Risk Of Early Pregnancy Loss Research Articles

P-384 The risk of early pregnancy loss following medicated frozen embryo transfer

Abstract Study question Do exogenous gonadocorticoids protect against early pregnancy loss (EPL) following frozen embryo transfer (FET)? Summary answer Exogenous gonadocorticoids conferred a 59.5% increased risk of EPL (p<.05) without any advantage to biochemical pregnancy rates. This corresponded to a significantly thinner pre-FET endometrium. What is known already During a medicated FET cycle, exogenous progestogens and/ or oestrogens are administered with the intention of inducing endometrial maturation prior to implantation. However, the concomitant administration of both these gonadocorticoids is known to produce secretory changes alongside endometrial proliferation. It is unclear whether this non-physiological morphology is truly favourable for implantation, with some authors reporting similar EPL rates between medicated and “natural” FET cohorts while others have found exogenous gonadocorticoids to reduce the risk of EPL compared to alternative protocols. Study design, size, duration Retrospective, single-centre cohort study assessing the rates of biochemical pregnancy and EPL following 819 FETs. All FETs were conducted between January 2019 and November 2022 within a single British centre. Participants were followed up at 6-8 weeks post-FET to assess for biochemical pregnancy and EPL. The former was defined as a positive urinary human chorionic gonadotropin; the latter was defined as the absence of pregnancy on transvaginal ultrasound despite previous confirmation of biochemical pregnancy. Participants/materials, setting, methods Participants comprised 586 women undergoing medicated FET cycles and 233 women undergoing “natural” cycles. Electronic healthcare records (EHRs) were accessed to record pregnancy outcomes, hormonal therapies and endometrial thickness at 48hrs prior to FET. Binomial variables were compared using Pearson’s chi-squared test; continuous variables were analysed via T-tests and logistic regressions. Cut-offs of 8mm, 9mm and 10mm were applied to endometrial thickness in sub-group analyses. Statistical test were conducted using STATA v18.0 (StataCorp LLC, Texas). Main results and the role of chance Women undergoing medicated FET cycles achieved 16.9% higher rates of biochemical pregnancy compared to women undergoing “natural” cycles (57.7% versus 49.4%, p<.05). However, they also suffered a 59.5% higher rate of EPL (28.8% versus 18.0%, p<.05), which corresponded to significantly thinner endometrium at pre-FET ultrasound in comparison to women on “natural” cycles (9.13mm versus 9.48mm, p<.05). Logistic regressions revealed that, within the medical FET cohort, each 1mm increase in thickness conferred a 13.8% increased risk of EPL (95%CI: 3.1%-25.5% p<.01) but no advantage in biochemical pregnancy rates. “Natural” cycles demonstrated no such association. Endometrial thickness was then dichotomised using three thresholds. Women undergoing medicated FET cycles whose endometrium exceeded 9mm or 10mm had 62.1% and 71.4% greater risk of EPL, respectively, compared to those below either threshold. Biochemical pregnancy rates did not differ. Women undergoing “natural” FET cycles did not exhibit any significant difference using either threshold, suggesting that the disparate EPL rate in medicated cycles may result from non-physiological endometrial stimulation by exogenous gonadocorticoids. The 8mm cut-off was insignificant in both cohorts. Although these results cannot confirm a causal relationship between exogenous gonadocorticoids, endometrial thickness and EPL, they are sufficiently striking to warrant further investigation into their pathophysiological basis. Limitations, reasons for caution EHRs failed to report endometrial thickness for 125 participants (15.3%), limiting statistical power in logistic regressions. Our results cannot be confidently applied to other centres until further studies are conducted. Additionally, our design did not allow for the disparity in EPL rates to be attributed to a particular pathophysiological mechanism. Wider implications of the findings This data generates further uncertainty within the literature with regards to the relative risk of EPL in medicated versus “natural” FET cycles. The empirical evidence to support one protocol over the other is insufficient at present, and thus clinical recommendations should be based on the individual preferences of each patient. Trial registration number not applicable

P-429 Measuring serum progesterone levels on the day of a fresh blastocyst transfer is debatable as there is no evidence for correlation with ongoing pregnancy results

