Incidence Of Pregnancy Loss Research Articles

P-672 Is there a sweet spot for follicular size and/or estradiol level for the initiation of micronized progesterone to optimize natural proliferative phase (NPP) cryo-cycle outcome?

Abstract Study question Is there an optimal follicular size and/or estradiol level for the initiation of micronized progesterone to optimize outcomes in NPP cycles potentially restricting scheduling flexibility? Summary answer All follicular sizes >12 mm and estradiol levels >120 pg./mL do not significantly correlate with ongoing pregnancy rates (OPR) or pregnancy loss (PL). What is known already Planning of a frozen embryo transfer (FET) is feasible within either a natural (NC) or artificial cycle (AC). While AC-FETs offer flexibility in planning, concerns have raised due to studies indicating a higher risk for obstetric complications. Conversely, NC-FETs show a protective effect against these complications but are usually less flexible in planning and ask for more monitoring. Recently, the natural proliferative phase (NPP) protocol was described, in which luteal phase support is initiated as soon as the endometrium reaches 7mm. NPP-FETs were associated with ongoing pregnancy rates comparable to AC- and NC-FETs. Study design, size, duration A retrospective single-centre study including a total of 300 consecutive single frozen embryo transfers (FET), performed at a tertiary fertility centre between March 2023 and December 2023. All cycles were single blastocyst transfer cycles retained from IVF/ICSI cycles with autologous oocytes. Participants/materials, setting, methods A total of 227 patients underwent one or more frozen embryo transfer cycles. Administration of MVP 800mg BID was initiated after fulfilling the following criteria: follicular size > 12mm, estradiol level ≥120ng/mL and endometrium thickness ≥7mm. Blastocyst transfers were scheduled on the fifth day of MVP administration. Serum progesterone (P4) levels were determined on the day of transfer. Associations between treatment outcome, patient and cycle characteristics were explored using generalized estimating equations analyses. Main results and the role of chance The follicular size and estradiol level on the day of MVP initiation was not significantly associated with pregnancy rate (PR), ongoing pregnancy rate (OPR) or pregnancy loss (PL) (p = 0.386 and p = 0.260; p = 0.830 and p = 0.467; p = 0.978 and p = 0.313 respectively). Mean number of visits needed prior to the initiation of the MVP for scheduling the embryo transfer was 2.4 (SD 1.3). PR, but not OPR, was significantly associated with both the duration of the follicular phase as well as the number of visits (p = 0.008 and p = 0.006 respectively). For 91.3 % (274/300) of patients, embryo transfer could be scheduled on a weekday. 49% (146/300) of patients had a positive hCG test after the fresh blastocyst transfer in the NPP cycle. Ongoing pregnancy rate was 35 % (104/300), whereas pregnancy loss (early clinical miscarriage and biochemical pregnancy) was 23% (33/146). The OPR was significantly related to the age of the patient (p = 0.029). Both the PR as the OPR were significantly related the blastocyst quality (p = 0.008 and 0.009 respectively). The incidence of pregnancy loss was only significantly associated with blastocyst quality (p = 0.027). Mean serum P4 level at day of transfer was 19.4 ng/ml (SD 6.1) with a P4 level above 10ng/ml in 97% of cycles. Limitations, reasons for caution The retrospective character is a limitation of this study as well as the absence of live birth rate as a clinical outcome variable. Wider implications of the findings Flexibility about the required follicular sizes and estradiol levels open the perspective for exploring more flexible planning criteria such as lower thresholds for endometrial thickness. Further studies are needed to investigate whether ovulation occurs with formation of functional corpora lutea to effectively protect against hypertensive disorders. Trial registration number ONZ-2024-0015

Discovery of Pathogenic Variants Associated with Idiopathic Recurrent Pregnancy Loss Using Whole-Exome Sequencing.

Idiopathic recurrent pregnancy loss (RPL) is defined as at least two pregnancy losses before 20 weeks of gestation. Approximately 5% of pregnant couples experience idiopathic RPL, which is a heterogeneous disease with various causes including hormonal, chromosomal, and intrauterine abnormalities. Although how pregnancy loss occurs is still unknown, numerous biological factors are associated with the incidence of pregnancy loss, including genetic variants. Whole-exome sequencing (WES) was conducted on blood samples from 56 Korean patients with RPL and 40 healthy controls. The WES data were aligned by means of bioinformatic analysis, and the detected variants were annotated using machine learning tools to predict the pathogenicity of protein alterations. Each indicated variant was confirmed using Sanger sequencing. A replication study was also conducted in 112 patients and 114 controls. The Variant Effect Scoring Tool, Combined Annotation Dependent Depletion tool, Sorting Intolerant from Tolerant annotation tool, and various databases detected 10 potential variants previously associated with spontaneous abortion genes in patients by means of a bioinformatic analysis of WES data. Several variants were detected in more than one patient. Interestingly, several of the detected genes were functionally clustered, including some with a secretory function (mucin 4; MUC4; rs200737893 G>A and hyaluronan-binding protein 2; HABP2; rs542838125 G>T), in which growth arrest-specific 2 Like 2 (GAS2L2; rs140842796 C>T) and dynamin 2 (DNM2; rs763894364 G>A) are functionally associated with cell protrusion and the cytoskeleton. ATP Binding Cassette Subfamily C Member 6 (ABCC6) was the only gene with two variants. HABP2 (rs542838125 G>T), MUC4 (rs200737893 G>A), and GAS2L2 (rs140842796 C>T) were detected in only the patient group in the replication study. The combination of WES and machine learning tools is a useful method to detect potential variants associated with RPL. Using bioinformatic tools, we found 10 potential variants in 9 genes. WES data from patients are needed to better understand the causes of RPL.

