Karyotype of first clinical miscarriage and prognosis of subsequent pregnancy outcome.

RESEARCH QUESTION: Is the karyotype of the first clinical miscarriage in an infertile patient predictive of the outcome of the subsequent pregnancy? DESIGN: Retrospective cohort study of infertile patients undergoing manual vacuum aspiration with chromosome testing at the time of the first (index) clinical miscarriage with a genetic diagnosis and a subsequent pregnancy. Patients treated at two academic-affiliated fertility centres from 1999 to 2018 were included; those using preimplantation genetic testing for aneuploidy were excluded. Main outcome was live birth in the subsequent pregnancy. RESULTS: One hundred patients with euploid clinical miscarriage and 151 patients with aneuploid clinical miscarriage in the index pregnancy were included. Patients with euploid clinical miscarriage in the index pregnancy had a live birth rate of 63% in the subsequent pregnancy compared with 68% among patients with aneuploid clinical miscarriage (adjusted odds ratio [aOR] 0.75, 95% CI 0.47-1.39, P = 0.45, logistic regression model adjusting for age, parity, body mass index and mode of conception). In a multinomial logistic regression model with three outcomes (live birth, clinical miscarriage or biochemical miscarriage), euploid clinical miscarriage for the index pregnancy was associated with similar odds of clinical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage for the index pregnancy (32% versus 24%, respectively, aOR 1.49, 95% CI 0.83-2.70, P = 0.19). Euploid clinical miscarriage for the index pregnancy was not associated with likelihood of biochemical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage (5% versus 8%, respectively, aOR 0.46, 95% CI 0.14-1.55, P = 0.21). CONCLUSION: Prognosis after a first clinical miscarriage among infertile patients is equally favourable among patients with euploid and aneuploid karyotype, and independent of the karyotype of the pregnancy loss.

High incidence of diminished ovarian reserve in young unexplained recurrent pregnancy loss patients.

Recurrent pregnancy loss (RPL) is a clinically challenging scenario for patients and providers since an evidence-based approach to evaluation results in no explanation at least 50% of the time. The most common cause of first trimester clinical miscarriage is chromosome imbalance in the embryo or aneuploidy and the incidence of aneuploidy increases with age and diminished ovarian reserve (DOR). Currently, no professional societies recommend ovarian reserve testing in RPL patients, but some research shows a higher rate of DOR in miscarriage patients. The objective of this study was to evaluate the prevalence of DOR in unexplained vs. explained RPL patients. A prospective cohort study was completed, including 264 patients with recurrent pregnancy loss, 87 with an identifiable cause and 177 patients unexplained. A higher percentage of patients with unexplained RPL had DOR compared to patients with a known cause for RPL (48% vs 29%, p = .005). This finding was most significant in patients less than 38 years old compared to patients 38 years old and older (22% vs. 12%, p = .04). In conclusion, DOR is associated with RPL in many patients with otherwise unexplained RPL. Providers should consider adding ovarian reserve testing to their evaluation of RPL patients to guide counseling for treatment options.

Antimullerian hormone is a predictor of live birth in patients with recurrent pregnancy loss.

BACKGROUND: Ovarian reserve testing is not routinely performed in the evaluation of recurrent pregnancy loss (RPL). The objective of this study was to determine if AMH levels are predictive of live birth rate in RPL patients pursuing expectant management (EM). METHODS: Retrospective cohort study of RPL patients. Patients tried to conceive spontaneously for 12 calendar months or until they achieved a live birth, whichever occurred first. All patients with the intent to conceive were included regardless of final outcome. RESULTS: One hundred fifty-five RPL patients treated from 2009 to 2017 were included. In a univariate logistic regression, AMH < 1 ng/mL was associated with decreased likelihood of live birth (OR 0.38; CI 0.16-0.87, p = 0.03) and increasing age (OR 0.91; CI 0.83-0.99, p = 0.04). Likelihood of live birth was not significantly associated with BMI (OR 1.21; CI 0.83-1.77, p = 0.31), three or four or more prior pregnancy losses (OR 0.93; CI 0.40-2.22, p = 0.87 and OR 0.52; CI 0.19-1.42, p = 0.20, respectively) and prior live births (OR 1.00; CI 0.48-2.08, p = 0.99). AMH < 1 ng/mL was shown to be a stronger predictor of live birth than age using a multivariate model adjusting for age, AMH, and time to conception. CONCLUSIONS: AMH < 1 ng/mL is associated with decreased likelihood of live birth among RPL patients pursuing EM, and may be a stronger predictor of live birth than age in this population.

