Preclinical Pregnancy Loss Research Articles

Effect of vaginal flora on clinical outcome of frozen embryo transfer.

Vaginal microbiota imbalance is a high risk factor for premature birth, and is closely related to female pelvic inflammation and sexually transmitted diseases. The effect of vaginal microbiota on the outcome of assisted reproductive technology is still unclear. In this study, the vaginal microbial composition and the pregnancy outcome of frozen embryo transfer (FET) was investigated. From October 2020 to December 2021, 275 FET cycles were selected from the center of reproductive medicine in Affiliated Hospital of Nantong University. Vaginal secretions were collected on the day of endometrium transformation, and smears were Gram stained. According to the Nugent score they were divided into three groups, including normal group, mild dysbiosis group and sever dysbiosis group. The clinical outcomes of each group were compared. In 275 FET cycles, the embryo implantation rate, clinical pregnancy rate and ongoing pregnancy rate in the normal group (66.9%,84.3% and 83.1%) were significantly higher than those in the mild dysbiosis group (45.5%, 57.3% and 49.3%) and in sever dysbiosis group (29.6%, 34.2% and 27%). The difference was statistically significant (P<0.01). When compared the preclinical pregnancy loss rate and the miscarriage rate, the normal group (1.3% and 1.3%) was significantly lower than those in the mild dysbiosis group (20.4% and 14.0%) and the sever dysbiosis group (25.5% and 21.1%). The difference was statistically significant (P<0.01), but there was no significant difference between the mild dysbiosis group and sever dysbiosis group (P>0.05). Nugent score is directly related to the clinical outcome of FET. The Lactobacilli-dominant vaginal flora was a favorable factor for the good clinical outcome of FET, while asymptomatic bacterial vaginosis had a negative correlation with the outcome of FET.

Non-Lactobacillus dominance of the vagina is associated with reduced live birth rate following IVF/ICSI: a propensity score-matched cohort study.

Whether the dominant status of vaginal Lactobacillus is associated with IVF/ICSI outcomes. This is a propensity score-matched retrospective cohort study consists of 2285 women undergoing their first fresh autologous IVF cycles. We divided the patients into the Lactobacillus-dominant group and non-Lactobacillus-dominant group based on the abundance of Lactobacillus in Gram-stained vaginal smear examined by microscopy. We compared IVF outcomes between the two groups. We matched Lactobacillus-dominant women with non-Lactobacillus-dominant women by propensity score (PS) to reduce the impact of confounding factors. We evaluated the effect of vaginal Lactobacillus on live birth using univariate and multivariate analysis models. We also conducted interaction and stratified analyses. Compare to the Lactobacillus-dominant group, the biochemical pregnancy rate (50.12% vs. 57.61%, P = 0.03), clinical pregnancy rate (40.98% vs. 50.82%, P < 0.01), and live birth rate (31.83% vs. 41.22%, P < 0.01) were significantly lower in the non-Lactobacillus-dominant group, the preclinical pregnancy loss rate (18.22% vs. 11.79%, P = 0.05) and preterm birth rate (33.09% vs. 21.59%, P = 0.02) were significantly higher in the non-Lactobacillus-dominant group. However, the miscarriage rate (18.86% vs. 15.67%, P = 0.40) and ectopic pregnancy rate (1.41% vs.1.64%, P = 0.78) were similar between the two groups. Loss dominance of Lactobacillus in the vagina was an independent risk factor for live birth (OR 0.66, 95% CI 0.50-0.88). Loss dominance of Lactobacillus in the vagina negatively affects IVF outcomes by decreasing the chances of pregnancy and live birth, increasing risks of preclinical pregnancy loss and preterm birth.

Is SARS-CoV-2 Infection a Risk Factor for Early Pregnancy Loss? ACE2 and TMPRSS2 Coexpression and Persistent Replicative Infection in Primitive Trophoblast.

