocyst transfer should be done immediately to avoid adverse effects of delayed time on perinatal outcomes.

Comprehensive analysis of the associations between previous pregnancy failures and blastocyst aneuploidy as well as pregnancy outcomes after PGT-A.

To investigate the associations of previous pregnancy failures, including implantation failures (IFs), biochemical pregnancy losses (BPLs), and early (EMs) and late miscarriages (LMs), with blastocyst aneuploidy and pregnancy outcomes after PGT-A. This study included 792 couples who underwent PGT-A after multiple pregnancy failures. Subgroup analyses were used to compare the blastocyst aneuploidy rate (BAR), implantation rate (IR), early miscarriage rate (EMR), and live birth rate (LBR). Multiple linear and logistic regression models were used to evaluate the associations. The control group comprised couples with ≤ 2 IFs, ≤ 1 BPL, ≤ 1 EM, and no LM. Notably, a history of ≥ 4 IFs was significantly associated with an increase in aneuploid blastocysts (42.86% vs. 33.05%, P = 0.044, B = 10.23 for 4 IFs; 48.80% vs. 33.05%, P = 0.002, B = 14.43 for ≥ 5 IFs). Women with ≥ 4 prior EMs also harbored more aneuploid blastocysts (41.00% vs. 33.05%, P = 0.048; B = 9.23). Compared with the control group, women with ≥ 4 prior EMs had a significantly higher EMR (6.58% vs. 31.11%, P < 0.001, OR = 6.49) and a lower LBR (53.49% vs. 34.18%, P = 0.007, OR = 0.56) after euploid transfer. Moreover, a history of LM(s) was associated with adverse pregnancy outcomes after PGT-A (OR for EM = 3.16; OR for live birth = 0.48). However, previous BPLs and 2 EMs were not associated significantly with blastocyst aneuploidy and pregnancy outcomes after PGT-A. A history of high-order IFs or EMs and existence of LM(s) were significantly associated with blastocyst aneuploidy and adverse pregnancy outcomes after PGT-A, whereas no such associations were observed with BPLs or 2 EMs.

Peri-implantation urinary hormone monitoring distinguishes between types of first-trimester spontaneous pregnancy loss.

BackgroundLutenising hormone (LH) and human chorionic gonadotropin (hCG) hormone are useful biochemical markers to indicate ovulation and embryonic implantation, respectively. We explored “point‐of‐care” LH and hCG testing using a digital home‐testing device in a cohort trying to conceive.ObjectiveTo determine conception and spontaneous pregnancy loss rates, and to assess whether trends in LH‐hCG interval which are known to be associated with pregnancy viability could be identified with point‐of‐care testing.MethodsWe recruited healthy women aged 18‐44 planning a pregnancy. Participants used a home monitor to track LH and hCG levels for 12 menstrual cycles or until pregnancy was conceived. Pregnancy outcomes (viable, clinical miscarriage, or biochemical pregnancy loss) were recorded. Monitor data were analysed by a statistician blinded to pregnancy outcome.ResultsFrom 387 recruits, there were 290 pregnancies with known outcomes within study timeline. Adequate monitor data for analysis were available for 150 conceptive cycles. Overall spontaneous first‐trimester pregnancy loss rate was 30% with clinically recognised miscarriage rate of 17%. The difference to LH‐hCG interval median had wider spread for biochemical losses (0.5‐8.5 days) compared with clinical miscarriage (0‐5 days) and viable pregnancies (0‐6 days). Fixed effect hCG profile change distinguished between pregnancy outcomes from as early as day‐2 post‐hCG rise from baseline.ConclusionsThe risk of first‐trimester spontaneous pregnancy loss in our prospective cohort is comparable to studies utilising daily urinary hCG collection and laboratory assays. A wider LH‐hCG interval range is associated with biochemical pregnancy loss and may relate to late or early implantation. Although early hCG changes discriminate between pregnancies that will miscarry from viable pregnancies, this point‐of‐care testing model is not sufficiently developed to be predictive.

The optimal timing of immunotherapy may improve pregnancy outcome in women with unexplained recurrent pregnancy loss: A perspective follow-up study in northeastern China.