Higher rates of aneuploidy in blastocysts and higher risk of no embryo transfer in recurrent pregnancy loss patients with diminished ovarian reserve undergoing in vitro fertilization.

OBJECTIVE: To study the prediction of aneuploidy rate in blastocysts from patients with recurrent pregnancy loss (RPL) on the basis of ovarian reserve testing. DESIGN: Prospective cohort analysis. SETTING: Private, university-affiliated fertility clinic. PATIENT(S): A total of 239 patients with RPL, defined as two or more clinical miscarriages, were screened for inclusion. One hundred two (102) cycles in patients with unexplained RPL resulted in at least one euploid embryo transferred. Outcomes were compared by ovarian reserve test results, with diminished ovarian reserve (DOR) defined as a cycle day 3 FSH >10 IU/mL and/or antimüllerian hormone <1 ng/mL. INTERVENTION(S): In vitro fertilization with blastocyst biopsy and aneuploidy screening of all 23 chromosome pairs. MAIN OUTCOME MEASURE(S): Rate of aneuploidy in blastocysts and incidence of IVF cycles with no transfer owing to no euploid blasts. RESULT(S): Patients with DOR had a higher percentage of aneuploid blastocysts (57% vs 49%) and a higher incidence of no euploid embryos to transfer (25% vs 13%). The higher rate of aneuploidy in blastocysts was most significant in patients aged <38 years (67% vs 53%). Implantation rates after transfer of euploid blastocysts were similar (61% compared with 59%), and miscarriage rates were low (14% and 10%). CONCLUSION(S): Unexplained RPL patients with DOR have a higher percentage of aneuploid blastocysts and risk of no euploid embryo to transfer compared with unexplained RPL patients with normal ovarian reserve testing. The difference is most significant in patients aged <38 years. Patients with RPL and DOR with euploid embryo transferred had similar outcomes compared with patients with RPL and normal ovarian reserve testing.

Environmental exposure to endocrine-disrupting chemicals and miscarriage.

Establishment of early pregnancy is the result of complex biochemical interactions between the decidua and blastocyst. Any alteration in this chemical dialogue has the potential to result in adverse pregnancy outcomes including miscarriage. Sporadic miscarriage is the most common complication of pregnancy and can be caused by multiple factors. While the most common cause of miscarriage is genetic abnormalities in the fetus, other contributing factors certainly can play a role in early loss. One such factor is environmental exposure, in particular to endocrine-disrupting chemicals, which has the potential to interfere with endogenous hormone action. These effects can be deleterious, especially in early pregnancy when the hormonal milieu surrounding implantation is in delicate balance. The purpose of this paper is to review the current evidence on the role of environmental toxins in reproduction.

Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss.