In vitro-produced equine blastocysts exhibit dispersed ICM cell allocation

Although in vitro production (IVP) of horse embryos has increased markedly in clinical practice, pregnancy rates after transfer are lower, and the incidence of pregnancy loss and monozygotic twins, higher than for in vivo-derived (IVD) embryos. Cell lineage specification is critical to normal early embryo development, and starts with differentiation of trophectoderm (TE) from inner cell mass (ICM) cells, followed by division of the ICM into primitive endoderm (PE) and epiblast (EPI). We examined the influence of developmental stage and speed, IVP and culture (in vivo versus in vitro) on expression of markers for the 3 early cell lineages, namely CDX-2 (TE), GATA-6 (PE) and SOX-2 (EPI). Day 7 IVD blastocysts (n=3 early; n=3 expanded), and IVP embryos identified as blastocysts on day 7 (n=5) or day 9 (n=9) were examined using confocal microscopy to compare total cell number, proportions and distribution of cells expressing CDX-2, GATA-6 and SOX-2. Additional day 7 IVP blastocysts were cultured for 2 days, either in vitro (n=5) or in vivo (after transfer into recipient mares; n=3), to examine the impact on subsequent development. Numerical data were analyzed using T- or Mann-Whitney U-tests. In IVD embryos, CDX-2 expression was exclusive to the TE, whereas SOX-2 expression was detected in both ICM and TE cells in early blastocysts but only thepresumed EPI in expanded blastocysts. GATA-6 was co-expressed with SOX-2 in outer ICM cells in early blastocysts but specific to PE cells lining the EPI and TE in expanded blastocysts. In IVP blastocysts, CDX-2 was also specific to the TE. However, SOX-2 and GATA-6 positive cells were intermingled in the ICM, and both SOX-2 and GATA-6 were co-expressed in TE cells. Strikingly, the EPI cells of IVP blastocysts were more dispersed, with larger mean inter-EPI cell distances (day 7 blastocysts, 52±6µm; day 9, 68±9µm), than in IVD embryos (35±3µm). Total cell number was higher in day 7 IVD (486±81) than IVP (day 7, 317±21; day 9, 377±104) blastocysts, but proportions of the different lineages didn't differ. Cell distribution in day 7 IVP embryos didn't change during an extra 2-day in vitro culture whereas, after 2 days in a mare's uterus, the SOX-2 (EPI) cells had aggregated and compacted, and segregated from PE cells. Overall, with respect to cell lineage allocation, IVP embryos resemble early IVD blastocysts in co-expressing SOX-2 and GATA-6 in TE cells, but differ by having a more dispersed ICM/EPI. While the EPI cells do compact following transfer to a recipient mare, the initial dispersal might contribute to both lower developmental competence (inadequate EPI aggregation) and a higher incidence of monozygotic twins (separated EPIs).

Granulocyte-macrophage colony-stimulating factor-containing medium treatment after thawing improves blastocyst-transfer outcomes in the frozen- thawed blastocyst-transfer cycle.

To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF)-containing medium could improve embryo-transfer outcomes in frozen-thawed blastocyst transfer. Patients who underwent frozen-thawed blastocyst transfer (430 women, aged 30-39years, 566 cycles) were analyzed. Frozen-thawed blastocysts were cultured in GM-CSF-containing medium or control medium for 3-5h, followed by transfer to the uterus. The embryo-transfer outcomes in the two groups were measured and compared, and a propensity score matching (1:1) method was used to balance the differences in baseline characteristics. We analyzed 213 matched samples. In patients who underwent frozen-thawed blastocyst transfer with GM-CSF, the percentage of human chorionic gonadotropin-positive cases, biochemical pregnancies, clinical pregnancies, ongoing pregnancies, and live birth rates was 60.6%, 7.98%, 52.6%, 42.9%, and 40.9%, respectively, as compared with 45.1%, 3.29%, 41.8%, 31.1%, and 30.5%, respectively, for the control groups. The rates of human chorionic gonadotropin positivity (odds ratio [OR]: 1.87, 95% confidence interval: [CI]: 1.27-2.75), biochemical pregnancy (2.55, 1.04-6.29), clinical pregnancy (1.54, 1.05-2.27), ongoing pregnancy (1.64, 1.13-2.41), and live birth (1.67, 1.14-2.45) were significantly higher in the GM-CSF group than the control group. The incidence of pregnancy loss (22.3% vs. 27.0%) did not significantly differ between the groups. The use of a GM-CSF-containing medium for blastocyst-recovery culture improved the live birth rate as a result of increased implantation rate in the frozen-thawed blastocyst-transfer cycle. The use of GM-CSF-containing medium following blastocyst thawing could be an effective choice for improving the blastocyst-transfer outcomes.

