Janis H. Fox

The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer

OBJECTIVE To select patients for day 3 vs. day 5 embryo transfer. DESIGN Retrospective analysis of assisted reproduction technology (ART) cycles comparing outcomes of day 3 and day 5 transfers. SETTING ART program of Brigham and Womens Hospital. PATIENT(S) Patients with day 3 or day 5 embryo transfers (n = 221 and 141, respectively). INTERVENTION(S) Cycles with eight or more zygotes were stratified by the number of eight-cell embryos available on day 3 (none, one or two, or three or more). MAIN OUTCOME MEASURE(S) Number of blastocysts, implantation rates, ongoing pregnancy rates, and number of fetal heart beats. RESULT(S) With no eight-cell embryos on day 3, 0% and 33% pregnancies resulted from day 5 vs. day 3 transfers. With one or two eight-cell embryos on day 3, ongoing and high order multiple rates were not different between day 3 and day 5 transfers. With three or more eight-cell embryos, day 5 transfer resulted in a decrease in multiple gestations but no difference in ongoing pregnancy rates compared with day 3 transfer. CONCLUSION(S) With no eight-cell embryos on day 3, a day 3 transfer is warranted. With one or two eight-cell embryos, any benefit of day 5 transfer appears to be equivocal. With three or more eight-cell embryos, day 5 transfer is recommended.

Early diagnosis and treatment of cervical pregnancy in an in vitro fertilization program

This is a report of three cervical pregnancies, one of which was a heterotopic twin cervical pregnancy that occurred in combination with a single intrauterine pregnancy. Transvaginal ultrasound examination was sufficient to establish the diagnosis in two of three patients, and MRI scanning was conclusive in the third. Early diagnosis lead to intervention before 7 weeks gestation in all cases with no complications. The incidence of cervical pregnancy may be higher in IVF-ET than recognized previously.

The association between severe obesity and characteristics of failed fertilized oocytes

STUDY QUESTION Is the cytoskeletal and chromosomal organization of failed fertilized oocytes from severely obese patients (BMI ≥ 35 kg/m²) altered compared with that in patients with normal BMI (BMI 18.5-24.9 kg/m²)? SUMMARY ANSWER Compared with normal BMI patients, severe obesity was associated with a greater prevalence of spindle anomalies and non-aligned chromosomes in failed fertilized oocytes. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Obesity is associated with poor reproductive outcomes, but little is known regarding the underlying mechanisms. To address potential mechanisms, our study compared the cytoskeletal and chromosome organization in failed fertilized oocytes from severely obese and normal BMI patients. DESIGN The study population was drawn from IVF patients treated in a hospital-based infertility clinic between February 2010 and July 2011. The prevalence of meiotic spindle and chromosome alignment anomalies in failed fertilized oocytes from patients with severe obesity (i.e. Class II and III; BMI 35.0-50.1 kg/m²) was compared with those from patients with normal BMI (BMI 18.5-24.9 kg/m²). Oocytes were fixed and then labeled for tubulin, actin and chromatin. Spindle number and integrity, as well as chromosome alignment, were assessed using immunofluorescence microscopy and, in some cases, confocal microscopy. Generalized estimating equations were applied, which account for the correlation among oocytes from the same patient to estimate odds ratio (OR), 95% confidence intervals (CIs) and two-sided Wald P-values. Models were adjusted for continuous age at cycle start, cycle type (IVF or ICSI) and polycystic ovarian syndrome (PCOS) a priori. PARTICIPANTS AND SETTING University-affiliated infertility clinic. A total of 276 oocytes that failed to fertilize from 137 patients were evaluated: 105 oocytes from severely obese women (n = 47) and 171 oocytes from normal BMI patients (n = 90). MAIN RESULTS AND THE ROLE OF CHANCE (i) Significantly more oocytes from the severely obese group exhibited two spindles compared with those from the normal BMI group (58.9 versus 35.1%; OR = 2.68, CI = 1.39-5.15, P-value = 0.003). (ii) Among oocytes with a single spindle, those from severely obese patients showed a significantly higher prevalence of disarranged spindles with non-aligned chromosomes compared with those from normal BMI patients (28.6 versus 8.6%; OR = 4.58, CI = 1.05-19.86, P-value = 0.04). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION Inclusion of only failed fertilized oocytes, small sample size, unknown factors such as non-PCOS comorbidity. GENERALIZABILITY TO OTHER POPULATIONS For this study, by design, it is unclear whether the findings are generalizable to successfully fertilized oocytes, and whether this oocyte-level influence of obesity is generalizable to infertile women who do not undergo stimulation or, more broadly, to spontaneous conceptions in fertile women. STUDY FUNDING/COMPETING INTEREST(S) none. TRIAL REGISTRATION NUMBER n/a.