STUDY QUESTION: In an intent to treat analysis, are clinical outcomes improved in recurrent pregnancy loss (RPL) patients undergoing IVF and preimplantation genetic screening (PGS) compared with patients who are expectantly managed (EM)? SUMMARY ANSWER: Among all attempts at PGS or EM among RPL patients, clinical outcomes including pregnancy rate, live birth (LB) rate and clinical miscarriage (CM) rate were similar. WHAT IS KNOWN ALREADY: The standard of care for management of patients with RPL is EM. Due to the prevalence of aneuploidy in CM, PGS has been proposed as an alternate strategy for reducing CM rates and improving LB rates. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 300 RPL patients treated between 2009 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among two academic fertility centers, 112 RPL patients desired PGS and 188 patients chose EM. Main outcomes measured were pregnancy rate and LB per attempt and CM rate per pregnancy. One attempt was defined as an IVF cycle followed by a fresh embryo transfer or a frozen embryo transfer (PGS group) and 6 months trying to conceive (EM group). MAIN RESULTS AND THE ROLE OF CHANCE: In the IVF group, 168 retrievals were performed and 38 cycles canceled their planned PGS. Cycles in which PGS was intended but cancelled had a significantly lower LB rate (15 versus 36%, P = 0.01) and higher CM rate (50 versus 14%, P < 0.01) compared with cycles that completed PGS despite similar maternal ages. Of the 130 completed PGS cycles, 74% (n = 96) yielded at least one euploid embryo. Clinical pregnancy rate per euploid embryo transfer was 72% and LB rate per euploid embryo transfer was 57%. Among all attempts at PGS or EM, clinical outcomes were similar. Median time to pregnancy was 6.5 months in the PGS group and 3.0 months in the EM group. LIMITATIONS, REASONS FOR CAUTION: The largest limitation is the retrospective study design, in which patients who elected for IVF/PGS may have had different clinical prognoses than patients who elected for expectant management. In addition, the definition of one attempt at conception for PGS and EM groups was different between the groups and can introduce potential confounders. For example, it was not confirmed that patients in the EM group were trying to conceive for each month of the 6-month period. WIDER IMPLICATIONS OF THE FINDING: Success rates with PGS are limited by the high incidence of cycles that intend but cancel PGS or cycles that do not reach transfer. Counseling RPL patients on their treatment options should include not only success rates with PGS per euploid embryo transferred, but also LB rate per initiated PGS cycle. Furthermore, patients who express an urgency to conceive should be counseled that PGS may not accelerate time to conception. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLLMENT: N/A.

Recurrent pregnancy loss: evaluation and treatment.

Recurrent pregnancy loss (RPL) is a multifactorial condition. Approximately half of patients with RPL will have no explanation for their miscarriages. De novo chromosome abnormalities are common in sporadic and recurrent pregnancy loss. Testing for embryonic abnormalities can provide an explanation for the miscarriage in many cases and prognostic information. Regardless of the cause of RPL, patients should be reassured that the prognosis for live birth with an evidence-based approach is excellent for most patients. The authors review current evidence for the evaluation and treatment of RPL and explore the proposed use of newer technology for patients with RPL.

Embryo selection with preimplantation chromosomal screening in patients with recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a multifactorial disorder which is often challenging for both patients and providers. Guidelines for the evaluation and treatment of patients with RPL include screening for uterine abnormalities, parental chromosomes, and antiphospholipid antibodies, but approximately half of RPL patients remain unexplained. The current recommendation for patients with unexplained RPL is expectant management which offers most patients a 60 to 80% success rate over time. Genetic imbalances in the embryo, including inherited unbalanced translocations and de novo aneuploidy, are frequent causes of miscarriage. Preimplantation genetic screening (PGS) has been proposed as an effective method for selecting viable embryos for transfer that may result lower risk of miscarriage for patients with unexplained RPL and carriers of balanced translocations. The current evidence examining the use of in vitro fertilization with PGS in patients with RPL reveals variable results, due to differences in technologies used and variable patient populations. Newer approaches, which include blastocyst biopsy and the ability to screen for all 24 chromosomes, show the most promise in reducing miscarriage rates. Studies that identify which patients are most likely to benefit from PGS and include live birth rates per initiated cycles are needed before universally recommending this treatment to couples with RPL.

Day 2 versus day 3 embryo transfer in poor responders: a prospective randomized trial.