Incidence of pregnancy loss and characterization of fetal development in red pandas.

Previous reports indicate that red pandas (Ailurus fulgens styani) may experience fetal loss during gestation; however, neither the rate nor timing of pregnancy failure has been described in this species. The objective of this study was to utilize ultrasound video and images collected between 2010 and 2020 at the Cincinnati Zoo and Botanical Garden to better characterize pregnancy loss and fetal development. Trans-abdominal ultrasound examinations were performed on six female red pandas over a 10-year period, resulting in 12 profiles. Pregnancy was diagnosed via ultrasound in 10 of 12 profiles, and 40.0% of pregnancies showed evidence of fetal loss prior to parturition. Pregnancy loss was classified into lost (2 of 10; 20.0%), in which no cubs were produced, or partial loss (2 of 10; 20.0%), in which two concepti were visualized via ultrasound, but only one cub was born. Fetal loss occurred between days 51 and 23 pre-partum. Fetal growth characteristics were documented, including skeletal ossification (occurring between days 32 and 27 pre-partum), crown-rump length, head length, cranial length, and fetal heart rate (173–206 b.p.m.). These findings provide novel insights into pregnancy loss, may serve as a reference for milestones of fetal development, and may be useful in diagnosing pregnancy and assessing pregnancy loss in red pandas.Lay summaryFor many wildlife species, there is no non-invasive method of determining pregnancy; therefore, the rate of pregnancy loss oftentimes is unknown. Many red pandas in human care that are paired for breeding are observed exhibiting normal mating behaviors; however, only a relatively low proportion of females produce cubs. We utilized animals conditioned for ultrasound examination to diagnose pregnancy and characterize the incidence and timing of pregnancy loss. In total, 12 potential pregnancies were monitored, beginning after breeding season and ending ~2 weeks prior to anticipated cubbing. Of these, ten were (83.3%) were diagnosed as pregnant, with 40% undergoing either full or partial pregnancy loss. Fetal growth characteristics, such as body length and head size, are described which may be useful for monitoring pregnancies and estimating fetal age. Results of this study provide novel data on pregnancy loss in red pandas. Insights into the rate and timing of reproductive failure may illuminate causes and contributing factors, ultimately allowing for improvements in husbandry which may result in greater reproductive success of individuals recommended for breeding.

P–120 Selecting spermatozoa with the highest genomic integrity in order to enhance clinical outcomes in men with high DNA fragmentation levels

