Vasiliki A. Moragianni

The effect of body mass index on the outcomes of first assisted reproductive technology cycles.

OBJECTIVE To provide assisted reproductive technology (ART) outcome rates per body mass index (BMI) category after controlling for potential confounders. DESIGN Retrospective cohort study. SETTING Large university-affiliated infertility practice. PATIENT(S) Women undergoing ART. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The primary outcome was live birth. Analyses were stratified according to BMI category and adjusted for potential confounders, including maternal and paternal age, baseline serum FSH, duration of gonadotropin stimulation, mean daily gonadotropin dose, peak serum E(2), number of oocytes retrieved, use of intracytoplasmic sperm injection, embryo quality and number, transfer day, and number of embryos transferred. RESULT(S) We analyzed the first autologous fresh IVF or IVF-ICSI cycle of 4,609 patients. There were no differences in the rates of cycle cancellation, spontaneous abortion, biochemical and ectopic pregnancies, or multiple births. After adjusting for potential confounders, patients with BMI ≥ 30.0 kg/m(2) had significantly decreased odds of implantation, clinical pregnancy, and live birth. The adjusted odds ratio (95% confidence interval [CI]) of live birth were 0.63 (0.47-0.85) for BMI 30.00-34.99, 0.39 (0.25-0.61) for BMI 35.00-39.99, and 0.32 (0.16-0.64) for BMI ≥ 40.0 compared with normal-weight cohorts. CONCLUSION(S) Obesity has a significant negative effect on ART outcomes. Patients with BMI > 30 kg/m(2) have up to 68% lower odds of having a live birth following their first ART cycle compared with women with BMI < 30.

The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond

STUDY QUESTION What is the current literature on the safety and efficacy of selective serotonin reuptake inhibitor (SSRI) use in infertile women? SUMMARY ANSWER There is little evidence that infertile women benefit from taking an SSRI, therefore they should be counseled appropriately about the risks and be advised to consider alternate safer treatments to treat depressive symptoms. WHAT IS KNOWN ALREADY SSRI use is associated with possible reduced infertility treatment efficacy as well as higher rates of pregnancy loss, preterm birth, pregnancy complications, neonatal issues and long-term neurobehavioral abnormalities in offspring. STUDY DESIGN, SIZE, DURATION Review of existing literature. PARTICIPANTS/MATERIALS, SETTING, METHODS We conducted a review of all published studies that evaluate females with depressive symptoms who are taking antidepressant medications and who are experiencing infertility. MAIN RESULTS AND THE ROLE OF CHANCE Antidepressant use during pregnancy is associated with increased risks of miscarriage, birth defects, preterm birth, newborn behavioral syndrome, persistent pulmonary hypertension of the newborn and possible longer term neurobehavioral effects. There is no evidence of improved pregnancy outcomes with antidepressant use. There is some evidence that psychotherapy, including cognitive-behavioral therapy as well as physical exercise, is associated with significant decreases in depressive symptoms in the general population; research indicates that some forms of counseling are effective in treating depressive symptoms in infertile women. LIMITATIONS, REASONS FOR CAUTION Our findings are limited by the availability of published studies in the field, which are often retrospective and of small size. WIDER IMPLICATIONS OF THE FINDINGS Practitioners who care for infertility patients should have a thorough understanding of the published literature so that they can adequately counsel their patients. STUDY FUNDING/COMPETING INTEREST(S) None.

Cumulative live-birth rates after assisted reproductive technology.

Purpose of review Despite the promising success rates of IVF, many couples have to undergo several cycles before achieving live birth. In counseling patients faced with subfertility, it is important to provide cumulative live-birth rates. This review evaluates the current knowledge on cumulative rates, summarizing recently published evidence. Recent findings Existing data have been mostly presented in the form of live-birth rates per IVF cycle as a function of maternal age or reason for subfertility. Recent publications have been reporting IVF success rates in terms of cumulative live-birth rate (CLBR) per woman, thus providing a more realistic estimate that becomes applicable to individual couples. In general, CLBR following IVF has been reported between 45 and 55%. Maternal age has been shown to significantly reduce these rates, as has preimplantation genetic diagnosis. On the contrary, techniques mostly used to decrease the chance of multiple births, such as elective single embryo transfer and natural cycle IVF, do not affect CLBR while achieving a significant reduction in the rates of multiples. Summary Couples should be counseled that CLBR following IVF lies mostly around 50% and that maternal age as well as genetics of transferred embryos remain factors that influence success.