Day 2 embryo transfer has been suggested as a method to improve pregnancy rates in poor responders compared with day 3 transfer. Our prospective randomized controlled trial does not show a difference in outcomes based on day of embryo transfer.

Ovarian stimulation and the risk of aneuploid conceptions.

OBJECTIVE: To examine the rate of aneuploidy in missed abortions in patients who conceived after FSH ovarian stimulation compared with women who conceived in a natural cycle. DESIGN: Retrospective cohort. SETTING: Academic reproductive endocrinology and infertility center. PATIENT(S): Women with karyotyping of products of conception (POC) from a missed abortion from January 1999 through August 2007. The rate of aneuploidy was compared between patients with a history of infertility who conceived naturally and patients with a history of infertility who conceived with FSH treatment. INTERVENTION(S): Ovarian stimulation with FSH, intrauterine insemination, and in vitro fertilization; genetic testing of POC after dilation and curettage. MAIN OUTCOME MEASURE(S): Embryonic karyotype. RESULT(S): A total of 229 pregnancies met inclusion criteria, and of these, 64% had an abnormal karyotype. The rate of aneuploidy was 63% in the study group and 70% in the control group. This difference was not statistically significant. CONCLUSION(S): The incidence of embryonic aneuploidy was not higher in pregnancies conceived with FSH stimulation compared with spontaneous conceptions in infertility patients. This suggests that exogenous FSH exposure does not increase the risk of aneuploidy.

Deep phenotyping to predict live birth outcomes in in vitro fertilization.

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVFBT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003-2006, followed by external validation with 634 cycles from 2007-2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVF(BT), that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p<0.05), and increased discrimination by receiver-operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVFBT provided predictions that were more accurate for approximately 83% of C1 and approximately 60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.

Asian ethnicity and poor outcomes after in vitro fertilization blastocyst transfer.

OBJECTIVE: To estimate the effect of ethnicity on in vitro fertilization (IVF) outcomes after blastocyst transfer. METHODS: We conducted a review of fresh blastocyst transfer IVF cycles from January 1, 2005, to December 31, 2006. Data collection included demographic information, infertility history, treatment protocol details, and treatment outcomes. Statistics were performed using the Student t test and chi2 test. To establish the independent contribution of Asian ethnicity, a multivariable logistic regression analysis was performed. RESULTS: We reviewed 180 blastocyst transfer cycles among white (62%) and Asian (38%) women. The groups were similar in most baseline characteristics. Asian women, however, had a lower body mass index (22.6 compared with 24.2, P=.02), were more likely to be nulligravid (53% compared with 35%, P=.03), and were more likely to have had at least one prior IVF cycle (37% compared with 20%, P=.02) The groups were similar in treatment characteristics, number of oocytes retrieved, fertilization rate, and number of blastocysts transferred. However, Asian women had a thicker endometrial lining (10.9 compared with 10.2, P=.02). Despite these similarities, Asian women had a lower implantation rate (28% compared with 45%, P=.01), clinical pregnancy rate (43% compared with 59%, P=.03), and live birthrate (31% compared with 48%, P=.02). In multivariable analysis, the decreased live birthrate among Asian women persisted (adjusted odds ratio 0.48, 95% confidence interval 0.24-0.96, P=.04). CONCLUSION: When compared with white women, Asian women have lower clinical pregnancy and live birthrates after blastocyst transfer.

Controlled ovarian hyperstimulation and gestational surrogacy in a patient with lung transplant: a case report.

BACKGROUND: Cystic fibrosis (CF) is one of the most common genetic disorders that can often lead to chronic pulmonary disease. Patients with respiratory failure due to CF may achieve a good quality of life after lung transplant, and many will desire to have children. CASE: A 26-year-old, nulliparous female with CF and double lung transplant presented for fertility treatment. She was successfully treated with controlled ovarian hyperstimulation and gestational surrogacy. CONCLUSION: Controlled ovarian hyperstimulation and gestational surrogacy is a safe option for patients with lung transplant to have a genetic child.