To determine whether patients with unexplained recurrent pregnancy loss (URPL) can benefit from pre-conception immunotherapy or on the early phase of the first trimester. The prospective follow-up study which involved pre-conception patients diagnosed with URPL following rigorous etiology screening in the medical center of recurrent pregnancy loss. In this study, pre-conception immunotherapy included lymphocyte immunotherapy (pre-LIT). Post-conception immunotherapy (post-IM) included LIT or intravenous immunoglobulin (IVIG). Patients were recommended to undergo post-IM immediately from human chorionic gonadotrophin (hCG) elevation. Autoimmune antibodies (AIA) and anti-paternal lymphocytotoxic antibodies (APLA) were tested before and after pre-LIT. Favorable outcome was defined as pregnancy over 14weeks. Unfavorable outcomes included biochemical pregnancy loss (BPL) and pregnancy loss with clear implantation location (PLCIL). In this study, URPL accounted for 12.9% of recurrent pregnancy loss (217/1682). Frequency of BPL was significantly lower in patients with post-IM than that without post-IM [2.8% vs 28.2%; adjusted relative risk (aRR), 0.06; 95% confidence interval (CI), 0.01-0.24]. There was a significant positive conversion in the AIA induced by pre-LIT (0.0% vs 31.0%). Frequency of PLCIL in patients with positive iatrogenic AIA conversion induced by pre-LIT was higher than that in patients without AIA conversion [30.4% vs 5.8%; aRR, 7.53; 95% CI, 1.31-43.34]. Pre-LIT of patients with URPL contributed to a positive iatrogenic AIA conversion, which was associated with an increased risk of PLCIL. Post-IM immediately initiated from the time of hCG elevation can reduce the incidence of BPL.

D-Dimer Assay May Guide LMWH Treatment in Repeated Biochemical Pregnancy Losses in Women with Positive Antiphospholipid Antibody.

Do D-dimer levels influence the pregnancy outcomes after treatment with low molecular weight heparin (LMWH) in women of recurrent miscarriage (RM), repeated biochemical pregnancy losses (BPL), and a positive test for antiphospholipid antibodies (aPLs)? This study was a retrospective chart review of 569 RM patients who were identified as having a history of BPL and a positive aPL. These patients were grouped into three groups according to their treatment plan including those who received low dose aspirin (LDA) alone (group A), LDA plus LMWH after ovulation therapy (group B), and LDA plus LMWH after pregnancy confirmation (group C). We hypothesized that the administration of LMWH after ovulation increased the rates of live birth. D-dimer may predict the pregnancy outcome after treatment. The live birth rate of group B and group C is significantly higher than group A (86.96% and 66.80% vs. 52.89%, p < 0.0001, respectively). The live birth rate in group A, B, and C with elevated D-dimer is 36.92%, 90.52%, and 61.60% respectively. However, there is no significant difference in live birth rate among those who had normal baseline D-dimer. These results suggest that LMWH therapy is more effective in improving the live birth rate when given after ovulation than after pregnancy confirmation. The plasma D-dimer assay can possibly guide LMWH treatment appropriately.

Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure

Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)? PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups. PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40-50% and 5-25% in patients with RPL, respectively. A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35-36, 37-38, 39-40 or 41-42years) were selected for PGT-A groups. All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted. There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16-13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28-10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02-0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03-0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients. The sample size was too small to find any significant advantage for improving the live birth rate and reducing the clinical miscarriage rate per patient. Further study is necessary. A large portion of pregnancy losses in the RPL group might be due to aneuploidy, since PGT-A reduced the overall incidence of pregnancy loss in these patients. Although PGT-A did not improve the live birth rate per patient, it did have the advantage of reducing the number of embryo transfers required to achieve a similar number live births compared with those not undergoing PGT-A. This study was supported by the Japan Society of Obstetrics and Gynecology and grants from the Japanese Ministry of Education, Science, and Technology. There are no conflicts of interest to declare. N/A.

Revisiting serum β-hCG cut-off levels and pregnancy outcomes using single embryo transfer.