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.

Biweekly ultrasound assessment of cervical shortening in triplet pregnancies and the effect of cerclage placement

Preterm delivery is a major cause of neonatal morbidity and mortality that especially affects multiple gestations. This potentially devastating complication can often be predicted from sonographic evidence of shortened cervical length. However, the data remain limited and no guidelines exist on the optimal timing and frequency of sonographic surveillance in triplet pregnancies. Preterm delivery in triplets has been found to be associated with shortened cervical length diagnosed by transvaginal ultrasound at various gestational ages: between 12 and 20 weeks1, between 16 and 20 weeks2, between 15 and 24 weeks3, or at 23 weeks’ gestation4. Furthermore, once cervical shortening has been diagnosed the clinical question becomes whether to perform a cervical cerclage or manage the pregnancy expectantly. Most evidence for multiple gestations is derived from studies of twins5, where ultrasound-indicated cerclage does not appear to prolong gestation or improve outcome. In triplets, routine prophylactic cerclage placement has not been found to be associated with significant pregnancy prolongation6. We have previously presented our preliminary data on 24 triplet pregnancies that were followed with biweekly transvaginal ultrasonography7. We demonstrated that patients diagnosed with cervical shortening following biweekly sonographic surveillance were at greater risk of delivering earlier and having babies that weighed less than patients without a shortened cervix. However, within the subset of patients with a short cervix, the placement of cervical cerclage did not appear to affect gestational age at delivery or neonatal outcome. We have since recruited more patients and completed our data analysis, and we present here our final results. We analyzed a total of 50 triplet gestations that underwent biweekly transvaginal ultrasound assessment of cervical length at between 11 + 1 and 28 + 3 weeks’ gestation. Of these, 24 (48.0%) were diagnosed with a short cervix, defined as a shortest cervical length of ≤ 25 mm. These patients went on to deliver 24 days earlier (P = 0.001), have babies that weighed 451 g less (P < 0.001) and had lower 1-min (P < 0.001) and 5min (P = 0.006) Apgar scores, compared with patients without cervical shortening. Once diagnosed with a shortened cervix and following appropriate counseling, 11 of the 24 patients (45.8%) underwent cervical cerclage placement at an average gestational age of 20 + 4 weeks, whereas the remaining patients were managed expectantly. When comparing the two groups (Table 1), cervical cerclage did not appear to affect gestational age at delivery, birth weight, 1or 5-min Apgar scores or fetal demise (all, P > 0.05). Statistical analysis was performed using the Student’s t-test for continuous Gaussian variables and chi-square test for categorical variables (Stata v.11, StataCorp LP, College Station, TX, USA). We can thus conclude that, in triplet pregnancies, transvaginal ultrasound ascertainment of a shortened cervix at between 11 + 1 and 28 + 3 weeks’ gestation is associated with an increased risk of preterm delivery and poorer neonatal outcome. However, once identified, these patients do not benefit from ultrasound-indicated cervical cerclage placement and can instead be safely managed expectantly.