Abstract Study question What are the best methods of selecting spermatozoa with the highest genomic integrity in order to improve embryo implantation and term pregnancy rates with ICSI? Summary answer Testicular or ejaculate spermatozoa isolated by microfluidic sperm selection (MFSS) were characterized by superior genomic integrity with improved clinical pregnancy and delivery rates. What is known already In couples with unexplained infertility, a subtle male factor can often be identified. Both single-strand (ss) and double-strand (ds) DNA nicks and breaks hinder the ability of the male gamete to support embryonic development. Surgical retrieval of spermatozoa from the proximal male genital tract can prevent their exposure to oxidative stress. Moreover, use of membrane-based microfluidics chips has been shown to allow for selection of the most progressively motile spermatozoa with higher genomic integrity. Study design, size, duration Over the course of 48 months, 86 consenting men presenting with high sperm chromatin fragmentation (SCF) in their ejaculate with prior ART failure underwent a subsequent cycle with specimens retrieved by testicular biopsy or ejaculate processed by MFSS. A concurrent TUNEL assay was performed on samples collected or selected by each method. Sperm specimens of both origins were utilized for ICSI cycles. Semen parameters, chromatin integrity, and pregnancy outcomes were compared between the two methods. Participants/materials, setting, methods Fresh ejaculates from consenting men were collected for standard semen analysis (WHO 2010). Testicular biopsy and MFSS were used to isolate spermatozoa with a higher genomic integrity after previous ART failure. SCF was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) on at least 500 spermatozoa under a fluorescent microscope with a threshold of ≥ 15%. MFSS was carried out by Zymot® chips. ICSI was performed in the standard fashion. Main results and the role of chance A total of 86 men (36.5±5 years) had the following semen parameters: volume of 2.6 ±1mL, concentration of 27.0±33 x 106/mL, 35.6±15% motility, and high SCF (24.1±10%). They underwent 146 ICSI cycles with their partners (maternal age, 33.7±3) resulting in a high incidence of pregnancy loss (100%; 13/13). Of those who failed to conceive, 22 couples used surgically retrieved spermatozoa (SRS) with a concentration of 1.8 ± 4 x 106/mL (P < 0.01), 5.0±11% motility (P < 0.01), and an SCF of 12.6 ± 6% (P < 0.0001). SRS was used in 37 ICSI cycles, yielding a fertilization rate of 61.6% (204/331, P < 0.01), an implantation rate of 10.6% (9/85, P < 0.01), a CPR of 23.5% (8/34, P < 0.01), and a delivery rate of 17.6% (6/34, P < 0.01). Another 24 couples underwent ICSI cycles with ejaculated spermatozoa processed by MFSS with a concentration of 1.8±3 x 106/mL (P < 0.01), but an increased motility of 99±1% (P < 0.01) and an SCF of 1.2 ±1%, lower than both the raw and testicular specimens (P < 0.0001). MFSS-processed specimens resulted in a fertilization rate of 76% (335/441, P < 0.01), an implantation rate of 26.3% (15/57, P < 0.05), and a CPR of 67.9% (19/28, P < 0.01), of which 15 patients delivered and 2 pregnancies are ongoing (89.5%; P < 0.01). Limitations, reasons for caution This is a preliminary study on a small number of subjects. A randomized prospective study conducted on a larger cohort would be required to confirm our findings. Wider implications of the findings: SCF severely affects pregnancy by impairing embryonic development, consequently promoting implantation failure. While retrieving spermatozoa from the germinal epithelium is a viable option, MFSS provides an alternative. Although MFSS requires an adequate number of sperm with good kinetic characteristics, it provides a more palatable option, reducing surgical risk and costs. Trial registration number Not applicable

Educational Program for Pregnant Women Regarding Obstetrics Dangerous Signs in Rural Areas

Background: Complications linked to postpartum & pregnancy are one of the major causes of female death. In order to understand the causes of complications and encourage women to take sufficient action in order to receive emergency treatment, a critical step should therefore be taken to minimize complications related to pregnancy, in order to ensure the safety of both women and newborns. Aim of the work: Evaluate the effectiveness of the education programs for pregnant women on obstetric danger signs in rural areas and help minimize the incidence of pregnancy loss and comorbidities. Methods: A quasi-experimental design on 70 women from a population of through 372 women in six-month in antenatal clinics recruited from the previously mentioned settings with pre- and post-test was conducted at antenatal clinics (M.C.H centers) affiliated to the available geographical health zones in EL-fayoum rural area including: Al-sheikh hassan at sanorse. We collected the data of women characteristics by a self-administered interview questionnaire & a structured reported knowledge and practices checklist to evaluate pregnant women practices and knowledge. Follow up was done to the studied groups & histopathology assessments of the product of conception in cases of abortion secondary to the complications to compare between effect of antenatal care program on the woman who followed the program and those who did not. Results: There is an improvement in 63% of pregnant women knowledge and practices after educational program in all aspects. The most common danger signs that may occur during pregnancy were miscarriage and vaginal bleeding, intrauterine fetal death as reported by women & confirmed by the histopathology reports. Conclusion: The educational program had an efficient improving women knowledge and practice regarding danger signs for pregnant women in rural areas, with highly statically significant differences in all the tested items between pre/post program implementation (P 0.001). Recommendations: Establishment of in-service training programs and continuous supervision in rural areas to a raise women knowledge and practice regarding educational pregnant women and developing antenatal classes for all pregnant women about obstetric danger signs.

Urinary selective serotonin reuptake inhibitors across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss

To prospectively investigate the association of selective serotonin reuptake inhibitor (SSRI) exposure through critical windows of pregnancy establishment with fecundability and pregnancy loss. Prospective cohort study using longitudinal urine measurements of common SSRIs while women are actively trying to conceive. Four clinical sites. A total of 1,228 women without uncontrolled depression/anxiety, attempting natural conception while participating in a randomized trial of preconception-initiated low-dose aspirin. Not applicable. Urinary SSRIs (fluoxetine, sertraline, escitalopram/citalopram) were measured while trying to conceive and, for women who became pregnant, at weeks 0, 4, and 8 of pregnancy. Fecundability odds ratios and incidence of pregnancy loss and live birth were estimated. A total of 172 women (14%) were exposed to SSRIs while trying to conceive. SSRI exposure was associated with 24% reduced fecundability, and accordingly, a nonsignificant 9% lower live birth incidence, with significantly lower live birth in fluoxetine-exposed women. SSRI exposure was not associated with subsequent pregnancy loss, whether exposure was before conception or at 0, 4, or 8 weeks of gestation, although estimates varied by specific SSRI drug. Women using SSRIs may have more difficulty becoming pregnant, and although SSRI exposure overall was not associated with pregnancy loss, fluoxetine deserves caution and future study. NCT00467363.

