The association between pre-treatment maternal alcohol and caffeine intake and outcomes of assisted reproduction in a prospectively followed cohort.

STUDY QUESTION: Is pre-treatment alcohol and caffeine intake associated with infertility treatment outcomes among women undergoing ART? SUMMARY ANSWER: Low to moderate alcohol and caffeine intakes in the year prior to infertility treatment were not related to ART outcomes. WHAT IS KNOWN ALREADY: Alcohol and caffeine intake have been found to be associated with infertility in some studies. Nevertheless, data on their relation with outcomes of infertility treatments are scarce and inconsistent. STUDY DESIGN, SIZE, DURATION: We included 300 women (493 ART cycles) from the Environment and Reproductive Health Study, an ongoing cohort study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pre-treatment intakes of alcohol and caffeine were assessed retrospectively using a validated food frequency questionnaire. Intermediate and clinical endpoints of ART were abstracted from electronic medical records. Generalized linear mixed models with random intercepts to account for multiple ART cycles per woman were used to evaluate the association with ART outcomes adjusting for age, BMI, smoking status, infertility diagnosis, protocol type, race, dietary patterns, and calories, vitamin B12 and folate intake. MAIN RESULTS AND THE ROLE OF CHANCE: Median (range) pre-treatment alcohol and caffeine intakes were 5.6 (0.0-85.8) g/day and 124.9 (0.3-642.2) mg/day, respectively. The adjusted percentage of initiated cycles resulting in live birth (95% CI) for women in increasing categories of pre-treatment alcohol intake was 34% (20, 52%) for non-consumers, 46% (36, 57%) for 0.1-6 g/day, 41% (29, 53%) for 6.1-12 g/day, 42% (31, 55%) for 12.1-24 g/day, and 41% (22, 63%) for >24 g/day (P, trend = 0.87). The adjusted percentage of cycles resulting in live birth (95% CI) for women in increasing categories of caffeine intake was 46% (36-57%) for <50 mg/day, 44% (29, 60%) for 50.1-100 mg/day, 42% (31, 53%) for 100.1-200 mg/day, 40% (28, 53%) for 200.1-300 mg/day and 40% (21, 63%) for >300 mg/day (P, trend = 0.34). When specific types of alcoholic and caffeinated beverages were evaluated, no relations with ART treatment outcomes were observed. LIMITATIONS, REASONS FOR CAUTION: Residual confounding by other diet and lifestyle factors cannot be ruled out owing to the observational nature of this study. It is also unclear how generalizable these results are to women who are conceiving without the assistance of ART. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide reassurance that low to moderate intakes of alcohol (e.g. ≤12 g/day) and caffeine (e.g. <200 mg/day) in the year prior to infertility treatment initiation do not have an adverse effect on intermediate or clinical outcomes of ART. STUDY FUNDING/COMPETING INTEREST(S): The authors are supported by National Institutes of Health (NIH) grants ES022955, R01ES009718, R01ES000002, P30DK46200 and L50-HD085359. No conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT00011713.

Effect of a baseline ovarian cyst on the outcome of in vitro fertilization-embryo transfer.

OBJECTIVE: To determine the significance of prestimulation ovarian cysts on the response to controlled ovarian hyperstimulation and the outcome of IVF. DESIGN: Retrospective study. SETTING: In vitro fertilization unit in an academic center. PATIENT(S): One hundred thirty-seven patients undergoing IVF. INTERVENTION(S): The outcome of 71 patients who had an ovarian cyst of >10 mm detected at ultrasound examination performed on day 3 was compared with that of 66 patients who underwent a similar protocol and did not have an ovarian cyst. MAIN OUTCOME MEASURE(S): Parameters evaluated were the E2 level on the day of hCG administration, the number of follicles, the number of oocytes retrieved, the number of embryos transferred, and the pregnancy rate. RESULT(S): The E2 level on the day of hCG administration and the number of mature oocytes retrieved were lower in the group with a baseline cyst. The pregnancy rate also was significantly lower in the group with a cyst (24% versus 41%). The presence of a baseline ovarian cyst decreases the odds of pregnancy 0.37-fold (95% confidence interval, 0.16-0.87). CONCLUSION(S): A baseline ovarian cyst on cycle day 3 was associated with a poorer outcome after IVF-ET.