Management of a cervical heterotopic pregnancy presenting with first-trimester bleeding: case report and review of the literature

OBJECTIVE To report a rare case of a cervical heterotopic pregnancy resulting from intrauterine insemination (IUI) that presented with first-trimester bleeding. DESIGN Case report and literature review. SETTING Large university-affiliated infertility practice. PATIENT(S) A 40-year-old gravida 2 para 1 Asian woman at 7-3/7 weeks gestational age following clomiphene citrate/IUI for the treatment of secondary infertility presented with heavy vaginal bleeding for several days. INTERVENTION(S) Transvaginal ultrasound on admission revealed a single live intrauterine pregnancy and a cervical gestational sac containing a nonviable embryo. The patient continued to have vaginal bleeding and 2 days later underwent removal of the cervical ectopic pregnancy tissue with ring forceps, as well as an ultrasound-guided intracervical Foley balloon and cerclage placement. The bleeding subsided, and 48 hours later the Foley and cerclage were removed. MAIN OUTCOME MEASURE(S) Pregnancy outcome. RESULT(S) The remainder of the pregnancy was uncomplicated and the patient had a full-term cesarean delivery for footling breech of a healthy male infant. CONCLUSION(S) Cervical heterotopic pregnancy is a very rare event that almost universally results from infertility treatment. We present a case where we were able to remove the cervical ectopic and tamponade the bleeding, thus preserving the intrauterine pregnancy for this subfertile couple, and we review the existing literature.

Follicular Fluid-Specific Distribution of Vascular Endothelial Growth Factor Isoforms and sFlt-1 in Patients Undergoing IVF and Their Correlation With Treatment Outcomes

Objective: To investigate the distribution of vascular endothelial growth factor (VEGF) isoforms and soluble form of VEGF receptor 1 (sFlt-1) in the follicular fluid (FF) of in vitro fertilization (IVF) patients in relationship to age, body mass index (BMI), diagnosis of polycystic ovary syndrome (PCOS), and their correlation with IVF outcomes. Design: Prospective study. Main Outcome Measures: VEGF 121 and VEGF165 isoforms were detected using Western blotting and pixel density analysis. The concentration of sFlt-1 was determined by enzyme-linked immunosorbent assay (ELISA). In vitro fertilization outcomes measured included number of oocytes retrieved, fertilization rate, and clinical pregnancy. Statistical analysis used the Kruskal-Wallis and Mann-Whitney U test where appropriate. Results: There was a statistically significant association between higher VEGF165 levels and the diagnosis of PCOS, BMI ≥ 30, and age ≥40 years. In vitro fertilization cycles resulting in pregnancy were linked to statistically lower VEGF165 levels in the FF. No statistically significant trend was identified in levels of VEGF121 or sFlt-1 relative to patient characteristics or IVF outcomes. Conclusion: Our results suggest that elevated VEGF165 levels are associated with less favorable patient characteristics and clinical IVF outcomes.

Short-Term Energy Deprivation Alters Activin A and Follistatin But Not Inhibin B Levels of Lean Healthy Women in a Leptin-Independent Manner

CONTEXT Leptin is a potent modulator of the hypothalamic-pituitary-gonadal axis mediating the effect of energy deprivation on several hypothalamic-pituitary-peripheral axes. Activin A, inhibin B, and follistatin (FST) also regulate the hypothalamic-pituitary-gonadal axis in humans. It remains unknown whether energy deprivation affects these hormone levels in a leptin-dependent or -independent manner. OBJECTIVE We investigated 1) day-night variability patterns of activin, inhibin, and FST in the fed state, 2) whether their levels are affected by fasting, and 3) whether such an effect is mediated by leptin in physiological replacement or pharmacological doses. DESIGN We conducted two studies in healthy, eumenorrheic females, each comprising three separate admissions. In study 1, six women were maintained for 72 h 1) on isocaloric diet, 2) fasting while receiving placebo, or 3) fasting while receiving metreleptin in physiological replacement doses. In study 2, five women were administered physiological or pharmacological metreleptin doses (0.01, 0.1, or 0.3 mg/kg i.v. four times daily). RESULTS Neither activin A nor FST had a pulsatile or day-night variability pattern. Inhibin B levels were also nonpulsatile, but a trend toward a day-night pattern was noted. When compared with the fed state, inhibin B levels remained unchanged, whereas FST levels increased (P = 0.01) and activin A decreased (P = 0.01) in the fasting state. These changes were not corrected with metreleptin administered in replacement or pharmacological doses. CONCLUSIONS Short-term energy deprivation alters levels of activin A and FST, but these effects are not mediated by leptin.