Abstract Study question Does serum progesterone (P4) level on the day of a fresh blastocyst transfer relate to ongoing pregnancy rate (OPR)? Summary answer OPR after a fresh single blastocyst transfer seems not to be associated with serum P4 level on the day of transfer. What is known already Several studies have suggested an optimal serum P4 threshold for embryo transfers in frozen embryo transfer cycles. However, for fresh embryo transfers, data are scarce and conflicting. Study design, size, duration A retrospective single-center cohort study was performed on 598 complete data cycles, retained out of 631 consecutive fresh single blastocyst transfer cycles. Data were collected from patients undergoing a fresh IVF/ICSI cycle with autologous oocytes at a tertiary fertility center between June 2022 and August 2023. Participants/materials, setting, methods A total of 482 unique patients underwent one or more single fresh blastocyst transfers using micronized vaginal progesterone (MVP) 800mg BID for luteal phase support starting day after oocyte retrieval. Serum P4 levels were determined on day of transfer. The primary endpoint was OPR, positive hCG-test and early pregnancy loss (EPL) were secondary endpoints. Unadjusted and adjusted generalized estimating equations (GEE) assessed P4 level association with the endpoints, using an exchangeable working correlation matrix. Main results and the role of chance No association was identified between P4 levels on day of transfer and OPR after accounting for maternal age, blastocyst quality, P4 and estradiol level at last ultrasound, BMI and endometrial thickness. Data were grouped according to 10/50/90 and 25/50/75 percentiles, resulting in groups < = or > 27ng/ml and < = or > 40ng/ml, with omission of 90th and 75th percentile groups due to right-skewed distribution. With serum P4 levels higher than 40ng/ml, the probability of a positive hCG-test significantly increased (OR 1.79, CI 1.11-2.91; p = 0.018). No significant difference was observed in patients with serum P4 < = or > 27ng/ml (OR 1.23, CI 0.66-2.30; p = 0.506). Regarding OPR, no significant differences were observed when comparing patients with serum P4 < = or > 27/ng/ml or < = or > 40ng/ml (OR 0.88, CI 0.42-18.85; p = 0.736 and OR 1.41, CI 0.83-2.37; p = 0.203, respectively). Moreover, EPL did not significantly differ between serum P4 level groups (OR 1.93, CI 0.61-6.13; p = 0.265 and OR 1.2, CI 0.51-2.84; p = 0.674). Age (p < 0.001) and embryo quality (p < 0.001) are significantly related with OPR. Additionally, late follicular progesterone levels and OPR are significantly associated (OR 2.39, CI 1.16-4.95 in patients with P4 < = or > 27/ng/ml and OR 2.21, CI 1.07-4.55 in patients with < =40ng/ml and >40ng/ml). Limitations, reasons for caution Limitations include the retrospective design and the lack of live birth outcome data. Progesterone levels exceeding 60 ng/ml were not further analyzed to their precise value but grouped as 60 plus which did not allow to identify potential detrimental effects of very high P4 levels on treatment outcome. Wider implications of the findings Our data suggest that measuring P4 on the day of a single blastocyst transfer with MVP luteal phase support may not be indicative of OPR or the risk of EPL. This raises questions regarding the necessity for routine P4 measurements as well as the development of rescue strategies. Trial registration number ONZ-2023-0628

O-286 Weight loss interventions prior to infertility treatment does it make sense?

Abstract Obesity in women is negatively associated with reproductive outcomes such as decreased natural conception and pregnancy rate in assisted reproductive technique (ART), as well as increased risks of miscarriage and maternal and foetal complications, including risks of perinatal and neonatal death. The reproductive consequences of obesity stem from a combination of ovarian, uterine and systemic pathophysiological changes, although not all fully elucidated. These alterations contribute to reduced oocyte and embryo quality, reduced uterine receptivity and systemic inflammatory responses. Various guidelines recommend lifestyle interventions based on dietary and/or physical activity targeting at a 5 to 10% reduction in body weight as an initial step prior to fertility treatment for women with infertility and overweight or obesity. However, evidence from well powered randomised controlled trials (RCTs) assessing the effectiveness of lifestyle interventions aiming at weight loss prior to fertility treatments is scarce and not unequivocally positive with respect to reproductive outcomes. First, this presentation will focus on the effectiveness of pre-conception lifestyle intervention targeting weight loss, on reproductive outcomes documented in the latest systematic review (SR) and meta-analysis and preliminary results of an individual participant data meta-analysis (IPDMA). The latest SR in 2021 (Obesity reviews DOI: 10.1111/obr.13325) including 15 RCTs until March 2020 (N = 1852 women) suggests more weight loss in the intervention group. An increase in live birth rates (LBR) in nine RCTs (N = 1203 women) and a higher natural conception rate following lifestyle intervention compared to no intervention were reported. However, no effect of lifestyle intervention preceding ART in six RCTs (N = 1040 women). With respect to potential harm of lifestyle intervention there is no significant increased risk of early pregnancy loss. Complications during pregnancy, such as early pregnancy loss and maternal, fetal and neonatal outcomes are underreported in most included studies. The VENUS IPDMA (BMJ Open 2022;12:e065206) analyzed individual patient data of 11 RCTs of 14 eligible RCTs (N = 1903 participants; 1010 in the intervention group and 893 in the control group). Preliminary data (abstract ESHRE 2023) showed that physical activity and/or dietary interventions prior to fertility treatment resulted in more weight reduction compared to those in the control group in 11 RCTs. The intervention group, however, did not have a significantly higher rate of LBR in nine RCTs (N = 1702 participants). Compared to the control group, the intervention group had smaller waist and hip circumference, lower systolic and diastolic blood pressure, and lower triglycerides, total cholesterol, glucose, and insulin levels at the time of study follow up. Do we have a definitive answer to the question: “weight loss interventions prior to fertility treatment; does it make sense” using data of IPDMA? Shortcomings of the available evidence regarding the effectiveness and safety of dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatments will be presented. Limitations of the studies and future perspectives and challenges in this field of research will be highlighted. Finally, the question “does it make sense” is broader than the effectivity of the intervention. Do we as clinicians adopt our role as health advocates to advice and guide future parents to adopt a healthy lifestyle, with weight reduction as a result? Could this lead to a healthier lifestyle for the future of parents and children? To conclude: “does it make sense” is not an easy question to answer.