BackgroundSARS-CoV-2 infection in term placenta is rare. However, growing evidence suggests that susceptibility of the human placenta to infection may vary by gestational age and pathogen. For several viral infections, susceptibility appears to be greatest during early gestation. Peri-implantation placental infections that result in pre-clinical pregnancy loss would typically go undetected. Little is known about the effects of SARS-CoV-2 on the peri-implantation human placenta since this time in pregnancy can only be modeled in vitro.MethodsWe used a human embryonic stem cell (hESC)-derived model of peri-implantation placental development to assess patterns of ACE2 and TMPRSS2 transcription and protein expression in primitive trophoblast. We then infected the same trophoblast cell model with a clinical isolate of SARS-CoV-2 and documented infection dynamics.ResultsACE2 and TMPRSS2 were transcribed and translated in hESC-derived trophoblast, with preferential expression in syncytialized cells. These same cells supported replicative and persistent infection by SARS-CoV-2, while non-syncytialized trophoblast cells in the same cultures did not.ConclusionsCo-expression of ACE2 and TMPRSS2 in hESC-derived trophoblast and the robust and replicative infection limited to syncytiotrophoblast equivalents support the hypothesis that increased viral susceptibility may be a defining characteristic of primitive trophoblast.

Unresolved problem of modern obstetrics: The problem of addicted missing of pregnancy

According to the definition of the World Health Organization, spontaneous miscarriage (abortion) is understood as spontaneous expulsion of an embryo or fetus weighing up to 500 g from the uterine cavity within 22 weeks of pregnancy [4;17]. A habitual miscarriage is considered to be a woman's history of 3 or more spontaneous abortions up to 22 weeks in a row. Spontaneous miscarriage (SPV) is the most common complication of early pregnancy, with an incidence ranging from 8 to 20%. Up to 80% of miscarriages occur in the first 12 weeks of pregnancy [2]. After 15 weeks, the overall risk of PWV is 0.6%, provided the fetus has a normal karyotype [13]. Preclinical termination of pregnancy occurs even more often and reaches 26% [10]. In 2003, the study confirmed that in the population the frequency of preclinical pregnancy loss is 26%, and after confirmation of pregnancy - 8% [12]. According to the timing of occurrence, an early spontaneous abortion is distinguished - up to 12 weeks and a late spontaneous abortion - from 12 to 22 weeks of pregnancy. ICD 10 structures SPV into: O03 Spontaneous abortion; O02.1 Failed miscarriage; O20.0 Threatened abortion; N96 Habitual miscarriage and O26.2 Medical care for a woman with recurrent miscarriage. A literature review is devoted to the problem of early pregnancy loss. The modern classification is presented, the issues of the etiology and pathogenesis of this complication, the criteria for diagnosis and differential diagnosis, as well as the standards of therapy and the possibilities of prevention are highlighted.

P1.027 Risks Associated with Bacterial Vaginosis in Infertility Patients: A Systematic Review and Meta-Analysis

BackgroundSeveral studies have shown that bacterial vaginosis (BV) is particularly prevalent in patients with infertility, though it has not been firmly established which risks infertility patients with BV incur for...

Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis

Is bacterial vaginosis (BV) associated with the cause of infertility and does BV impinge on conception rates and early pregnancy loss following IVF? The incidence of BV is significantly higher among patients with tubal infertility when compared with patients with non-tubal infertility. BV does not impinge on conception rates but is significantly associated with preclinical pregnancy loss, though not with first trimester abortion. BV is prevalent in patients with infertility, as evident from studies across the world. This study is a meta-analysis of data on the prevalence of BV in women with infertility, the association between BV and the cause of infertility, and the associations between BV and conception rates and early pregnancy loss following IVF. The meta-analyses of the various topics involved different numbers of studies: prevalence of BV with infertility--12 studies, association with tubal infertility--3 studies and associations with conception rates--6 studies, with early preclinical pregnancy loss--2 studies and with clinical pregnancy loss--4 studies. Systematic literature searches of the electronic databases, PubMed, EMBASE, CINAHL, the Cochrane Library and ISI Web of Knowledge were performed up to September 2012. Studies were included if they reported on, at least, one of the following: prevalence of BV in infertility patients, association between BV and the cause of infertility, association between BV and conception rates with IVF or association between BV and early pregnancy loss. Studies were considered eligible if BV was diagnosed through standardized criteria like Nugent's criteria or Hay-Ison's criteria. In none of the studies, infertility as such was defined, but patients were described as unselected patients undergoing IVF. The estimated prevalence of BV (Nugent score >6) in infertile women is 19% [95% confidence interval (CI): 14-25%]. Abnormal microflora including BV and intermediate microflora (Nugent scores 4-10) occurs in 39% of the infertile patients (95% CI: 26-52%). BV is significantly more prevalent in women with infertility compared with antenatal women in the same population [OR (odds ratio) 3.32, 95% CI 1.53-7.20]. BV is significantly more prevalent in women with tubal infertility compared with women with other causes of infertility (OR 2.77, 95% CI 1.62-4.75). BV is not associated with decreased conception rates (OR 1.03, 95% CI 0.79-1.33). Similarly, none of the studies found an association between abnormal vaginal flora and conception rates following IVF treatment. BV is associated with a significantly elevated risk of preclinical pregnancy loss (OR 2.36, 95% CI: 1.24-4.51). BV is not associated with an increased risk of first trimester miscarriage (OR 1.20, 95%CI: 0.53-2.75). All included studies were centre based. In addition, publication bias cannot be ruled out. Furthermore, all estimates are obtained using an absolute minimum of studies. The standard error on the estimates is so large that it does not allow for any formal statistical conclusions regarding heterogeneity between the effects reported in different studies. It needs to be recognized that most inferences drawn in our study rely on a limited number of studies, potentially, endangering the generalizability of our findings. Moreover, all studies on cause of infertility in relation to BV included had a cross-sectional design and, therefore, do not allow for causal inferences. Still, there is strong circumstantial evidence that supports a causal link between BV and tubal infertility. Studies with a longitudinal design, on the other hand, strongly support a relation between BV and early pregnancy loss. Unfortunately, no study looked beyond first trimester fetal loss, although it is plausible that the high preterm birth rates with IVF are, at least, in part attributable to BV.