Transcervical placement of a Malecot catheter ∗ after hysteroscopic evaluation provides for easier entry into the endometrial cavity for women with histories of difficult intrauterine inseminations and/or embryo transfers: a prospective case series

OBJECTIVE To evaluate a new technique designed to improve access to the endometrial cavity through tortuous and/or stenotic endocervical canals in women with histories of difficult IUIs, ETs, or endometrial biopsies. DESIGN Prospective case series. SETTING Tertiary care center. PATIENT(S) Women with histories of difficult intrauterine procedures because of tortuous and/or stenotic endocervical canals who continued to undergo treatment. INTERVENTION(S) Hysteroscopic evaluation and/or correction of the endocervix, followed by transcervical placement of a Malecot catheter (CR Bard Inc., Covington, GA) for an average of 10 days. MAIN OUTCOME MEASURE(S) Improvement in the ease of access to the endometrial cavity during IUIs or ETs. RESULT(S) Thirty-two of 36 patients had significantly easier procedures after the placement and removal of a Malecot catheter. CONCLUSION(S) Hysteroscopic evaluation and placement of a Malecot catheter is a useful technique that allows easier entry through the cervical canal in patients in whom previous IUIs, ETs, and endometrial biopsies have been difficult. This procedure may lead to improved pregnancy rates, particularly with IVF-ET, as the ease of ET has been correlated with improved implantation rates.

In Vitro Fertilization Is Successful in Women With Ulcerative Colitis and Ileal Pouch Anal Anastomosis.

Background:Women with ulcerative colitis (UC), who require ileal pouch anal anastomosis (IPAA), have up to a threefold increased incidence of infertility. To better counsel patients who require colectomy, we examined the success rates of in vitro fertilization (IVF) among women who have undergone IPAA.Methods:This was a retrospective cohort study conducted at the Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center. Female patients with UC were identified via ICD-9 codes and cross-referenced with those presenting for IVF from 1998 through 2011. UC patients with IPAA were compared with the following two unexposed groups that underwent IVF: (1) patients with UC, who had not undergone IPAA, and (2) patients without inflammatory bowel disease (IBD). The primary outcome was the cumulative live birth rate. Secondary outcomes included number of oocytes retrieved, proportion of patients who underwent embryo transfer, pregnancy rate, and live birth rate at first cycle.Results:There were 22 patients with UC and IPAA, 49 patients with UC and without IPAA, and 470 patients without IBD. The cumulative live birth rate after six cycles in the UC and IPAA groups was 64% (95% confidence interval (CI): 44–83%). This rate did not differ from the cumulative live birth rate in the UC without IPAA group (71%, 95% CI: 59–83%; P=0.63) or the group without IBD (53%, 95% CI: 48–57%; P=0.57).Conclusions:This study demonstrates that in our cohort, women who undergo IPAA achieve live births following IVF at comparable rates to women with UC without IPAA and to women without IBD.

Diagnosing cellular defects in an unexplained case of total fertilization failure

Despite the advent of ICSI, cases of total fertilization failure (TFF) often lead to cycle cancellation with limited diagnostic and therapeutic strategies currently available. We report on the case of an infertile couple who failed to conceive after repeated IVF and ICSI. Sperm of the husband were morphologically normal and passed a functional test assessing their ability to activate mouse oocytes. Whether oocytes were activated artificially with calcium ionophore after injection of husbands or with donor sperm, all oocytes failed to fertilize. Multiple polar bodies and two disorganized spindle structures were predominantly observed, pointing towards a cytoplasmic defect in the oocytes as the primary cause of the couples infertility. In fact, injection of husbands sperm into donor oocytes resulted in the delivery of healthy twins. This report describes a course of action that may be applied for couples with TFF after both IVF and ICSI.

Techniques and InstrumentationTranscervical placement of a Malecot catheter∗ after hysteroscopic evaluation provides for easier entry into the endometrial cavity for women with histories of difficult intrauterine inseminations and/or embryo transfers: a prospective case series

OBJECTIVE To evaluate a new technique designed to improve access to the endometrial cavity through tortuous and/or stenotic endocervical canals in women with histories of difficult IUIs, ETs, or endometrial biopsies. DESIGN Prospective case series. SETTING Tertiary care center. PATIENT(S) Women with histories of difficult intrauterine procedures because of tortuous and/or stenotic endocervical canals who continued to undergo treatment. INTERVENTION(S) Hysteroscopic evaluation and/or correction of the endocervix, followed by transcervical placement of a Malecot catheter (CR Bard Inc., Covington, GA) for an average of 10 days. MAIN OUTCOME MEASURE(S) Improvement in the ease of access to the endometrial cavity during IUIs or ETs. RESULT(S) Thirty-two of 36 patients had significantly easier procedures after the placement and removal of a Malecot catheter. CONCLUSION(S) Hysteroscopic evaluation and placement of a Malecot catheter is a useful technique that allows easier entry through the cervical canal in patients in whom previous IUIs, ETs, and endometrial biopsies have been difficult. This procedure may lead to improved pregnancy rates, particularly with IVF-ET, as the ease of ET has been correlated with improved implantation rates.