The objective of this study is to identify the pregnancy outcomes based on day-16 β-hCG level assessed with modern assays, in fresh single embryo transfers. A retrospective cohort study at a single academic center between 2013 and 2017. A total of 1076 pregnancies were included. Pregnancies were divided into 10% groupings of 107-108 patients each. The 10 groups did not differ for baseline characteristics. There was no difference on outcomes based on cleavage or blastocyst transfer. At a serum β-hCG level of 103 ± 13 (range 74-135), 50% had a biochemical loss. Biochemical pregnancy losses remained 21% at serum β-hCG range (136-197). It was only once serum β-hCG level reached 199-252 that the probability of a biochemical pregnancy loss was 12%. Interestingly, if a clinical pregnancy is present even at low day-16 serum β-hCG levels, the likelihood of live birth is approximately 50%. This maximizes to 75% when the serum β-hCG level was at least 253IU/L. The relationship between serum day-16 β-hCG levels and clinical pregnancy or live birth is quite strong with correlation coefficients above 0.8 which accounted for more than 75% of the variability in outcomes in both cases. Receiver operator curves determined that the cut-off for a clinical pregnancy was 190 and for live birth, it was 213IU/L. An increase in the serum β-hCG levels at which to expect a reassuring outcome is required based on modern assays, as compared with the old cut-off levels.

Could ethnicity have a different effect on fresh and frozen embryo transfer outcomes: a retrospective study.

Does a woman's ethnicity affect her fresh and frozen embryo transfer outcomes differently? A retrospective cohort study of the first fresh and first frozen embryo transfer per woman carried out at a single tertiary level fertility unit between 2010 and 2016 using data retrieved from an electronic database. Biochemical pregnancy, biochemical pregnancy loss, clinical pregnancy, miscarriage and live birth rates per embryo transfer were compared between 5876 white Caucasian, 1071 South Asian and 114 Black Afro-Caribbean women undergoing their first fresh embryo transfer and for 1418 Caucasian, 273 South Asian and 31 Afro-Caribbean women undergoing their first frozen embryo transfer. Logistic regression was used to adjust for age, number of oocytes retrieved, and number and stage of embryos transferred. South Asian (26% versus 32%, adjusted OR 0.622, 95% CI 0.533 to 0.725) and Black Afro-Caribbean women (21% versus 32%, adjusted OR 0.528, 95% CI 0.332 to 0.839) had a lower live birth rate per fresh embryo transfer compared with white Caucasian women. In contrast, the live birth rates per frozen embryo transfer were not significantly different between South Asian and Caucasian women (26% versus 28%, adjusted OR 0.890, 95% CI 0.661 to 1.200) and between Afro-Caribbean and Caucasian women (29% versus 28%, adjusted OR 0.983, 95% CI 0.447 to 2.162). South Asian and Black Afro-Caribbean women have a significantly lower live birth rate than white Caucasian women after fresh embryo transfer, but their frozen embryo transfer live birth rates are not significantly different.

Vitamin D and assisted reproductive treatment outcome: a prospective cohort study

BackgroundVitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation leading to obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on reproductive treatment outcomes in couples undergoing assisted reproductive treatment is poorly understood. This study investigates the association between vitamin D and reproductive treatment outcomes in women undergoing assisted reproductive treatments?MethodsA prospective cohort study conducted at a large tertiary teaching hospital, United Kingdom. Five hundred women undergoing assisted reproductive treatment were recruited between September 2013 and September 2015. All participants had their serum vitamin D measured and their reproductive treatment outcomes collated. Women were categorised in to three groups: vitamin D replete (> 75 nmol/L), insufficient (50-75 nmol/L) and deficient (< 50 nmol/L) according to Endocrine Society guidance. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, clinical pregnancy and pregnancy loss rates.ResultsVitamin D deficiency was found in 53.2% (266/500) of participants and vitamin D insufficiency was found in 30.8% (154/500) of participants. Only 16% (80/500) of women were vitamin D replete. The live birth rates for vitamin D deficient, insufficient and replete women were 23.2% (57/246), 27.0% (38/141) and 37.7% (29/77) respectively (p = 0.04). The respective live birth rates for vitamin D deficient, insufficient and replete women were 24.3, 27.1, 34.4% after adjustment for key prognostic factors (p = 0.25).ConclusionsVitamin D deficiency and insufficiency are common in women undergoing assisted reproductive treatments. The crude live birth rate achieved in women undergoing assisted reproductive treatments are associated with serum vitamin D, although statistical significance is lost when adjusting for important prognostic variables. Vitamin D deficiency could be an important condition to treat in women considering fertility treatment. A research trial to investigate the benefits of vitamin D deficiency treatment would test this hypothesis.Trial registrationClinicaltrials.gov - NCT02187146.