Review on Polycystic Ovarian Syndrome (PCOS) In Case of Pregnancy

Women with polycystic ovary syndrome (PCOS) have a higher risk of infertility, miscarriage, obesity, cardiovascular disease, diabetes mellitus, obstructive sleep apnea, depression, nonalcoholic fatty liver disease, endometrial hyperplasia, and cancer. Women with PCOS are more likely to undergo cesarean or c-section deliveries, which are associated with a high risk of early pregnancy loss. The most effective therapies for PCOS include regular exercise, a good diet, and weight management. In fact, the harmful consequences of obesity on reproductive potential can be reversed with effective therapy, whether or not there is insulin resistance. Based on the outcomes of trials conducted in recent years, this promise appears to be coming true.

Outcome of Monochorionic Diamniotic Twins with Twin Reversed Arterial Perfusion Sequence: Interstitial Laser versus Endoscopic Cord Occlusion.

Twin reversed arterial perfusion sequence (TRAP) is a rare complication of monochorionic twins (MC). This study aimed to describe and compare the short- and long-term outcomes of MC pregnancies with the TRAP sequence treated with two different techniques: interstitial fetal laser (IFL) (n = 22) versus endoscopic cord occlusion (CO) (n = 24). The study population included 46 MC pregnancies with TRAP. Pregnancy loss within 2 weeks after the procedure occurred in 27% of cases (6/22) in the group treated with IFL and in 8% of cases (2/24) in the group treated with CO. The survival rate of the pump twin was 73% (16/22) in the IFL group and 83% (20/24) in the group treated with CO. The median gestational age at birth was 38 weeks in the group treated with IFL and 35 weeks in the group treated with CO. The rate of preterm birth before 34 weeks was 12.5% (2/16) in the group treated with IFL and 32% (7/22) in the group treated with CO. In the group treated with IFL, there were no cases of neurological disabilities reported by the parents compared to three cases in the CO group. IFL is associated with a higher risk of early pregnancy loss; however, if the pregnancy progresses, it is associated with lower risks of preterm birth and neurological disabilities in the survivors.

Impacts of the COVID-19 pandemic on early pregnancy outcomes among women undergoing frozen-thawed embryo transfer: a retrospective cohort study

The effect of COVID-19 pandemic on early pregnancy outcomes among women undergoing frozen-thawed embryo transfer (FET) remains unclear. We aimed to evaluate whether early pregnancy outcomes were altered in patients undergoing FET during the pandemic. In this retrospective cohort study, women conceived through FET in 2016–2021 from two hospitals in China were included. The early pregnancy outcomes were compared using Logistic regression model, including biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), and early pregnancy loss rate (EPLR). A total of 16,669 (67.2%) and 6,113 (26.8%) FET cycles enrolled before and during the pandemic, respectively. Univariate analyses showed that women undergoing FET during the pandemic had significantly increased BPR (72.9% vs. 69.7%) and CPR (59.5% vs. 55.0%), and significantly decreased EPLR (13.7% vs. 16.7%) compared to pre-pandemic (all P < 0.001). Moreover, after adjustment, the results were in accordance with univariate analysis for CPR [adjusted OR (95%CI) = 1.08 (1.01–1.14)] and EPLR [adjusted OR (95%CI) = 0.82 (0.73–0.91)], while the statistical significance between BPR and the pandemic disappeared. In summary, women conceived by FET did not have a reduced possibility of clinical pregnancy and a higher risk of early pregnancy loss during the pandemic compared with the pre-pandemic.

P-357 Downregulation (DR) with combined gonadotropin-releasing hormone agonist (GnRHa) and aromatase inhibitor (AI) optimizes the frozen-thawed embryo transfer (FET) results in women with adenomyosis

