Preclinical Pregnancy Research Articles

Effectiveness and Safety of COVID-19 Vaccination During Preconceptional and Preclinical Pregnancy Period: A National Population Study.

We aimed to assess the risk of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and early abortive outcomes after the association between coronavirus disease 2019 (COVID-19) vaccination during the preconceptional period and preclinical pregnancy, which are likely to be inadvertent vaccination. We used data from the Korea Disease Control and Prevention Agency-COVID19-National Health Insurance Service cohort from December 2020 to December 2021. The vaccinated pregnant women were matched to unvaccinated pregnant controls at a 1:4 ratio. The risks of SARS-CoV-2 infection and intensive care unit (ICU) admission within 14 days of infection were analyzed to assess its effectiveness. For safety measures, the adjusted relative risks (aRRs) of early abortive outcomes for the first COVID-19 vaccination during the preconceptional and preclinical periods were calculated considering covariates. We compared the risk of early abortion between mRNA and viral vector vaccines. The overall COVID-19 vaccination rates during the preconceptional period and preclinical pregnancy were 3.1% (6,662/215,211) and 2.6% (5,702/215,211), respectively. The cumulative incidence of ICU admission within 14 days of SARS-CoV-2 infection was 6/100,000 in the unvaccinated group, whereas there were no ICU admissions in the vaccinated groups. The risks of early abortive outcomes were not significantly different between the preconceptional vaccination group and the unvaccinated group (aRR, 1.04; 95% confidence interval [CI],0.99-1.10) or between preclinical pregnancy vaccination and their matched controls (1.02; 95% CI, 0.96-1.08). mRNA and viral vector vaccines have shown similar risks for early abortive outcomes and miscarriages. Our findings have provided compelling evidence regarding the effectiveness and safety of COVID-19 vaccination prior to and during early pregnancy. Further research is required to extend the safety and efficacy profiles of COVID-19 vaccines to pregnant women and their babies.

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.

An update on preclinical pregnancy models of Zika virus infection for drug and vaccine discovery

ABSTRACT Introduction Congenital Zika syndrome is caused by Zika virus (ZIKV) infection during pregnancy and can culminate in structural and neurological defects in the fetus, including a spectrum of symptoms such as brain calcifications, hydrocephalus, holoprosencephaly, lissencephaly, ventriculomegaly, and microcephaly. Using animal models to study ZIKV infection during pregnancy represents a critical tool for understanding ZIKV pathophysiology, drug testing, vaccine development, and prevention of vertical transmission. Areas covered In this review, the authors cover state-of-the-art preclinical pregnancy models of ZIKV infection for drug discovery and vaccine development to prevent vertical transmission. Expert opinion The discovery of drugs against ZIKV infection represents an urgent necessity, and until now, no effective drug that can prevent the effects of vertical transmission has been tested in humans. Even after six years of the ZIKV outbreak in Brazil, no drugs or vaccines have been approved for use in humans. In part, this failure could be related to the lack of translatability from available preclinical models to humans.

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.

THE STUDY OF CORRELATION BETWEEN LEIDEN V FACTOR AND METHYLEN TETRAHYDROFOLATE REDUCTASE ENZYME GENE MUTATIONS IN PRIMIGRAVIDA WITH MISSED ABORTION IN LATE FIRST TRIMESTER

Pregnancy is a hypercoagulable state secondary to an increase in coagulation factors, a reduction in naturally occurring anticoagulants, and impairment of fibrinolysis. Pregnancy losses were divided into preclinical, first trimester clinical, and second trimester. A meaningfully increased rate of preclinical pregnancy failure in Leiden mutation carriers was found than in no activated protein C deficiency patients. Another cause of miscarriages is inherited thrombophilia following damage to the maternal factor V gene G1691A (Leiden mutation) and prothrombin gene (G20210A mutation). These alterations are well studied and the test is part of the routine diagnostics of recurrent mis-carriages. In the case of factor V, both the Leiden mutation G1691A and the T1328C mutation appear to be important in the pathogenesis of RM, mainly in cases observed before the 7th week of gestation. The most common causes of inherited thrombophilia are polymorphisms in genes encoding factor V, prothrombin (factor II), factor VII, MTHFR, and plasminogen activator inhibitor, while protein C, protein S and ant thrombin deficiency is less common. The finding of a link between FVL carrier state and early RPL would have significant implications for clinical practice, as it would provide a scientific rationale for screening for FVL mutation and targeted thromboprophylaxisin affected women.