Ambient air pollution and risk of pregnancy loss among women undergoing assisted reproduction

Accumulating evidence suggests that air pollution increases pregnancy loss; however, most previous studies have focused on case identification from medical records, which may underrepresent early pregnancy losses. Our objective was to investigate the association between acute and chronic exposure to ambient air pollution and time to pregnancy loss among women undergoing assisted reproductive technologies (ART) who are closely followed throughout early pregnancy. We included 275 women (345 human chorionic gonadotropin (hCG)-confirmed pregnancies) undergoing ART at a New England academic fertility center. We estimated daily nitrogen dioxide (NO2), ozone (O3), fine particulate matter <2.5 μm (PM2.5), and black carbon (BC) exposures using validated spatiotemporal models estimated from first positive hCG test until day of failure or live birth. Air pollution exposures were averaged over the past week and the whole pregnancy. Multivariable Cox proportional hazards models were used to estimate the hazards ratio (HR) for pregnancy loss for an interquartile range (IQR) increase in pollutant exposure. We tested for violation of proportional hazards by considering an interaction between time (in days) since positive hCG (<30 days vs. ≥30 days) and air pollution. The incidence of pregnancy loss was 29 per 100 confirmed pregnancies (n = 99). Among pregnancies not resulting in live birth, the median (IQR) time to loss was 21 (11, 30) days following positive hCG. Average past week exposures to NO2, O3, PM2.5, and BC were not associated with time to pregnancy loss. Exposure throughout pregnancy to NO2 was not associated with pregnancy loss; however, there was a statistically significant interaction with time (p-for-interaction<0.001). Specifically, an IQR increase in exposure to NO2 was positively associated with pregnancy loss after 30 days (HR = 1.34, 95% CI: 1.13, 1.58), but not in the first 30 days after positive hCG (HR = 0.83, 95% CI: 0.57, 1.20). Overall pregnancy exposure to O3, PM2.5, and BC were not associated with pregnancy loss regardless of timing. Models evaluating joint effects of all pollutants yielded similar findings. In conclusion, acute and chronic exposure to NO2, O3, PM2.5, and BC were not associated with risk of pregnancy loss; however, higher exposure to NO2 throughout pregnancy was associated with increased risk of loss 30 days after positive hCG. In this cohort, later pregnancy losses appeared more susceptible to the detrimental effects of air pollution exposure.

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.

Ambient Air Pollution and Risk of Pregnancy Loss among Women Undergoing Assisted Reproduction

TPS 742: Adverse birth outcomes 1, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: Accumulating evidence suggests that air pollution increases pregnancy loss; however, most previous studies have focused on spontaneous pregnancies where the date of conception and implantation is unknown. Methods: We included 275 women (345 human chorionic gonadotropin (hCG)-confirmed pregnancies) undergoing assisted reproduction at a New England fertility center. We estimated daily nitrogen dioxide (NO2), ozone (O3), fine particulate matter <2.5 µm (PM2.5), and black carbon (BC) exposures using validated spatiotemporal models from first positive hCG test until day of failure or live birth. Air pollution exposures were averaged over the past week and the whole pregnancy. Adjusted Cox proportional hazards models were used to model time to pregnancy loss (post-implantation days) to estimate hazard ratios (HRs) corresponding to an interquartile range (IQR) increase in pollutant concentration. We tested for violation of proportional hazards by considering an interaction between post-implantation days (<30 days vs. ≥30 days) and air pollution. Results: The incidence of pregnancy loss was 29% (n=99) with a median (IQR) time to loss of 21 (11, 30) days post-implantation. Average past week exposures to NO2, O3, PM2.5, and BC were not associated with time to pregnancy loss. Overall pregnancy exposure to NO2 was not associated with pregnancy loss; however, there was a statistically significant interaction with time (p-for-interaction=0.01). Specifically, an IQR increase in exposure to NO2 was positively associated with pregnancy loss after 30 days (HR=1.23, 95% CI: 1.09, 1.41), but not in the first 30 days post-implantation (HR=0.84, 95% CI: 0.66, 1.08). Overall pregnancy exposure to O3, PM2.5, and BC were not associated with pregnancy loss regardless of timing. Models evaluating joint effects of all pollutants yielded similar findings. Conclusion: Higher exposure to NO2 during pregnancy was associated with increased risk of pregnancy loss after 30 days post-implantation. Timing of exposure to pregnancy loss is important to consider.