Abstract Study question Does combined GnRHa &amp; AI therapy for downregulation in women with adenomyosis optimize the FET success rates / outcomes on par with women without adenomyosis? Summary answer GnRHa combined with AI used for downregulation in women with adenomyosis optimized the outcomes of frozen–thawed embryo transfer cycle on par with women without adenomyosis. What is known already Women with adenomyosis have lower rates of successful implantation via altered molecular expressions in the endometrium due to local hyperestrogenism &amp; also an increased risk of early pregnancy loss (Munro et al 2019). DR improves the clinical pregnancy rate by reducing the endometrial inflammatory reaction and/or myometrial contractility and their impact on uterine receptivity in women with adenomyosis undergoing FET (Sania Latif et al 2021). Combined treatment for uterine adenomyosis with Anastrazole plus GnRHa showed better results than dienogest treatment with a higher reduction of symptoms &amp; higher pregnancy rates (M Sbracia &amp; F Scarpellini, 2018). Study design, size, duration A Retrospective cohort study conducted at a tertiary care fertility unit. Data for 326 women with/without adenomyosis undergoing frozen–thawed embryo transfer after IVF was was retrieved from the hospital's database and analyzed for a period between September 2021 to November 2022. Participants/materials, setting, methods Women with adenomyosis (n = 107) received Anastrozole 1mg/day for 2months plus 3doses of Inj. Goserelin 3.6mg subcutaneously at 28days interval between 2successive doses. Hormone replacement therapy (HRT) was started 2weeks after the 3rddose of Inj. Goserelin &amp; FET was performed after an optimum endometrial thickness (EMT) was achieved. For women without adenomyosis (n = 219) HRT was started on cycle Day-2 &amp; FET was performed after achieving an optimum EMT. Serum beta-hCG was performed on Day15 after FET. Main results and the role of chance Statistical analysis was performed using SPSS20version. Normally distributed continuous variables were compared using a student t-test, and categorical variables were compared by χ2 and Fisher's exact test, where appropriate. To reduce selection bias, propensity score matching was used, and propensity matching yielded 99 pairs. Baseline characters like age (p-value=0.36), BMI (p-value=0.12), duration (p-value=0.28), type (p-value=1) &amp; cause (p-value=0.3) of infertility, endometrial thickness (p-value=0.37), day of embryo transfer (p-value=0.57) were comparable for the two groups. FET results in terms of positive pregnancy test (Serum beta-hCG &amp;gt; 50mIU/ml) were found to be 68.21% for the DR- FET group and 67.71% for the HRT group which were comparable(p-value=0.17). This suggests that downregulation in women with adenomyosis helps achieve success rates similar to women without the disease. Pregnancy outcomes like miscarriage (15 vs 13.13 %, p-value=1.00), biochemical pregnancy (3.03 vs 2.02 %, p-value=1.00) and ectopic pregnancy (1.01 vs 0 %, p-value=0.49) rates analyzed between the DR FET and HRT groups showed no statistically significant difference. Clinical pregnancy rates were almost similar for the 2 groups (55.71 Vs 57.46%, p-value=0.65). Thus, we conclude that downregulation with combined GnRHa and AI optimizes the frozen-thawed embryo transfer results in women with adenomyosis on par with women without adenomyosis. Limitations, reasons for caution This is a retrospective study and hence randomized comparison was not possible. Women were followed up for 12 weeks of pregnancy, hence live birth rates were not analyzed in our study. Wider implications of the findings Combining the two treatment modalities (GnRHa + AI) which work at different sites optimizes IVF success rates &amp; pregnancy outcomes. Hence we suggest that well-designed prospective randomized studies are needed to further analyze the synergistic role of this drug combination for downregulation in women with varied severity of adenomyosis. Trial registration number Not applicable

O-021 The dose of micronised vaginal progesterone prior to frozen embryo transfer in artificially prepared cycles: the more the better?

Abstract Study question Does a higher daily dose of micronized vaginal progesterone (MVP) increase live birth rates (LBR) or diminishes risk of early pregnancy loss (EPL)? Summary answer An increased dose of MVP does not affect reproductive outcomes. What is known already Endometrial preparation in frozen embryo transfer (FET) cycles can be achieved either in a natural cycle (NC), a stimulated cycle or an artificial cycle (AC). Despite growing advocacy for utilization of NC for FET mainly because of pregnancy complications, there are still numerous indications and strengths of AC, such as convenient monitoring and planning. In AC-FET cycles exogenous estradiol (E2) and progesterone (P) are administered consecutively in order to mimic a natural cycle. Although MVP still being the most widely used medication for LPS in AC-FET cycles, dose finding studies are lacking. Study design, size, duration This is a retrospective study performed at a university-affiliated centre including patients performing a single blastocyst transfer from January 2016 till June 2021. Pregnancy outcomes were compared between patients receiving 600mg (3x200mg) or 800mg (2x200mg) of MPV in the second phase of an AC-FET cycle. The time period was chosen to incorporate the empiric change made in the inner guidelines regarding artificial cycles LPS in autumn 2018. Participants/materials, setting, methods Patients aged 19-39, who underwent the first frozen single blastocyst transfer were included. Only HRT cycles, where after exogenous estradiol endometrium preparation LPS was started with MVP 600mg or 800mg were included. Patients lost to follow-up, with missing data, with known uterine pathology, recurrent miscarriages, with switch to MNC, with more than one progesterone route planned or modified LPS were excluded. Main results and the role of chance 1825 artificial cycles for FET were included. 827 supplemented with 600mg of MVP -MVP600 group and 998 with 800mg of MVP – MVP800 group. The MVP600 and MVP800 groups did not differ in BMI 24.02 (SD 4.73) vs 23.81 (SD 4.6) (p = 0.37), rank of embryo transfer 1.93 (SD 1.41) vs 1.77 (SD1.19) (p = 0.11), or the thickness of the endometrium at planning 8.67mm (SD1.79) vs 8.51mm (SD 1.7) (p = 0.06). Yet, MVP 800mg group was slightly older than MVP600 group 31.99 (SD 3.72) vs 30.84 (SD 3.9) (p &amp;lt; 0.001). Positive hCG was 58.65% (485 out of 827) for MVP600 and in 62.12% (620 out of 998) for MVP800 group (p = 0.13). LBR per positive hCG 64.18% (292 out of 455) in MVP600 and 67.17% (397 out of 591) in MVP800 group (p = 0.31). Early pregnancy loss per positive hCG did not differ between the groups, and including biochemical losses, was 32.75% in MVP600 (149 out of 455) vs 30.8% in MVP800 (182 out of 591) (p = 0.5). Multivariable regression analysis adjusting for relevant confounders (eg. BMI, endometrium thickness) revealed that the dose of MVP 600mg vs 800mg is not significantly associated with EPL OR 0.92 (95% CI 0.71-1.22) p &amp;gt; 0.592. Limitations, reasons for caution The main limitation is the retrospective design of our study, with an inherent risk of bias. Furthermore, we could not compare the blood progesterone values at the day of the transfer as in MVP600 they were not routinely performed, so the need for additional LPS could not be compared. Wider implications of the findings This is the largest study dose finding study comparing the two progesterone administration doses. The higher dose of MVP does not improve reproductive outcomes, but might be more convenient due to a twice daily application. Trial registration number BUN: 1432022000074 EC number: EC-2022-102