Integrin β1 coordinates survival and morphogenesis of the embryonic lineage upon implantation and pluripotency transition

SummaryAt implantation, the embryo establishes contacts with the maternal endometrium. This stage is associated with a high incidence of preclinical pregnancy losses. While the maternal factors underlying uterine receptivity have been investigated, the signals required by the embryo for successful peri-implantation development remain elusive. To explore these, we studied integrin β1 signaling, as embryos deficient for this receptor degenerate at implantation. We demonstrate that the coordinated action of pro-survival signals and localized actomyosin suppression via integrin β1 permits the development of the embryo beyond implantation. Failure of either process leads to developmental arrest and apoptosis. Pharmacological stimulation through fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1), coupled with ROCK-mediated actomyosin inhibition, rescues the deficiency of integrin β1, promoting progression to post-implantation stages. Mutual exclusion between integrin β1 and actomyosin seems to be conserved in the human embryo, suggesting the possibility that these mechanisms could also underlie the transition of the human epiblast from pre- to post-implantation.

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.

Pre-Clinical Pregnancy Models for Evaluating Zika Vaccines.

Zika virus (ZIKV) infection during pregnancy can result in a variety of developmental abnormalities in the fetus, referred to as Congenital Zika Syndrome (CZS). The effects of CZS can range from the loss of the viable fetus to a variety of neurological defects in full-term infants, including microcephaly. The clinical importance of ZIKV-induced CZS has driven an intense effort to develop effective vaccines. Consequently, there are approximately 45 different ZIKV vaccine candidates at various stages of development with several undergoing phase I and II clinical trials. These vaccine candidates have been shown to effectively prevent infection in adult animal models, however, there has been less extensive testing for their ability to block vertical transmission to the fetus during pregnancy or prevent the development of CZS. In addition, it is becoming increasingly difficult to test vaccines in the field as the intensity of the ZIKV epidemic has declined precipitously, making clinical endpoint studies difficult. These ethical and practical challenges in determining efficacy of ZIKV vaccine candidates in preventing CZS have led to increased emphasis on pre-clinical testing in animal pregnancy models. Here we review the current status of pre-clinical pregnancy models for testing the ability of ZIKV vaccines to prevent CZS.

BG-12 (dimethyl fumarate) and pregnancy: Preclinical studies and pregnancy outcomes reported during the clinical development program

BG-12 (dimethyl fumarate) and pregnancy: Preclinical studies and pregnancy outcomes reported during the clinical development program

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.

The Fate and Function of Therapeutic Antiaddiction Monoclonal Antibodies across the Reproductive Cycle of Rats

During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (+)-methamphetamine, we discovered novel, gestation stage-specific changes in mAb disposition spanning the entire reproductive cycle of female rats. Each pharmacological change was independent of mAb dose and antigen target but was precisely coincident with transitions between the gestational trimesters, parturition, and lactation periods of the female reproductive cycle. Whereas anti-PCP mAb6B5 terminal elimination half-life (t(1/2λz)) in nonpregnant females was 6.6 ± 1.6 days, the mAb6B5 t(1/2λz) significantly changed to 3.7 ± 0.4 days, then 1.4 ± 0.1 days, then 3.0 ± 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p < 0.05 for each change). Initially, these evolving changes in mAb6B5 clearance (3.3-fold), distribution volume (1.8-fold), and elimination half-life (4.7-fold) affected our ability to sustain sufficient mAb6B5 levels to sequester PCP in the bloodstream. However, understanding the mechanisms underlying each transition allowed development of an adaptive mAb-dosing paradigm, which substantially reduced PCP levels in dam brains and fetuses throughout pregnancy. These mAb functional studies also revealed that antidrug mAbs readily cross the placenta before syncytiotrophoblast barrier maturation, demonstrating the dynamic nature of mAb pharmacokinetics in pregnancy and the importance of maintaining maternal mAb levels. These studies provide the first preclinical pregnancy model in any species for chronic mAb dosing and could have important implications for the use of antibody therapies involving blood organ barriers (such as addiction) or other chronic diseases in women of childbearing age (e.g., irritable bowel diseases, multiple sclerosis, breast cancer, rheumatoid arthritis).