Prevention of estrogen deficiency-related bone loss with human parathyroid hormone-(1-34): a randomized controlled trial.

CONTEXT: Short-term intermittent administration of parathyroid hormone (PTH) prevents bone loss from the spine in women treated with a gonadotropin-releasing hormone (GnRH) analog. However, the effects of a longer period of PTH administration on bone mass in estrogen-deficient women, particularly on the hip and on cortical bone of the total body, are unknown. OBJECTIVE: To determine whether more prolonged PTH administration can prevent estrogen deficiency bone loss from the hip, spine, and total body in young women with endometriosis receiving GnRH analog (nafarelin acetate) therapy. DESIGN: Randomized controlled trial. SETTING: General Clinical Research Center of a tertiary care, university-affiliated hospital. PATIENTS: Forty-three women between the ages of 21 and 45 years with symptomatic endometriosis. INTERVENTION: Nafarelin alone (200 microg intranasally twice daily) or nafarelin plus human parathyroid hormone-(1-34) (hPTH-[1-34]) (40 microg subcutaneously daily). MAIN OUTCOME MEASURES: The primary end points were bone mineral density (BMD) of the anterior-posterior and lateral spine, femoral neck, trochanter, radial shaft, and total body at 12 months of treatment. RESULTS: In the women who received nafarelin alone, the mean (SEM) BMDs of the anterior-posterior spine, lateral spine, femoral neck, trochanter, and total body were 4.9% (0.6%) (P<.001), 4.9% (0.8%) (P<.001), 4.7% (1.1%) (P<.001), 4.3% (0.9%) (P<.001), and 2.0% (0.6%) (P= .003) lower than at baseline after 12 months of therapy. In contrast, coadministration of hPTH-(1-34) increased BMD of the anterior-posterior spine by 2.1% (1.1%) (P=.09) and lateral spine by 7.5% (1.9%) (P=.002) and prevented bone loss from the femoral neck, trochanter, and total body, despite severe estrogen deficiency. Radial shaft BMD did not change significantly in either group. Serum bone-specific alkaline phosphatase and osteocalcin concentrations and urinary excretion of hydroxyproline and deoxypyridinoline increased 2-fold to 3-fold during the first 6 to 9 months of therapy in the women who received nafarelin plus hPTH-(1-34) and then declined. Changes in urinary deoxypyridinolone excretion were strongly predictive (r= 0.85) of changes in spinal BMD in the women who received nafarelin plus hPTH-(1-34). CONCLUSIONS: Parathyroid hormone prevents bone loss from the proximal femur and total body and increases lumbar spinal BMD in young women with GnRH analog-induced estrogen deficiency.

Fertility options for patients with stages IA2 and IB cervical cancer: presentation of two cases and discussion of technical and ethical issues.

BACKGROUND: Ten percent to 15% of women diagnosed with cervical cancer are in their childbearing years. Traditional therapy for stage IA2 and IB lesions, radical hysterectomy, negates future fertility potential. Assisted reproductive technology might offer these women fertility options. CASES: Two cases of young nulliparous women with stage IA2 cervical cancer, who underwent ovarian stimulation and oocyte retrieval followed by radical hysterectomy, were presented to illustrate the technical difficulties of oocyte stimulation and retrieval in the setting of cervical carcinoma. CONCLUSION: Many issues should be considered when counseling a woman with early-stage cervical cancer about future fertility. These include ethical issues of embryo freezing and gestational surrogacy and practical issues of ovarian preservation and transposition. No current guidelines exist to identify appropriate candidates for assisted reproductive technology in this setting.

Malignancy may adversely influence the quality and behaviour of oocytes.