Poor prognosis with in vitro fertilization in Indian women compared to Caucasian women despite similar embryo quality.

BACKGROUND: Disease prevalence and response to medical therapy may differ among patients of diverse ethnicities. Poor outcomes with in vitro fertilization (IVF) treatment have been previously shown in Indian women compared to Caucasian women, and some evidence suggests that poor embryo quality may be a cause for the discrepancy. In our center, only patients with the highest quality cleavage stage embryos are considered eligible for extending embryo culture to the blastocyst stage. We compared live birth rates (LBR) between Indian and Caucasian women after blastocyst transfer to investigate whether differences in IVF outcomes between these ethnicities would persist in patients who transferred similar quality embryos. METHODOLOGY/PRINCIPAL FINDINGS: In this retrospective cohort analysis, we compared IVF outcome between 145 Caucasians and 80 Indians who had a blastocyst transfer between January 1, 2005 and June 31, 2007 in our university center. Indians were younger than Caucasians by 2.7 years (34.03 vs. 36.71, P = 0.03), were more likely to have an agonist down regulation protocol (68% vs. 43%, P<0.01), and were more likely to have polycystic ovarian syndrome (PCOS), although not significant, (24% vs. 14%, P = 0.06). Sixty eight percent of Indian patients had the highest quality embryos (4AB blastocyst or better) transferred compared to 71% of the Caucasians (P = 0.2). LBR was significantly lower in the Indians compared to the Caucasians (24% vs. 41%, P<0.01) with an odds ratio of 0.63, (95%CI 0.46-0.86). Controlling for age, stimulation protocol and PCOS showed persistently lower LBR with an adjusted odds ratio of 0.56, (95%CI 0.40-0.79) in the multivariate analysis. CONCLUSIONS/SIGNIFICANCE: Despite younger age and similar embryo quality, Indians had a significantly lower LBR than Caucasians. In this preliminary study, poor prognosis after IVF for Indian ethnicity persisted despite limiting analysis to patients with high quality embryos transferred. Further investigation into explanations for ethnic differences in reproduction is needed.

Effect of selective serotonin reuptake inhibitors on in vitro fertilization outcome.

A review of 950 patients was performed to investigate the impact of selective serotonin reuptake inhibitors (SSRIs) on in vitro fertilization outcome. The 41 patients (4.3%) taking an SSRI had a higher cycle cancellation rate but no statistically significant difference in pregnancy rate and live birth rate per cycle started.

Oocyte retrieval versus conversion to intrauterine insemination in patients with poor response to gonadotropin therapy.

We compared cycle characteristics and outcomes for planned in vitro fertilization cycles with five or fewer developing follicles that proceeded to retrieval (n = 170) with those that converted to intrauterine insemination (IUI) (n = 50). The risk of no embryo transfer was 24% in cycles that proceeded to retrieval. Live birth rate per cycle started was similar for IUI (6%) compared with retrieval (7%).

Embryo quality before and after surgical treatment of endometriosis in infertile patients.

PURPOSE: To investigate the hypothesis that surgical treatment of endometriosis in infertile patients may improve pregnancy rates by improving embryo quality. METHODS: We conducted a retrospective evaluation of 30 infertile patients treated with in vitro fertilization (IVF) before and after surgery for endometriosis. Patients served as their own controls and only cycles with similar stimulation protocols were compared. RESULTS: Using standard visual evaluation, embryo quality on day 3 was similar before and after surgical treatment of endometriosis. Fifty seven percent of patients had stage I-II endometriosis and 43% had stage III-IV disease. No patients had a live birth after the first IVF cycle and 43% of patients had a live birth with the IVF cycle after surgery. CONCLUSIONS: Surgical treatment of endometriosis does not alter embryo quality in patients with infertility treated with IVF.

Defining human embryo phenotypes by cohort-specific prognostic factors.