Outcomes Of Assisted Reproductive Technologies At The Nairobi In Vitro Fertilisation Centre

Infertility is a common problem affecting up to ten per cent of married couples. A systematic evaluation of aetiologic factors forms the basis for choice of treatment and future fertility. On the global perspective, Assisted Reproductive Technologies (ART) has become internationally recognised treatment option for some infertile couples. A report on the current outcomes of ART practice at The Nairobi IVF Centre is presented. To describe the practice of assisted reproduction and present a report on the current outcomes. A retrospective survey of data on assisted reproduction practice from August 2005 to July 2008. The Nairobi IVF Centre a private medical practice in Nairobi, Kenya. Treatment of infertile couples by various assisted reproductive technologies including in vitro fertilisation (IVF), intra-cytoplasmic sperm injection (ICSI), uterine fresh embryo transfer (ET), and frozen/thawed uterine ET (FTET). Fertilisation, embryo cleavage, ET, embryo freeze/thaw survival, preclinical pregnancy and clinical pregnancy rates, live births and other obstetric outcomes. A total of 362 IVF cycles were performed. Following controlled ovarian hyperstimulation, an average of 12 oocytes were retrieved per patient while the fertilisation and subsequent embryo cleavage rates were 67 and 91.2% respectively. An average of three embryos were transferred and the embryo transfer rate was 93.3% per cycle started and 96.6% per oocyte retrieval. Surplus embryos were available for cryopreservation in 106 (50.1%) cycles. On thawing frozen embryos, the survival rate was 65.5%. Following ET, the overall pre-clinical pregnancies were 124 (36.2%) of which 99 (28.9%) developed into clinical pregnancies per cycle. Of the clinical pregnancies, 72 (73%) were singletons, 23 (23%) twin gestations and four triplets (4%). A total of 52 mothers have been delivered either by Caesarian section 45 (86.5%) or spontaneous vertex delivery seven (13.5%) to 61 live babies of whom 36 were females and 25 males. A further 28 IVF clinical pregnancies are ongoing, 26 following fresh embryo transfer and two from frozen/thawed embryos. Our results on ART practice reflects a pregnancy outcome comparable to that reported by other fertility centres globally. Couples with infertility in East and Central Africa for whom ART treatment is indicated may now access the service locally.

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.

Pregnancy outcome, once viability is ascertained, is not associated with endometrial thickness on day of hCG in patients with polycystic ovarian syndrome (PCOS) or other infertility diagnoses undergoing controlled ovarian hyperstimulation (COH)

Objective: The putative increased incidence of miscarriage in women with PCOS may be related to alterations of the endometrium. Both endogenous and exogenous hormones can affect histologic and sonographic appearance, and regulation of factors important for implantation and ongoing pregnancy. We asked whether endometrial thickness on dhCG can predict differences in pregnancy outcomes (liveborn vs. miscarriage) between PCOS and other patients undergoing COH. Design: Prospective cohort study in a tertiary REI teaching center. Materials/Methods: 163 consecutive patients achieving a viable pregnancy were prospectively enrolled. PCOS patients were oligo-anovulatory, without ovulatory progesterone, who failed to ovulate or conceive with clomiphene citrate, had evidence of either hyperandrogenism or hyperandrogenemia and all had polycystic appearing ovaries on endovaginal sonography (EVS). Comparison patients were ovulatory, had one or more diagnoses of unexplained infertility, mild male factor, pelvic factor or mildly diminished ovarian reserve. All patients had at least one open tube. Patients with total motile inseminates between 5 and 20 million/ml underwent washed intrauterine insemination. Endometrial thickness was measured on dhCG with EVS (Acuson 128) using a 5 mHz transducer. Viability was determined at 6w 3d to 7w 2d by hCG-adjusted LMP. Pregnancy outcome was determined by reviewing medical records. Data were analyzed using SAS. Fisher’s exact test was used to analyze classification versus outcome data and t-test was used for continuous variables. Significance for p <0.05 was tested using two-tailed distributions. Results: Outcome records were available for all patients having early clinical pregnancy. Patients having only a biochemical pregnancy, early pregnancy loss prior to the 6–7 weeks exam, or a missed abortion, e.g, blighted ovum or no fetal cardiac activity at EVS visit for viability, were not included in this analysis. Mean ages were: PCOS = 33.1, other infertility = 36.7, (p = 0.001). 31% of patients had PCOS and 69% had other diagnoses. 5.1% of PCOS and 10.8% of comparison patients experienced pregnancy loss subsequent to the EVS for viability. Endometrial thickness on dhCG was: PCOS = 10.2 mm, SD 1.7; other patients = 10.1 mm, SD 2.5 (p = n.s.). No differences were seen for thickness within either infertility group related to chances of subsequent SAB or live birth. Conclusions: This pilot study suggests that once a viable pregnancy is attained, chances of subsequent pregnancy loss in either group are small, but not negligible. Additionally, endometrial thickness on dhCG does not appear to differ between pregnant PCOS and comparison patients undergoing COH. Endometrial thickness and pregnancy outcomes within each group were also not different. Some limits of this pilot study are that only patients with viable pregnancies were included. Patients with pre-clinical pregnancy losses were not. Inclusion of these patients may influence the prognostic utility of this EVS measure. Patients with pre-clinical losses are being examined and will be included in a separate analysis in this presented paper.

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.