Cannabis sativa and pregnancy: a review

Cannabis sativa, ou maconha, é a droga de abuso mais utilizada durante a gravidez. A gravidez é um período em que ocorrem mudanças fisiológicas consideráveis na mãe e, como resultado dessas mudanças, o feto pode ser diretamente afetado. A droga apresenta em sua composição uma gama de compostos químicos considerados medicinais ou psicoativos, os canabinoides. Um dos mais conhecidos é o tetrahidrocanabinol (Δ9-THC), componente psicoativo capaz de atravessar a barreira placentária, atingindo o feto em desenvolvimento. O uso crônico de C. sativa na gravidez pode resultar em diminuição da perfusão uteroplacentária, restrição do crescimento intra-uterino (RCIU) e distúrbios comportamentais nos fetos. Os canabinoides podem causar alguns distúrbios nos órgãos reprodutores dos usuários até atingir o feto. Em um estudo, 4.000 gestantes usuárias da droga apresentaram aumento na incidência de perdas gestacionais, conceptos com baixo peso e pequenos para a idade gestacional. Além do baixo peso nos neonatos, a droga aumenta o risco de complicações durante o parto e um desenvolvimento cognitivo tardio nos lactentes. Muitas controvérsias giram em torno do tema C. sativa e seus efeitos sobre a saúde, sendo necessário abranger a discussão de políticas públicas sobre a liberação do uso de drogas ilícitas levando em consideração evidências científicas.

Safety of a bivalent, killed, whole-cell oral cholera vaccine in pregnant women in Bangladesh: evidence from a randomized placebo-controlled trial

BackgroundCholera increases the risk of harmful effects on foetuses. We prospectively followed pregnant women unaware of their pregnancy status who received a study agent in a clinical trial evaluating the association between exposure to an oral cholera vaccine (OCV) and foetal survival.MethodsStudy participants were selected from a randomized placebo-controlled trial conducted in Dhaka, Bangladesh. The vaccination campaign was conducted between January 10 and February 4, 2014. We enrolled women who were exposed to an OCV or placebo during pregnancy (Cohort 1) and women who were pregnant after the vaccination was completed (Cohort 2). Our primary endpoint was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were preterm delivery and low birth weight. We employed a log-binomial regression to calculate the relative risk of having adverse outcomes among OCV recipients compared to that among placebo recipients.ResultThere were 231 OCV and 234 placebo recipients in Cohort 1 and 277 OCV and 299 placebo recipients in Cohort 2. In Cohort 1, the incidence of pregnancy loss was 113/1000 and 115/1000 among OCV and placebo recipients, respectively. The adjusted relative risk for pregnancy loss was 0.97 (95% CI: 0.58–1.61; p = 0.91) in Cohort 1. We did not observe any variation in the risk of pregnancy loss between the two cohorts. The risks for preterm delivery and low birth weight were not significantly different between the groups in both cohorts.ConclusionsOur study provides additional evidence that exposure to an OCV during pregnancy does not increase the risk of pregnancy loss, preterm delivery, or low birth weight, suggesting that pregnant women in cholera-affected regions should not be excluded in a mass vaccination campaign.Trial registrationThe study is registered at (http://clinicaltrials.gov). Identifier: NCT02027207.

Whether poor responses have worse perinatal prognosis (retrospective analysis of assisted reproductive technologies cycle)

The prevalence of poor ovarian response is 5.6–35.1% in women undergoing controlled ovarian stimulation in ART cycles. The frequency of delivery of poor responders after ART is on average from 9.9% to 23.8%. In clinical practice, the vast majority of poor responders are older women, which may have an effect on perinatal outcomes, respectively. Although numerous studies have reported that the fertility rate after ART in women of this age group is quite low, data on perinatal outcomes in this group of women is limited. Therefore, the aim of our study was to retrospectively analyze and compare perinatal outcomes in women with poor ovarian response to stimulation compared to control group (normal response to stimulation) in assisted reproductive technology programs. 278 women with infertility with a reduced response to stimulation (poor responders), who were the main group, were screened. Indications for the inclusion of women in the main group were the presence of at least two of the following criteria for a poor ovarian response according to the 2011 Bologna criteria and 93 infertile patients with a normal ovarian response to stimulation of the control group. Subsequently, retrospective study of perinatal effects such as preterm labor, low birth weight, gestational diabetes, preeclampsia in 50 women with infertility with reduced response to stimulation and 37 controls with normal response to stimulation in which pregnancy was diagnosed was performed. Variational-statistical processing of the results of the study was performed using the program “Statistica 6.0”. The study demonstrated a significantly lower pregnancy rate in poor responders compared with women from the control group — 50 (17.9%) vs. 37 (39.8%), respectively. Perinatal outcome were similar only to the statistically significant difference in the percentage of spontaneous abortions before 12 weeks of gestation — 9 (18%) vs. 4 (10.8%), respectively, in groups with no significant difference in the preterm labor frequency — 10 (20.8%) and 6 (18.1%) of the low weight of the child at birth — 9 (18.7%) versus 5 (15.1%), respectively, in poor responders patients and in women with normal ovarian response. The frequency of complications such as gestational diabetes and high blood pressure were not significantly different in both clinical groups — 3 (6.25%) versus 2 (6.1%) and 5 (10.4%) versus 3 (9.1%) respectively. Thus, he poor responders in ART programs have a significantly lower pregnancy rate and a higher incidence of pregnancy loss up to 12 weeks compared with women who had a normal response to ovarian stimulation without a significant difference in the rates of various complications of pregnancy and perinatal outcomes. Wide randomized multicentric trials are needed to find out the causal relationships with regard to the effect on pregnancy, miscarriage, perinatal effects of controlled ovarian stimulation regimens, embryotransfers in fresh or cryo cycles etc.