Miscarriage history association with euploid embryo transfer outcomes.

Is a history of miscarriage (including recurrent pregnancy loss) associated with euploid cryopreserved embryo transfer outcomes? Retrospective cohort study from 2014 to 2018 of patients at an academic medical centre, undergoing their first cycle of IVF with 24-chromosome Day 5/6 preimplantation genetic testing for aneuploidies (IVF-PGT-A). Multivariate logistic regression was used to investigate the relationship between history of miscarriage and euploid single cryopreserved embryo transfer outcomes (ongoing pregnancy, miscarriage), adjusting for an extensive list of patient and cycle confounders. In the study cohort of 283 patients, the overall unadjusted positive beta human chorionic gonadotrophin (bHCG) rate was 70.0%, ongoing pregnancy rate was 52.3%, and the total pregnancy loss (biochemical and clinical pregnancy loss) rate per positive bHCG cycle was 24.7%. While 35.3% of patients had a history of at least one previous miscarriage, 14.5% of patients had a history of recurrent pregnancy loss (RPL). For patients with a history of miscarriage, it was found that the adjusted odds ratios (OR) and 95% confidence intervals (CI) for positive bHCG were 1.30 (0.51-3.27), for ongoing pregnancy were 0.88 (0.38-2.03) and for total pregnancy loss were 1.41 (0.49-4.05), when compared with patients without a history of miscarriage. For RPL patients, OR for positive bHCG, ongoing pregnancy and total pregnancy loss also did not significantly differ when compared with patients with no history of miscarriage. In this cohort, there was no significant association between miscarriage history and euploid cryopreserved embryo transfer outcomes (ongoing pregnancy, total pregnancy loss) after adjustment for potential confounders. Further study in larger data sets is warranted.

Prognostic value of repeated serum kisspeptin measurements in early first trimester pregnancy: a preliminary study.

What is the diagnostic value of maternal kisspeptin in patients with asymptomatic first-trimester pregnancies, and what is the prognostic significance of kisspeptin versus beta-HCG in early pregnancies. Case-control study in academic medical centres. Patients with no confounding co-morbidities who conceived by IVF and intracytoplasmic sperm injection were analysed. Maternal serum samples were assessed at the time of pregnancy testing. Women who achieved a positive pregnancy test were asked to take serum samples 4 days later. According to the follow-up results, patients who experienced biochemical pregnancy loss (n = 24) and early miscarriage (n = 21), and women who achieved a viable pregnancy (n = 28), were included in this study. Serum samples were collected to detect kisspeptinand beta-HCG, respectively. Single serum determinations of kisspeptin and beta-HCG were correlated with the different pregnancy outcomes. Women who experienced biochemical pregnancy loss showed lower kisspeptin levels than those in groups B and C. No significant difference, however, was observed at the time of pregnancy testing in women who had experienced early miscarriage and those who had achieved viable pregnancy. Sequential measurements of serum kisspeptin are not as effective as beta-HCG in determining pregnancy outcome. Increased kisspeptin level was associated with reduced miscarriage risk. Single serum measurement of kisspeptin is significantly altered in pregnant and non-pregnant women. However, it failed to discriminate between miscarriage and ongoing pregnancies in first-trimester pregnancy. Neither single nor sequential kisspeptin have higher diagnostic performance for miscarriage than beta-HCG in early stage.