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

COVID-19 impact in early pregnancy losses: A retrospective study

Background: Severe acute lung disease, known as coronavirus disease 2019 [COVID-19] had multifaced impacts on human lives especially in pregnant women. However, no clear-cut consensus have been made on the effect of COVID 19 on pregnancy and fetal effects due to limited data. Aim: To study pregnant women presenting to our department with missed miscarriages or early fetal demise in the COVID pandemic time for a period of 2 years (April 2020 to March 2022) and to assess the risk of early pregnancy loss due to COVID 19 infection if any. Materials and Methods: A Retrospective comparative study was carried out among pregnant women attending the department of Obstetrics & Gynaecology for MTP at SVS Medical College, Mahabubnagar in view of miscarriages both embryonic and anembryonic and early fetal demise till 20weeks Gestational age in the period April2020 to March 2021 and a control group of pregnant ladies who presented for MTPs before 20 weeks for miscarriages and early IUFDs till 20 weeks gestational age in the period of April 2019 to march 2020 were taken. Results: A total of 232 women were registered during pre-pandemic period and 180 women were registered during pandemic period for the study. The two groups were similar in demographic characteristics including the mean maternal age in both the groups which were 22+/-2 and 23+/-2yrs. Parity affected in both the study groups i.e, precovid which were 38.2% in primigravida and 61.7% in multigravida and the pregnancy loss during covid-there were 44.6% in primigravida and 55.3% in multigravida, showing no significant difference in pregnancy loss during and before covid. The percentages of missed miscarriages, early IUFDS less than 20 weeks Gestational age, MTPs done for various congenital anomalies also showed only marginal changes in both the groups. Conclusion: In our study, we did not find any significant difference between the early fetal demise, missed miscarriages, MTPs done for congenital anomalies during the pre-covid and COVID periods. Though some studies support early pregnancy loss due to COVID infection, because of our small sample size, we could not find attribute the marginal changes in the study group i.e, during COVID pandemic due to small sample size and also many studies reporting no significant difference, large multicentric studies are needed to evaluate any association between the COVID-19 SARS virus infection and its effect on fetal demise, any miscarriages or congenital anomalies.

Fetal Reduction of Triplet Pregnancies to Twins vs Singletons: A Meta-analysis of Survival and Pregnancy Outcome

ABSTRACT Fetal reduction (FR) for higher-order multiples accounted for 103.6 per 100,00 births across the United States in 2015, and the need for this service has expanded over the last 30 years. Despite improvements in neonatal care, triplet pregnancies are more likely to experience adverse outcomes, including infant mortality and morbidity, than twin or singleton pregnancies. In triplet pregnancies, prematurity is associated with an 11-fold increase and low birth weight with a 2.2-fold increase in infant deaths compared with singleton and twin prematurity pregnancies. This contributes to higher all-cause healthcare expenses for triplet pregnancies (US $407,000) versus singleton pregnancies (US $21,500). Fetal reduction has been shown to improve outcomes, including a lower risk of premature birth, in triplet pregnancies reduced to twins compared with triplet pregnancies with no FR. Another study found improved outcomes when triplet pregnancies were reduced to singleton or twin pregnancies versus expectant management. However, it remains unclear whether FR in triplet pregnancies to singleton pregnancy (RTS) improved outcomes compared with a reduction to twin pregnancies (RTT). The aim of this study was to compare perinatal outcomes and survival rates of RTS pregnancies versus RTT pregnancies, and FR in any triplet pregnancies versus expectant management. This was a systematic review and meta-analysis based on a literature search for studies with data comparing selective RTT and RTS pregnancies. Excluded were studies with multiple pregnancies &gt;3 fetuses, monochorionic triplets, and missing data. The primary outcome was the rate of fetal survival of RTT and RTS pregnancies, defined as a live birth &gt;24 weeks of gestation. Secondary outcomes included gestational age (GA) at birth, birth weight, incidence of preterm birth, early pregnancy loss at &lt;24 weeks, and neonatal death, up to 28 days after birth. A total of 10 studies directly comparing RTT pregnancies with RTS pregnancies and another 10 studies comparing FR with no FR were included in the analysis. The studies represented 1903 RTT pregnancies and 489 RTS pregnancies. There was a significantly lower survival rate among RTT pregnancies versus RTS pregnancies (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.40–0.92; 95% prediction interval [PI], 0.36–1.03; P = 0.02; I 2 = 0%). There was a comparable risk of early pregnancy loss (OR, 0.89; 95% CI, 0.58–1.38; 95% PI, 0.54–1.48; P = 0.61; I 2 = 0%) and neonatal death (OR, 0.56; 95% CI, 0.10–3.21; P = 0.55; I 2 = 28%). RTT pregnancies had significantly lower GA (mean difference, −2.20; 95% CI, −2.80 to −1.61; 95% PI, −4.27 to −0.14; P &lt; 0.001; I 2 = 79%) and lower birth rates (OR, 8.76; 95% CI, 5.56–13.80; 95% PI, 4.60–16.67; P &lt; 0.001; I 2 = 0%) than RTS pregnancies. RTT pregnancies also had a greater risk of preterm birth at &lt;34 weeks (OR, 3.04; 95% CI, 1.45–6.36; 95% PI, 0.54–17.18; P = 0.003; I 2 = 22%) and at &lt;32 weeks (OR, 2.14; 95% CI, 1.02–4.49; 95% PI, 0.64–7.13; P = 0.04; I 2 = 0%). No difference in live birth rate was observed between RTT pregnancies and expectant management. In conclusion, triplet pregnancies RTS pregnancies had better outcomes than RTT pregnancies, including higher fetal survival rate, higher GA at birth, lower risk of preterm birth, and higher birth weight. Understanding the potential risks and benefits of FR in triplet pregnancies is essential for obstetricians providing parental counseling.