BACKGROUND: Hundreds of thousands of human embryos are cultured yearly at in vitro fertilization (IVF) centers worldwide, yet the vast majority fail to develop in culture or following transfer to the uterus. However, human embryo phenotypes have not been formally defined, and current criteria for embryo transfer largely focus on characteristics of individual embryos. We hypothesized that embryo cohort-specific variables describing sibling embryos as a group may predict developmental competence as measured by IVF cycle outcomes and serve to define human embryo phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We retrieved data for all 1117 IVF cycles performed in 2005 at Stanford University Medical Center, and further analyzed clinical data from the 665 fresh IVF, non-donor cycles and their associated 4144 embryos. Thirty variables representing patient characteristics, clinical diagnoses, treatment protocol, and embryo parameters were analyzed in an unbiased manner by regression tree models, based on dichotomous pregnancy outcomes defined by positive serum beta-human chorionic gonadotropin (beta-hCG). IVF cycle outcomes were most accurately predicted at approximately 70% by four non-redundant, embryo cohort-specific variables that, remarkably, were more informative than any measures of individual, transferred embryos: Total number of embryos, number of 8-cell embryos, rate (percentage) of cleavage arrest in the cohort and day 3 follicle stimulating hormone (FSH) level. While three of these variables captured the effects of other significant variables, only the rate of cleavage arrest was independent of any known variables. CONCLUSIONS/SIGNIFICANCE: Our findings support defining human embryo phenotypes by non-redundant, prognostic variables that are specific to sibling embryos in a cohort.

Abruptio placentae in the setting of an atypical presentation of acute appendicitis: a case report.

BACKGROUND: Causes of placental abruption include traumatic events, cocaine use, hypertension, cigarette smoking and advanced maternal age. Recent studies also implicate inflammatory precursors, such as preterm premature rupture of membranes and chorioamnionitis. Clear precipitating events are often not identified, and precise etiologic determinants are still being determined. CASE: A 25-year-old woman, grayida 4, para 2012, presented with acute onset of severe abdominal pain; frequent, low-amplitude contractions; and a nonreassuring fetal heart tracing. While performing an urgent cesarean section for acute placental abruption, a ruptured appendicitis was identified. CONCLUSION: This case suggests that appendicitis in the third trimester may be a risk factor for placental abruption.

Patient willingness to participate in a clinical trial with preimplantation genetic diagnosis.

OBJECTIVE: To investigate patients' interest in preimplantation genetic diagnosis (PGD) as a method for aneuploidy screening and their willingness to participate in a clinical trial using PGD. DESIGN: Anonymous questionnaire. SETTING: University infertility clinic. PATIENT(S): Women seeking treatment for infertility at the study clinic. INTERVENTION(S): Subjects completed a two-part structured questionnaire. The questionnaire included demographic and fertility history questions, followed by opinion questions on testing for genetic diseases. The second portion of the questionnaire included opinion questions about willingness to use PGD and to participate in a clinical trial using PGD after reading a document explaining PGD. MAIN OUTCOME MEASURE(S): Patients' interest in using PGD and willingness to participate in a clinical trial involving PGD. RESULT(S): Before reading a description of PGD, 84% of participants indicated that they were interested in having their embryos tested. The majority (86%) remained interested in testing their embryos with PGD after reading the informational paragraph. Most (91%) of the women who remained interested in PGD also indicated a willingness to participate in a clinical trial involving PGD. Of the patients who initially were not interested in testing their embryos, nearly half of them (47%) indicated an interest in PGD after reading the informational paragraph, and nearly all of those who changed their mind were willing to be in a trial. CONCLUSION(S): Many women undergoing IVF are interested in the possibility of utilizing PGD for aneuploidy screening. Better evidence is needed regarding outcomes using PGD for this indication before it can be routinely incorporated into practice. A clinical trial using PGD in this setting appears possible because a majority of the patients, in this survey, would be willing to participate.