A case series of eight cycles of in-vitro fertilization (IVF) in five women diagnosed with malignant disorders is presented. These patients chose to defer definitive treatment for a chance for preservation of potential fertility. The response of these patients to ovarian stimulation, and the outcome, was compared with 17 IVF cycles in 12 age-matched patients with isolated tubal infertility. An apparent adverse influence of malignant disease on the quality and behaviour of oocytes was observed. Despite a comparable total number of oocytes per cycle in the two groups, a significantly reduced percentage of mature oocytes was retrieved per cycle from patients with malignant diseases. The oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared to the controls. We propose that neoplastic processes, irrespective of the site or cell of origin, may have a detrimental impact on the biology of oocytes, an effect akin to that seen on spermatozoa in men with certain malignancies.

Cytoskeleton and polyploidy after maturation and fertilization of cryopreserved germinal vesicle-stage mouse oocytes.

PURPOSE: Our purpose was to assess the effect of cryopreservation on cytoskeleton of germinal vesicle (GV) mouse oocytes and determine whether irreversible spindle damage and related digyny associated with cryopreservation of metaphase II (MII) oocytes can be avoided. METHODS: The GV oocytes were cryopreserved using a slow-cooling (0.5 degree C/min) and slow-thawing (8 degrees C/min) protocol in 1.5 M dimethylsulfoxide supplemented with 0.2 M sucrose and analyzed before and during fertilization by multiple-label fluorescence and differential interference contrast microscopy techniques. RESULTS: When examined after in vitro maturation, the vast majority (> 95%) of cryopreserved and control oocytes displayed normal microfilament and microtubule organization. With respect to barrel-shaped spindle and normal chromosome alignment, no significant differences were observed between cryopreservation (78 and 86%, respectively) and control (85 and 95%, respectively) groups. In fertilization experiments, spindle rotation, formation of the second polar body, and pronuclear migration were displayed by similar percentages of cryopreserved (96, 94, and 37%, respectively) and control (98, 97, and 45%, respectively) oocytes, indicating normal functionality of the cytoskeleton during this period. However, pronuclear formation was significantly inhibited by cryopreservation (81%) compared with controls (100%). Regarding digyny and polyspermy, no significant increase was observed after cryopreservation (3 and 10%, respectively) compared with controls (3 and 6%, respectively). CONCLUSIONS: Cryopreservation of mouse oocytes at the GV stage is particularly advantageous to circumvent the spindle damage and increased digyny noted after cryopreservation of MII oocytes.

Alterations of the cytoskeleton and polyploidy induced by cryopreservation of metaphase II mouse oocytes.

OBJECTIVE: To determine cryopreservation-induced alterations in the cytoskeleton of metaphase II mouse oocytes and the implications of these alterations in functionality of the cytoskeleton and polyploidy after fertilization. DESIGN: Comparative study. SETTING: Clinical and academic research environment at a medical school teaching hospital. INTERVENTION(S): Oocytes were frozen using a slow-cooling (0.5 degrees C/min) and slow-thawing (8 degrees C/min) protocol in 1.5 M dimethyl sulfoxide and 0.2 M sucrose and were analyzed before and after fertilization. MAIN OUTCOME MEASURE(S): Cytoskeletal alterations, fertilization, and polyploidy rates. RESULT(S): When analyzed immediately after thawing, the oocytes displayed dramatic cytoskeletal alterations. Only slight recovery was observed upon removal of the cryoprotectants. However, incubation after thawing of 1 hour at 37 degrees C completely reestablished a normal microfilament and microtubule pattern while partially restoring normal spindle morphology and chromosome alignment. Accordingly, insemination immediately after removal of cryoprotectants resulted in a significantly decreased fertilization rate and aberrant dynamics of cytoskeleton-dependent events, whereas oocytes inseminated after the post-thaw incubation displayed fertilization rates and cytoskeletal dynamics comparable to those in controls. Cryopreservation did not increase polyspermy but significantly increased digyny when the oocytes were inseminated after the post-thaw incubation. All digynic eggs displayed an abnormal spindle remnant in comparison with diploid or polyspermic eggs. CONCLUSION(S): A brief period of incubation after thawing allows recovery and positively affects fertilization and cytoskeletal dynamics. Cryopreservation does not impair the functionality of microfilaments and cytoplasmic microtubules during postfertilization events. Our findings suggest that the increased rate of digyny in cryopreserved oocytes may be related to the spindle disorganization, leading to failure in segregation of the chromosomes, rather than to direct malfunction of the microfilaments in polar body formation.