Low-titer antiphospholipid antibodies is associated with increased risk of late preterm stillbirth

Antiphospholipid (aPL) antibodies are present in up to 42% of patients with pregnancy loss. Patients with low-titer aPL antibodies who do not meet Sapporo criteria for antiphospholipid syndrome (APLS) often receive conflicting counseling in regards to pregnancy loss and perinatal outcomes by both hematologists and perinatologists. We performed a retrospective cohort study of pregnant patients who had aPL testing and compared pregnancy outcomes between subjects with low-titer aPL and those with negative aPL. Low-titer aPL was defined as positive anticardiolipin or anti-B2 glycoprotein IgG or IgM < 40 GPL or MPL or < 99th percentile. The primary outcome consisted of early pregnancy loss (< 13 weeks), spontaneous abortion (≥13, < 20 weeks), and fetal demise/stillbirth (≥20 weeks). Bivariable and multivariable analyses were performed. There were 2,898 patients with a pregnancy episode and aPL testing. Compared to those with negative aPL, low-titer aPL individuals were more likely to be younger, identify as Black or African-American, have hematologic or autoimmune disorders, have a history of substance use disorder or psychiatric disorder. Notably, there was increased use of aspirin but no difference in anticoagulation use in this group. (Table 1). After multivariable analysis, patients with low-titer aPL were not at higher risk for early pregnancy loss or spontaneous abortion when compared to those with negative aPL. However, they were at higher risk for stillbirth between 28-37 weeks compared with their negative aPL counterparts with an OR 1.81 (1.01-3.23), once adjusted for high risk comorbidities. (Table 2). Patients with low-titer aPL had higher rates of expected autoimmune and hematologic disorders compared to those with negative aPL. While there was no increased risk of spontaneous abortion, these patients were more likely to have a late preterm fetal demise, even when adjusted for medical and social comorbidities and aspirin use. While these patients do not carry a formal APLS diagnosis, they have a higher risk of stillbirth than patients with negative aPL.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Restraint stress of female mice during oocyte development facilitates oocyte postovulatory aging.

Studies suggest that psychological stress on women can impair their reproduction and that postovulatory oocyte aging (POA) might increase the risk of early pregnancy loss and affect offspring's reproductive fitness and longevity. However, whether psychological stress during oocyte development would facilitate POA is unknown but worth exploring to understand the mechanisms by which psychological stress and POA damage oocytes. This study observed effects of female restraint stress during oocyte development (FRSOD) on oocyte resistance to POA. Female mice were restrained for 48 h before superovulation, and they were sacrificed at different intervals after ovulation to recover aging oocytes for analyzing their early and late aged characteristics. The effects of FRSOD on aging oocytes included: (1) increasing their susceptibility to activation stimulus with elevated cytoplasmic calcium; (2) impairing their developmental potential with downregulated expression of development-beneficial genes; (3) facilitating degeneration, cytoplasmic fragmentation and apoptosis; (4) worsening the disorganization of cortical granules and spindle/chromosomes; and (5) impairing redox potential with increased oxidative stress. In conclusion, FRSOD impairs oocyte resistance to POA, so that stressed oocytes become aged significantly quicker than unstressed controls. Thus, couples wishing to achieve pregnancy should take steps to avoid not only fertilization of aged oocytes but also pregestational stressful life events.

Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development.

Hyperhomocysteinemia may arise from folate/vitamin B12 deficiency, genetic polymorphisms, kidney disease, or hypothyroidism. It is associated with an increased risk of early pregnancy loss and placenta‐related complications of pregnancy, including pre‐eclampsia and fetal growth restriction. While the majority of studies of hyperhomocysteinemia focus on epigenetic changes secondary to metabolic disruption, the effects of homocysteine toxicity on placental development remain unexplored. Here, we investigated the influence of hyperhomocysteinemia on early blastocyst development and trophoblast differentiation. Exposure of cultured blastocysts to high homocysteine levels reduces cell number in the trophectoderm layer, most likely through increased apoptosis. Homocysteine also promotes differentiation of a trophoblast stem cell line. Both effects diminish the stem cell pool, and are mediated in an endoplasmic reticulum (ER) unfolded protein response (UPRER)‐dependent manner. Targeted alleviation of UPRER may therefore provide a new therapeutic intervention to improve pregnancy outcome in women with hyperhomocysteinemia.