Recurrent pre-clinical pregnancy loss is unlikely to be a 'cause' of unexplained infertility

A proportion of women with 'unexplained' infertility may present with subfertility because their pregnancies fail before they are clinically recognized. In order to test whether pre-clinical early pregnancy losses (EPL) occur more frequently in women with unexplained infertility, serial urinary hCG concentrations were measured to compare EPL per cycle rates following spontaneous conception in patients with unexplained infertility versus healthy volunteers. Sixty patients under 39 years of age with unexplained infertility and 60 healthy controls, who were trying to conceive spontaneously, participated in this study. All participants were asked to collect daily urine samples from cycle day 14 until menstruation for three consecutive cycles or until a positive pregnancy test was obtained. Urinary hCG and creatinine levels were measured by immunoassay. Implantation was detected when urinary hCG levels rose above reference levels constructed from samples obtained from 12 women not attempting to conceive. EPL rates were determined by a linear mixed model using logarithmically transformed hCG/creatinine data. In the 133 cycles of 60 women with unexplained infertility, just one implantation was detected, which became an ongoing pregnancy. In contrast, in 103 such cycles in 46 control patients, 30 implantations were detected (24 clinical pregnancies, 6 cases of EPL). The odds ratio for EPL/cycle in the unexplained versus control group was 0 (95% confidence interval: 0-0.795, P = 0.026). Our data do not support the hypothesis that recurrent EPL may present as unexplained infertility. Post-implantation failure is therefore unlikely to contribute significantly to the presentation of subfertility.

Reduced plasma fibrinolytic potential in patients with recurrent implantation failure after IVF and embryo transfer

Recurrent implantation failure (RIF) following embryo transfer (ET) is a major continuing problem in IVF. Women with haemostatic defects may be at increased risk of miscarriage and preclinical pregnancy loss. The fibrinolytic system is considered, at present, the key to new thrombotic pathogenic mechanisms. Patients with unexplained recurrent miscarriage have an impairment of fibrinolysis, as demonstrated by prolonged clot lysis time (CLT) in association with increased plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI). In this study, we investigated fibrinolytic potential in patients with RIF. Three groups of patients were studied: 30 women with RIF (RIF group), 60 patients undergoing a first successful IVF-ET cycle (IVF group) and 60 healthy fertile women (FER group). Plasma CLT was measured using a global fibrinolysis assay. TAFI antigen plasma levels and polymorphisms in the TAFI gene (+505A/G and +1542C/G) were analysed using enzyme-linked immunosorbent assay and allele-specific PCR, respectively. CLT was significantly longer (P < 0.0001 and P < 0.0009, respectively) and TAFI antigen levels were significantly higher (both P < 0.0001) in the RIF versus the IVF and FER groups. A direct relationship between CLT and TAFI antigen levels (r = 0.40; P = 0.001) was detected in the whole study population. There were no differences in distribution of TAFI polymorphisms between groups. Patients with RIF have reduced plasma fibrinolytic potential, as shown by a prolonged CLT, and this may be explained, at least in part, by increased TAFI antigen levels.

Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile

Ovarian hyperstimulation syndrome (OHSS) in IVF/ICSI cycles may occur either as an early (early onset) or a late pattern (late onset). This observational study was designed to identify whether the onset pattern of OHSS is associated with the occurrence of pregnancy and the early pregnancy outcome. Among 4376 consecutive IVF/ICSI cycles, 113 patients were hospitalized for OHSS after IVF/ICSI treatment and were included in the study. The setting was the Dutch-speaking Brussels Free University Hospital, between June 2000 and September 2002. Early OHSS occurred in 53 patients, and late OHSS complicated 60 patients. A total of 96.7% of the late OHSS cases occurred in a pregnancy cycle and were more likely to be severe than the early cases (P < 0.05). Although in the early group there initially was a 41.5% positive HCG rate per cycle, the clinical pregnancy rate fell to 28.3% as a result of a significantly (P < 0.05) increased preclinical pregnancy loss rate compared with the non-OHSS patients (31.8 versus 88.3%, respectively). The ongoing pregnancy rate per cycle was 14.4% in the early and 26.4% in the late group. Multiple pregnancy rates were high in both groups (40 and 45.5%, respectively), but only in the late group did the incidence reach significance compared with the non-OHSS population (45.5 versus 29.1%, P = 0.02). Estradiol levels and number of follicles on the day of HCG were significantly higher in the early OHSS group. However, there was no difference in estradiol values on the day of hospital admittance between the two groups. In addition, the number of follicles on the day of HCG administration appears to be a better prognostic indicator for the occurrence of severe OHSS than the estradiol values (87% of the severe cases had > or = 14 or follicles of a diameter > or = 11 mm, whereas only 50% of them had an estradiol value > or = 3000 ng/l). The early OHSS pattern is associated with exogenously administered HCG and a higher risk of preclinical miscarriage, whereas late OHSS may be closely associated with the conception cycles, especially multiple pregnancies, and is more likely to be severe. Further clarification of these two different clinical entities could have implications for research protocols as well as for preventive and management strategies for OHSS.

Risk factors associated with preclinical pregnancy loss following ART

Objective: Relatively high incidence of preclinical pregnancy loss (PPL) is one of the important causes of low fecundity in human. Various factors affecting early implantation may cause PPL, however, the potential risk factors of PPL are poorly understood. The aim of this study is to investigate the clinical and embryologic factors affecting PPL in pregnant women following ART. Design: A retrospective analysis of pregnant cycles following IVF or ICSI at our IVF center in university hospital Materials and Methods: During 1999–2001, a total of 1390 pregnant cycles from 4358 embryo transfers carried out in our center were included in this study. Serum hCG measurement was done on day 12, 14, 21, 28 postconception by RIA. Pregnancy was defined as serum hCG ≥ 5 mIU/ml. PPL was defined as final fall of hCG after initial confirmation of pregnancy with no identifiable gestational sac. Clinical abortion was defined as pregnancy loss from time of identifiable gestational sac till 20 gestational weeks. To determine whether the factors such as female age, basal FSH, basal E2, peak E2 on hCG day, endometrial thickness, etiology of infertility, fertilization method, No. of embryos transferred, No. of good embryos transferred, No. of poor embryos transferred affect the occurrence of PPL following ART, Univariate and multivariate analysis were done by chi-square test, Fisher‘s exact test, and multinomial logistic regression. Results: The mean age of study cohort was 32.7±3.0 years. Among 1390 pregnant cycles, 252 cycles (18.1%) ended in PPL, 130 cycles (9.4%) ended in clinical abortion, 1008 pregnant cycles (72.5%) were ongoing beyond 20 weeks gestation. In univariate analysis, pregnant cycles with female age ≥ 40 years old had a significant increased risk of PPL compared with female age < 30 years (27.9% vs. 15.7%, p<0.05). Pregnant cycles with female age ≥ 35 years old had a significant increased risk of clinical abortion compared with female age < 30 years (17.5% vs. 6.9%, p<0.01). Pregnant cycles with 25 pg/ml ≤ basal E2 < 50 pg/ml had a significant increased risk of PPL compared with basal E2< 25 pg/ml (27.8% vs. 16.5%, p<0.01). Pregnant cycles with endometrial thickness < 8 mm had a significant high risk of PPL and clinical abortion compared with endometrial thickness ≥ 8 (PPL: 25.6% vs. 16.9%, p<0.05, Clinical abortion: 16.5% vs. 8.7%, P< 0.001). No. of good embryos transferred ≤ 2 had a significant increased risk of PPL compared with the rest (25.3% vs. 14.1%, p<0.05). Adjusting confounding age factor, pregnant cycles with basal FSH ≥ 15 mIU/ml had a significant increased risk of PPL (p<0.05). Cause of infertility, peak E2 on hCG day, No. of ET, and fertilization method were not associated with the risk of PPL. After adjusting for possible confounding factors with multivariate logistic regression, female age (p=0.04), basal E2 (p=0.001), endometrial thickness (p=0.02) remained significant risk factors for PPL, but female age (p=0.001) was the only significant risk factor for clinical abortion following ART. Conclusion: This study demonstrated that female age, elevated basal estradiol, elevated basal FSH, thin endometrium are associated with an increased risk of preclinical pregnancy loss following ART.