Cellular and genetic analysis of oocytes and embryos in a human case of spontaneous oocyte activation

Unusual and consistent defects in infertility patients merit attention as these may indicate an underlying genetic abnormality, in turn necessitating tailored management strategies. We describe a case of repeated early pregnancy loss from in vivo conceptions, followed by cancelled embryo transfers after one IVF and one ICSI/PGD cycle. Following the unexpected presence of cleaved embryos at the fertilization check in the first IVF attempt, oocytes and embryos were subsequently analyzed in an ICSI/PGD case. Part of the oocyte cohort was fixed at retrieval for a cellular evaluation of microtubules, microfilaments and chromatin. The remaining oocytes were injected with sperm, and resultant embryos were biopsied for genetic analysis by fluorescence in situ hybridization (FISH), single-nucleotide polymorphism (SNP) microarray for 23 chromosome pairs, as well as with PCR for sex chromosomes. The presence of interphase microtubule networks and pronuclear structures indicated that oocytes were spontaneously activated by the time of retrieval. FISH revealed aneuploidy in all seven blastomeres analyzed, with all but two lacking Y chromosomes. Microarray SNP analysis showed an exclusively maternal origin of all blastomeres analyzed, which was further confirmed by PCR. From our multi-faceted analyses, we conclude that spontaneous activation, or parthenogenesis, was probably the pathology underlying our patients recurrent inability to maintain a normal pregnancy. Such analyses may prove beneficial not only in diagnosing case-specific aberrations for other patients with similar or related failures, but also for furthering our general understanding of oocyte activation.

Coasting vs. cryopreservation of all embryos for prevention of ovarian hyperstimulation syndrome in in vitro fertilization.

In the patient at risk for ovarian hyperstimulation syndrome, coasting will result in fewer eggs retrieved and embryos produced when compared with cryopreservation of all embryos. However, both strategies are associated with a similar incidence of ovarian hyperstimulation syndrome, with achievement of comparable cumulative pregnancy rates.

Evidence That Increased Ovarian Aromatase Activity and Expression Account for Higher Estradiol Levels in African American Compared With Caucasian Women

CONTEXT Serum estradiol levels are significantly higher across the menstrual cycle in African American (AAW) compared with Caucasian women (CW) in the presence of similar FSH levels, yet the mechanism underlying this disparity is unknown. OBJECTIVE The objective of the study was to determine whether higher estradiol levels in AAW are due to increased granulosa cell aromatase mRNA expression and activity. DESIGN The design of the study included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. SUBJECTS Healthy, normal cycling AAW (n = 15) and CW (n = 14) aged 19-34 years participated in the study. MAIN OUTCOME MEASURES Hormone levels in peripheral blood and follicular fluid (FF) aspirates and aromatase and FSH receptor mRNA expression in granulosa cells were measured. RESULTS AAW had higher FF estradiol [1713.0 (1144.5-2032.5) vs 994.5 (647.3-1426.5) ng/mL; median (interquartile range); P < .001] and estrone [76.9 (36.6-173.4) vs 28.8 (22.5-42.1) ng/mL; P < .001] levels than CW, independent of follicle size. AAW also had lower FF androstenedione to estrone (7 ± 1.8 vs 15.8 ± 4.1; mean ± SE; P = .04) and T to estradiol (0.01 ± 0.002 vs 0.02 ± 0.005; P = .03) ratios, indicating enhanced ovarian aromatase activity. There was a 5-fold increase in granulosa cell aromatase mRNA expression in AAW compared with CW (P < .001) with no difference in expression of FSH receptor. FSH, inhibin A, inhibin B, and AMH levels were not different in AAW and CW. CONCLUSIONS Increased ovarian aromatase mRNA expression, higher FF estradiol levels, and decreased FF androgen to estrogen ratios in AAW compared with CW provide compelling evidence that racial differences in ovarian aromatase activity contribute to higher levels of estradiol in AAW across the menstrual cycle. The absence of differences in FSH, FSH receptor expression, and AMH suggest that population-specific genetic variation in CYP19, the gene encoding aromatase, or in factors affecting its expression should be sought.