Prospectively assessed perceived stress associated with early pregnancy losses among women with history of pregnancy loss.

What is the association between perceived stress during peri-conception and early pregnancy and pregnancy loss among women who have experienced a prior pregnancy loss? Daily perceived stress above the median is associated with over a 2-fold risk of early pregnancy loss among women who have experienced a prior loss. Women who have experienced a pregnancy loss may be more vulnerable to stress while trying to become pregnant again. While prior research has indicated a link between psychological stress and clinically confirmed miscarriages, research is lacking among a pre-conceptional cohort followed prospectively for the effects of perceived stress during early critical windows of pregnancy establishment on risk of both hCG-detected pregnancy losses and confirmed losses, while considering important time-varying confounders. Secondary data analysis of the EAGeR trial (2007-2011) among women with an hCG-detected pregnancy (n = 797 women). Women from four US clinical centers enrolled pre-conceptionally and were followed ≤6 cycles while attempting pregnancy and, as applicable, throughout pregnancy. Perceived stress was captured via daily diaries and end-of-month questionnaires. Main outcome measures include hCG-detected and clinically recognized pregnancy losses. Among women who had an hCG-confirmed pregnancy, 188 pregnancies (23.6%) ended in loss. Women with high (>50th percentile) versus low (≤50th percentile) peri-implantation or early pregnancy weekly perceived stress had an elevated risk of experiencing any pregnancy loss (hazard ratio (HR): 1.69, 95% CI: 1.13, 2.54) or clinical loss (HR: 1.58, 95% CI: 0.96, 2.60), with higher risks observed for women experiencing an hCG-detected loss (HR: 2.16, 95% CI: 1.04, 4.46). Models accounted for women's age, BMI, employment, marital status, income, education, race, parity, prior losses, exercise and time-varying nausea/vomiting, caffeine, alcohol and smoking. We were limited in our ability to clearly identify the mechanisms of stress on pregnancy loss due to our sole reliance on self-reported perceived stress, and the lack of biomarkers of different pathways of stress. This study provides new insight on early pregnancy perceived stress and risk of pregnancy loss, most notably hCG-detected losses, among women with a history of a prior loss. Our study is an improvement over past studies in its ability to account for time-varying early pregnancy symptoms, such as nausea/vomiting, and lifestyle factors, such as caffeine, alcohol and smoking, which are also risk factors for psychological stress and pregnancy loss. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Additionally, K.C.S. was supported by the National Institute on Aging of the National Institutes of Health under Award Number K01AG058781. The authors have no conflicts of interest to disclose. #NCT00467363.

P-312 Effect on pregnancy outcomes of depot GnRH agonist pre-treatment before frozen-thawed embryo transfer cycles in patients with adenomyosis

Abstract Study question Is there any difference between using or not using depot GnRH agonist pre-treatment on pregnancy outcomes in patients with adenomyosis before frozen-thawed embryo transfer cycles? Summary answer GnRH agonist pre-treatment before frozen-thawed embryo transfer has no effect on pregnancy outcomes in adenomyosis patients. What is known already Uterine adenomyosis negatively affects implantation and clinical pregnancy rates and also increases the risk of early pregnancy loss. Increased inflammatory markers and increased myometrial peristalsis are thought to decrease the rate of implantation. Depot GnRH agonist pre-treatment is thought to increase implantation rate by both decreasing myometrial contractility and reducing inflammatory marker production. Study design, size, duration This retrospective cohort study was conducted at ART and Reproductive Genetics Centre, Memorial Sisli Hospital, Istanbul, Turkey. Patients with adenomyosis undergoing a FET cycle between 2011 and 2021 were evaluated. Patients between 25-45 years old with good and top-quality blastocysts were included and preimplantation genetic diagnosis (PGD) was applied to patients who were &amp;gt;37 years old. A total of 144 frozen embryo transfer cycles were examined. Participants/materials, setting, methods Diagnosis of adenomyosis was made using transvaginal ultrasound and/or pelvic magnetic resonance imaging which revealed an asymmetrically thickening between the anterior and posterior uterine walls, focal adenomyosis, myometrial cysts and irregular/interrupted junctional zone of the endometrium. 65 patients in the study group (Group I) who received depot GnRH agonist pre-treatment for minimum 2 and maximum 6 months and 79 patients without GnRH agonist pre-treatment (Group 2) were evaluated. Main results and the role of chance There was no significant difference in patient characteristics such as age, endometrial thickness on embryo transfer day, BMI, infertility duration, and anti mullerian hormone levels between groups 1 and 2. Endometrial preparation was done using artificial cycle in the depot agonist group, whereas both artificial and modified natural cycle were used in patients without depot GnRH agonist pre-treatment.The pregnancy rate was 53.8%(n = 35) in group 1 and 54.4%(n = 43) in group 2. The clinical pregnancy loss rate was 20% (n = 9) in group 1 and 15.7% (n = 6)in group 2. The live birth rate was 40% (n = 26) in group I and 39.2. (n = 31) in group II. There were no statistically significant differences in pregnancy rates, clinical pregnancy losses, and live birth rates between the groups. Limitations, reasons for caution The limitation of the study is its retrospective nature. Wider implications of the findings The lack of any statistically significant differences in pregnancy outcomes in this study suggests the need for further evaluation of the value/effectiveness of GnRHa treatment in adenomyosis patients before embryo transfer cycles. Trial registration number not applicable

Maternal Perfluorinated Compound Exposure and Risk of Early Pregnancy Loss: A Nested Case-control Study

Maternal Perfluorinated Compound Exposure and Risk of Early Pregnancy Loss: A Nested Case-control Study

Low Endogenous LH on the COS Initiation Day of a GnRH-Agonist Regimen Increases the Risk of Early Pregnancy Loss and Adverse ART Outcomes.