Outcome of IVF in DES-exposed daughters: experience in the 90s.

PURPOSE: The outcome of in vitro fertilization (IVF) in a group of infertile women with a history of in utero exposure to diethylstilbestrol (DES) was analyzed. Records from an academic IVF program were retrospectively reviewed. METHODS: Seventeen infertile women with a self-reported history of exposure to DES in utero, attending the IVF unit at Massachusetts General Hospital (MGH) for assisted reproductive technology (ART), underwent 27 IVF cycles. Analysis of the outcome of IVF including implantation and ongoing pregnancy rates was performed. The data were compared with results from a group of 20 infertile patients with idiopathic infertility undergoing 27 IVF cycles at MGH during the same period. The patients in the two groups were matched for age, basal day 3 levels of follicle stimulating hormone and serum estradiol, and the number and quality of embryos transferred. RESULTS: The response to controlled ovarian hyperstimulation was comparable in the two groups. Significantly lower implantation and ongoing pregnancy rates following IVF and embryo transfer were seen in the utero DES-exposed group compared to the control patients. CONCLUSIONS: Infertile patients with a history of in utero exposure to DES exhibit a significantly impaired implantation rate following IVF, and the outcome of ART remains poor.

Comparison of office hysteroscopy, transvaginal ultrasonography and endometrial biopsy in evaluation of abnormal uterine bleeding.

OBJECTIVE: A comparison between office hysteroscopy, transvaginal ultrasonography and endometrial biopsy was performed, in terms of detection of intrauterine lesions. A secondary objective was assessment of evaluatory approach in the management of abnormal uterine bleeding in an outpatient setting. DESIGN: Prospective observational study. MATERIAL AND METHODS: A total of 54 women were evaluated for abnormal uterine bleeding. Assessment included performance of an endometrial biopsy, a transvaginal ultrasound scan followed by office hysteroscopy. Results of hysteroscopy were taken as the gold standard. Sensitivity and specificity of the investigations were assessed. The bleeding pattern was classified as heavy regular, irregular, postmenopausal and heavy or unscheduled bleeding on hormone replacement therapy. RESULTS: The incidence of focal intrauterine lesions in patients presenting with abnormal bleeding was 52% for all ages and 31% for the postmenopausal group. Seventy-five percent of the patients with Hb < 11 gm% and 67% with an enlarged uterus harbored a focal pathology. The incidence of lesions in patients with heavy regular bleeding was 74%. The sensitivity and specificity of transvaginal ultrasound when compared with results of hysteroscopy was 0.60 and 0.88 respectively. A normal endometrial biopsy had a negative predictive value of 51%. The sensitivity and specificity of endometrial biopsy were 0.04 and 0.83, respectively. CONCLUSION: Both transvaginal ultrasound and endometrial biopsy exhibited poor sensitivity for detection of focal intrauterine lesions. Considering the significantly high incidence of intrauterine lesions in patients presenting with abnormal bleeding, the most cost-effective approach appears to be proceeding with hysteroscopy early in assessment.

Simulated dose reduction in conventional chest CT: validation study.