Repeated Measures of Urinary Phthalates, Benzophenones and Bisphenol A in Relation to Incident Pregnancy Loss

Background: Studies suggest nonpersistent endocrine disrupting chemicals such as phthalates, benzophenones and bisphenols may be associated with diminished fecundability, but little research has focused on their association with incident pregnancy loss.Methods: Using a prospective cohort design, 501 couples were recruited upon discontinuing contraception to try for pregnancy and followed daily until pregnant and through 7 weeks post-conception; 343 (68%) women with singleton pregnancies comprise the study cohort. Urine samples were collected upon enrollment (n&amp;#61;315; 92%), in the second (n&amp;#61;200), third (n&amp;#61;206), fourth (n&amp;#61;32) and sixth cycles (n&amp;#61;10). Bisphenols A, 5 benzophenones, and 13 phthalate metabolites were quantified using LC tandem MS. Generalized estimating equations estimated the relative risk (RR) of incident pregnancy loss for each chemical. Exposures were treated as continuous (log&amp;#43;1 transformed rescaled by standard deviation) and categorical (tertiles), adjusting for body mass index, race, serum cotinine, and age. Results: Incidence of pregnancy loss was 28% before 20 weeks&amp;#8217; gestation. Lower risk of loss was noted for mOP (RR&amp;#61;0.69; 95% CI 0.54, 0.88), while mEHHP and mEOHP were suggestive of higher risk of loss. Relative to the first tertile, a higher risk of loss was observed for 2 benzophenones, for women in the second tertiles of BP-1 (RR&amp;#61;3.44; 95% CI 1.69, 7.01) and BP-3 (RR&amp;#61;2.02; 95% CI 1.02, 3.97), whereas a lower risk was observed for 4-OH-BP (RR&amp;#61;0.28; 95% CI 0.15, 0.53) and also for 2 phthalate metabolites: mCPP for 3rd vs. 1st (RR&amp;#61;0.35; 95% CI 0.13, 0.93) and mBP for 2nd vs. 1st (RR&amp;#61;0.45; 95% CI 0.23, 0.91).Conclusion: Benzophenones, as a class of chemicals, were suggestive of a possible association with pregnancy loss, and specifically BP- 1 and BP-3, which are believed to have estrogenic activity. Given their widespread use in personal care and sunscreen products and opposing pattern for 4-OH-BP, further investigation is needed.

Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell-mediated pregnancy loss in mice.

Tokishakuyakusan (TSS) is a traditional herbal medicine that has been used empirically to prevent recurrent pregnancy loss. Its mode of action remains unclear. With their potent capacity to produce cytokines, invariant natural killer (iNKT) cells are involved in the control of fetomaternal immunity in early gestation. This study aimed to clarify the effect of TSS on iNKT cell activities in a well-studied murine miscarriage model. Pregnant mice were fed 1% TSS-containing or control diet from the day of vaginal plug formation. Alpha-galactosylceramide (AGC) was administered intraperitoneally to the pregnant mice at day 9.5 postcoitus (pc) to stimulate iNKT cells. Peripheral cytokine levels were evaluated using cytokine arrays. The percentage of iNKT cells among splenocytes was examined by flow cytometric analysis. The incidence of pregnancy loss was assessed at day 12.5 pc. The ratio of fetal resorptions to total conceptuses was significantly higher in the group exposed to TSS (34%) than in controls (78%). A rapid and robust surge in inflammatory cytokines, including IFN-γ and TNF-α, was detected in the peripheral blood of control animals 2hours after AGC administration. This peripheral cytokine induction was significantly attenuated in the TSS-fed group compared with the control. The percentage of iNKT cells among total splenocytes was lower in the TSS-fed group than in controls. The findings in this study suggest that the inhibitory effects of TSS on pregnancy loss may involve immune modulation of iNKT cells during early pregnancy.