ObjectiveTo assess the impact of serum luteinizing hormone (LH) levels on the day of initiation of controlled ovarian stimulation (COS) after pituitary suppression on early pregnancy loss and assisted reproductive technology (ART) outcomes.DesignRetrospective cohort study.SettingUniversity-affiliated hospital.PatientsA total of 9540 normogonadotrophic patients were treated with a GnRH agonist for in vitro fertilization (IVF). Based on the serum concentration of LH on the COS initiation day, patients were divided into low (<1 mIU/mL, n=2838), medium (1–1.49 mIU/mL, n=3357), or high (≥1.5 mIU/mL, n=3345) LH groups and received either fresh embryo transfer (ET) or frozen ET (women with high ovarian response, insufficient endometrial thickness, or requesting frozen ET). A total of 6279 cycles were fresh ET (1960, 2222, and 2097 in the low, medium, and high LH groups, respectively).Intervention(s)During IVF/ICSI, a GnRH agonist was used to suppress pituitary function in the midluteal phase or follicular phase, and then gonadotropin was used to induce COS.Main Outcome Measure(s)The early pregnancy loss rate (ePLR) and live-birth rate (LBR) for fresh ET, as well as the cumulative ePLR and LBR for the entire ovarian stimulation cycle, were compared.ResultsIn the fresh ET cycles, the high, medium and low LH groups had an ePLR of 8.6%, 11.9% and 12.5%, respectively, and LBR of 42.1%, 37.9% and 37.5%, respectively. There were no significant differences in terms of clinical pregnancy rate (CPR), late pregnancy loss rate (lPLR), and ectopic pregnancy rate (EPR) among the three LH groups. For the entire ovarian stimulation cycle, the high LH group had a greater number of retrieved oocytes compared with the low and medium LH groups. Among the groups of high, medium and low LH, the cumulative CPR were 72.8%, 69.8% and 68.8%, respectively, and the cumulative LBR were 63.4%, 60.4% and 58.5%, respectively. There were no significant differences in the cumulative ePLR, lPLR, or EPR. After multivariable logistic regression, compared with the high LH group, the adjusted odds ratio of early pregnancy loss in the low and medium LH group were 1.429 (1.065-1.919, P = 0.018) and 1.389 (1.041-1.853, P = 0.026).ConclusionsAfter pituitary suppression by a GnRH-agonist during IVF, a low LH level (<1.5 mIU/mL) on the COS initiation day was associated with adverse ART outcomes—including fewer oocytes, higher ePLR and lower LBR in fresh ET—and lower cumulative CPR and LBR in the entire ovarian-stimulation cycle. And LH on the COS initiation day was an independent factor affecting ePLR after multivariate regression.

Impact of endometrial preparation on early pregnancy loss and live birth rate after frozen embryo transfer: a large multicenter cohort study (14 421 frozen cycles).

STUDY QUESTIONDoes the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)?SUMMARY ANSWERIn FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC.WHAT IS KNOWN ALREADYTo date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population.STUDY DESIGN, SIZE, DURATIONA multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21–26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total.PARTICIPANTS/MATERIALS, SETTING, METHODSData were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG > 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another.MAIN RESULTS AND THE ROLE OF CHANCEAC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age >38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation >6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35–1.97]; P < 0.0001) and in AC vs SC (OR 1.87 [1.55–2.26]; P < 0.0001). The biochemical pregnancy rate (hCG > 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer.LIMITATIONS, REASONS FOR CAUTIONThis study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis.WIDER IMPLICATIONS OF THE FINDINGSOur study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses.STUDY FUNDING/COMPETING INTEREST(S)The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker’s fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker’s fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker’s fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d’A. declares Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics.TRIAL REGISTRATION NUMBERN/A.

Impact of Tobacco and Marijuana on Infertility and Early Reproductive Wastage.

Reducing exposure to tobacco and marijuana during preconception and early pregnancy is a critical area of intervention for obstetricians, gynecologists, and other reproductive health care professionals. Beyond the deleterious personal health effects, both substances have been extensively associated with short-term and long-term detrimental effects to gametogenesis, fecundity, as well as tissue level effects in the reproductive tracts. When tobacco and marijuana do not impair the ability to achieve pregnancy, an increasing body of literature suggests either may be associated with increased risk of early pregnancy loss and reproductive wastage. In this review, we will discuss what is known about how tobacco and marijuana affect the male and female reproductive systems and highlight how these consequences may impair attempts at successful conception and pregnancy continuation beyond the first trimester.