PURPOSE: To validate a technique of computer-simulated dose reduction for conventional chest computed tomography (CT). MATERIALS AND METHODS: In 27 patients, CT scans were obtained at 200, 100, and 40 mAs at two levels. The raw data from the 200-mAs scan were modified on a computer workstation to simulate the increased noise present on 100- and 40-mAs scans. Real and simulated 100- and 40-mAs images were independently assessed in random order for overall image quality and radiologic findings by four subspecialty-trained chest radiologists who were blinded to the technique. The four observers were given paired real and simulated images. They were asked to identify the real image and note any difference in diagnostic quality. RESULTS: No difference was seen in overall image quality or radiologic findings between real and simulated images (P > .05). In the paired comparison, 433 of 864 (50.1%) real images were correctly identified. CONCLUSION: Computer modification of 200-mAs raw scan data to simulate 100- and 40-mAs noise levels produces reconstructed images indistinguishable from real 100- and 40-mAs scans. This technique provides realistic reduced-dose images without patient radiation exposure and with identical image registration and motion artifact.

High incidence of triploidy in in-vitro fertilized oocytes from a patient with a previous history of recurrent gestational trophoblastic disease.

The patient described has a history of recurrent gestational trophoblastic disease following spontaneous conception. She subsequently underwent two cycles of in-vitro fertilization (IVF) for management of infertility related to tubal obstruction. IVF of the oocytes retrieved showed a significantly high incidence of abnormal fertilization resulting in the development of triploid embryos. This report explores the possible association of an oocyte defect predisposing to abnormal fertilization, resulting in a high incidence of triploid embryos. Since the development of partial hydatidiform moles is related to the origin of triploidy, this phenomenon is suggested to explain the occurrence of recurrent trophoblastic disease in this patient. We propose the use of intracytoplasmic sperm injection (ICSI) as a therapeutic option to minimize the incidence of triploidy in future IVF cycles; donor oocyte IVF would be another alternative.

Suppression and flare regimens of gonadotropin-releasing hormone agonist. Use in women with different basal gonadotropin values in an in vitro fertilization program.

OBJECTIVE: To evaluate the suppression and flare regimens of gonadotropin-releasing hormone agonist (GnRH-a) in ovarian hyperstimulation in women with variable basal gonadotropin values in an in vitro fertilization (IVF) program. STUDY DESIGN: A retrospective study comparing the initiation of GnRH-a in the midluteal phase of the preceding cycle (suppression protocol) and follicular phase of the stimulated cycle (flare protocol) in women with basal follicle-stimulating hormone (FSH) values < 15 mIU/mL and > or = 15 mIU/mL. RESULTS: The pregnancy rate per initiated cycle and implantation rate for women with basal FSH levels > or = 15 mIU/mL were 20.4% and 9.8% in flare GnRH-a cycles and 11.7% and 3.5%, respectively, in suppression GnRH-a cycles. Comparing the percent differences in clinical pregnancy and implantation rates between both protocols for women with different basal FSH values, pregnancy outcome was significantly greater in the flare protocols in women with values > or = 15 mIU/mL (P < .001). Individualization of the stimulation protocol by retrospective sorting of women undergoing IVF with respect to their basal gonadotropin levels significantly improved clinical pregnancy (P < .05) and implantation rates (P < .05) and reduced the cancellation rate (P < .05). CONCLUSION: The flare regimen with GnRH-a is a useful alternative for controlled ovarian hyperstimulation in women with elevated basal FSH values (> or = 15 mIU/mL) undergoing IVF.

Abnormal uterine bleeding in the perimenopause.

Abnormal uterine bleeding is probably one of the most common gynecologic complaints in the perimenopause. It is a significant cause of hysterectomy, which is the second most common surgical procedure performed on women in the United States, and thus is a major health issue. Management consists of a stepwise evaluation of all possible organic causes of uterine bleeding. Advancements in technology have allowed considerable improvements in the resolution of many diagnostic tools. Direct visualization of the uterine cavity is now an invaluable adjunct to blind endometrial sampling. Consequently, therapy can be tailored more appropriately and efficiently, either by newly developed medical strategies or through selective, minimally invasive surgery. In light of these perspectives, some of the recent diagnostic and therapeutic trends in the management of abnormal uterine bleeding in perimenopausal women are presented.