High serum IGF-1 levels are associated with pregnancy loss following frozen-thawed euploid embryo transfer cycles

An elevated level of insulin growth factor (IGF-1) in rat uterine fluid has been shown to exert detrimental effects of embryo development possibly leading to an increase in pregnancy loss. Interestingly, the administration of somatostatin to rats undergoing superovulation reduced IGF-1 levels in uterine luminal fluid and thus reversed its deleterious effects on embryo development and increased the number of normal embryos. Therefore, we investigated whether serum levels of IGF-1 correlate with the incidence of pregnancy loss following IVF. To account for aneuploidy and the effect of hormonal supplementation on serum IGF levels, we only included natural frozen-thawed euploid embryo transfer (N-FET) cycles. Sera collected in the follicular phase (cycle day 10) were tested for levels of IGF-1, IGF-2, and IGF-binding protein 1 (IGFBP-1) using quantitative ELISA. A total of 156 N-FET cycles were included: 120 resulted in a live birth whereas 36 led to a first trimester pregnancy loss. Women with a pregnancy loss had significantly higher serum IGF-1 levels compared to those who achieved a live birth (18.0 ± 1.1 vs. 14.6 ± 0.7 ng/mL, respectively). The two groups had comparable serum IGF-2 and IGFBP-1 levels. There was no significant difference in maternal age, body mass index, gravidity, parity, number of prior miscarriages, peak endometrial thickness, or infertility diagnosis between the two groups. In conclusion, women undergoing euploid blastocyst transfer with elevated serum IGF-1 concentrations may be at increased risk of pregnancy loss. This may constitute a novel molecular explanation of pregnancy loss of euploid conceptus.

Biomarkers of preconception stress and the incidence of pregnancy loss.

Are biomarkers of preconception stress associated with pregnancy loss? Preconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss. Many studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage. A prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis. Couples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider. Among the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders. Our prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen's Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women. In one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare. Not applicable.

Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice.

This study aimed to investigate the association of Th1/Th2 polarity induced by CD1d-restricted invariant natural killer T (iNKT) cells with pregnancy outcome. Two types of iNKT cell stimulants with different cytokine induction properties, alpha-galactosylceramide (AGC; Th1-biased inducer), and a sphingosine-truncated derivative of AGC (OCH; Th2-biased inducer) were administered to pregnant mice on day 9.5 post-coitus (pc), and the incidence of pregnancy loss was evaluated. Serum Th1/Th2 cytokine levels after the iNKT cell stimulations were assessed. Cytokine production from cultured splenocytes following iNKT cell activation was analyzed. No fetal loss was observed after OCH administration, in clear contrast with the high frequency of pregnancy loss after AGC exposure. High serum levels of IL-4 and IL-10 were detected upon OCH administration, whereas a temporary surge of IFN-γ was observed after AGC administration. In splenocyte cultures, increases in IL-4 and IL-10 were noted after OCH administration, whereas IL-12 production was enhanced by AGC. Additionally, AGC-induced pregnancy loss was inhibited by IL-4 administration. The resistance of mouse pregnancy to iNKT cell stimulation by OCH and the prevention of AGC-induced fetal loss by IL-4 were demonstrated. In pregnancy, the regulation of Th1/Th2 polarity by iNKT cells is a key to healthy fetal growth.

Difference between mean gestational sac diameter and crown-rump length as a marker of first-trimester pregnancy loss after in vitro fertilization

To investigate whether the difference between mean gestational sac diameter and crown-rump length (mGSD - CRL) is associated with first-trimester pregnancy loss or adverse pregnancy outcomes after invitro fertilization (IVF) and to determine if mGSD - CRL is a better predictor of pregnancy loss than either measurement alone. Retrospective cohort study. University hospital. A total of 1,243 IVF cycles with fresh or cryopreserved autologous embryo transfers resulting in singleton gestations performed at the University of Iowa Hospitals and Clinics from January 2005 through December 2014. Cycles included ultrasound measurements of mGSD and CRL at 45-56days' gestation. Mean gestational sac diameter to crown-rump length difference. Primary outcomes were first-trimester pregnancy loss and gestational age at delivery. Secondary outcomes were infant birth weight and pregnancy complications. First-trimester pregnancy loss rates were significantly higher in pregnancies with mGSD - CRL <5mm (43.7%) compared with 5-9.99mm (15.8%), 10-14.99mm (9.9%), and ≥15mm (7.1%). No correlations were found with infant birth weight, gestational age at delivery, or other pregnancy complications. mGSD - CRL was not a better predictor of pregnancy loss than mGSD or CRL alone. There is a strong inverse relationship between mGSD - CRL and first-trimester pregnancy loss in IVF patients, although the incidence of pregnancy loss with a mGSD - CRL <5mm was significantly lower than previously reported. Small mGSD - CRL was not associated with an increased risk of complications in pregnancies that continued beyond 20weeks. The association between mGSD, CRL, and miscarriage is complex.