Conception to ongoing pregnancy: the 'black box' of early pregnancy loss.

Even when conditions are optimal, the maximum chance of a clinically recognized pregnancy occurring in a given menstrual cycle is 30-40%. Increasing evidence points to preclinical pregnancy loss rather than failure of conception as the principal cause for the relatively low fecundity observed in humans. While sensitive assays for hCG have provided a glimpse of the events occurring between implantation and the missed menstrual period, new cytogenetic techniques have further opened this 'black box', providing novel insights into the causes of early pregnancy wastage. In this article, the evidence and causes of preclinical or 'occult' pregnancy are reviewed, and the implications for the infertile patient are addressed.

What is a preclinical pregnancy loss?

To evaluate the contribution of embryo quality to preclinical loss rates after in vitro fertilization (IVF)/embryo transfer (ET) pregnancy, multiple gestation, and clinical loss rates were compared to preclinical pregnancy loss rates over a 3-year period. The pregnancy outcomes after 1675 fresh ETs from 1994 to 1997 were studied. While establishment of a clinical pregnancy confirms uterine receptivity, multiple gestation rates reflect embryo quality. Because the majority of clinical losses are chromosomally abnormal, clinical loss rates serve as another indicator of embryo quality. The overall preclinical pregnancy loss rate was 5% (78/1675) of ETs and 17% (78/472) of pregnancies. During the 3-year period the pregnancy rates per ET increased from 19 to 36% (P < 0.0001), multiple gestation rates increased from 21 to 48% (P < 0.008), clinical loss rates decreased from 20 to 6% (P < 0.0001), and preclinical pregnancy loss rates remained unchanged from 13 to 19% (P = 0.1). Preclinical pregnancy loss more likely reflects abnormalities in uterine receptivity rather than embryo quality. If recurrent preclinical pregnancy loss occurs after IVF/ET, evaluation for abnormalities of uterine receptivity should be performed.

Comparisons of pregnancy loss patterns after intracytoplasmic sperm injection and other assisted reproductive technologies

To compare outcome of pregnancies after intracytoplasmic sperm injection (ICSI) with those of other assisted reproductive technologies. Pregnancy outcomes after ICSI were followed prospectively and compared with pregnancy outcomes after IVF with fresh and frozen ETs and donor oocyte cycles. A private tertiary referral center for genetics and infertility in Fairfax, Virginia. One hundred thirty-six couples achieving pregnancy after undergoing ICSI, 71 after IVF, 35 donor oocyte recipients, and 19 after transfer of frozen-thawed embryos. In vitro fertilization and/or ET for all couples. Dilatation and curettage to obtain products of conception for chromosome analysis in 28 women experiencing spontaneous abortion. Pregnancy outcomes were classified as preclinical loss, clinical loss, and ongoing pregnancy. The mean frequency of preclinical pregnancy loss was 26% after ICSI, 28% after IVF, 3% after ET using donor oocytes, and 11% after frozen ET. The rate of clinical loss after ICSI (21%) was compared with IVF (18%), donor oocyte cycles (11%), and frozen ETs (21%). Intracytoplasmic sperm injection is not associated with an increase in pregnancy losses, clinical or preclinical, compared with conventional IVF.