Thicker endometrial linings are associated with better IVF outcomes: a cohort of 6331 women

Abstract Our objective was to determine if a correlation exists between endometrial thickness measured on the day of ovulation trigger during an in vitro fertilization (IVF) cycle and pregnancy outcomes among non-cancelled cycles. We performed a retrospective cohort study looking at 6331 women undergoing their first, fresh autologous IVF cycle from 1 May 2004 to 31 December 2012 at Boston IVF (Waltham, MA). Our primary outcome was the risk ratio (RR) of live birth and positive β-hCG. We found that thicker endometrial linings were associated with positive β-hCG and live birth rates. For each additional millimetre of endometrial thickness, we found a statistically significant increased risk of positive β-hCG (adjusted RR: 1.14; 95% CI: 1.09–1.18) and live birth (RR: 1.08; 95% CI: 1.05–1.11). There was no association between endometrial thickness and miscarriage (RR: 0.99; 95% CI: 0.91–1.07). Similar results were seen when categorizing endometrial thickness. Compared with an endometrial thickness >7 to <11 mm, the likelihood of a live birth was significantly higher for an endometrial thickness ≥11 mm (adjusted RR: 1.23; 95% CI: 1.11–1.37) and significantly lower for the ≤7 mm group (adjusted RR: 0.64; 95% CI: 0.45–0.90). In conclusion, thicker endometrial linings were associated with increased pregnancy and live birth rates.

Methotrexate treatment of ectopic pregnancies does not affect ovarian reserve in in vitro fertilization patients.

The incidence of ectopic pregnancies (EP) is estimated to be 1%–2% of all pregnancies, and they account for 5%–6% of all maternal mortality in developed countries. One of the major risk factors of EP is the use of assisted reproductive technologies (ART). The first IVF pregnancy was reported to be ectopic in 1976, and even today the incidence of EP increases threefold when ART is used. The diagnosis of EP relies on early monitoring with serum hCG levels and serial ultrasounds. Early diagnosis is associated with earlier treatment and lower likelihood of complications. EP has traditionally been treated with conservative (salpingostomy) or radical (salpingectomy) surgery, but as early as 1982 medical treatment with methotrexate (MTX) was introduced as a promising alternative. Since then, clinical experience and multiple studies have demonstrated that MTX for the treatment of spontaneous EP is at least equivalent to surgery in terms of safety, efficacy, and return to fertility. MTX is an antimetabolite inhibitor of dihydrofolate reductase that interrupts DNA synthesis, repair, and cell replication. It thus affects actively proliferating tissue, such as the trophoblastic tissue of EP, and it is 75%–95% effective when administered to carefully selected patients. MTX could also affect antral and primordial ovarian follicles. Even though high doses of MTX and other chemotherapeutic agents are known to inflict ovarian damage, the doses used for the treatment of EP do not seem to have such an effect. However, it is worth noting that patients who undergo ART oftentimes have an already compromised ovarian reserve. Furthermore, controlled ovarian hyperstimulation and gonadotropin stimulation during ART results in an increase in the blood supply to the ovary and a metabolic activation of the follicular cohort. It has thus been hypothesized that these conditions could render post-ART ovaries that are exposed to MTX more vulnerable to its toxicity. The effect of MTX treatment was not studied specifically in the ART population until 2007, when a study of 14 patients demonstrated no difference in the dose of gonadotropins, length of stimulation, number of oocytes retrieved, or fertilization rates before and after MTX treatment for EP. A study by Oriol et al. in 2008 (1) was the only one to date to quantitate ovarian reserve by antim€ ullerian hormone levels before and after treatment with MTX after a mean waiting time of 7.5 months. This study failed to find a statistically significant difference in 14 IVF-intracytoplasmic sperm injection patients. It also found no difference in terms of stimulation parameters, oocytes retrieved, or embryos produced. In a more recent study (2), the subgroup analysis of 430 patients who had either a history of infertility or tubal disease or who were over 35 years of age showed that those previously treated medically or with salpingostomy were more likely to achieve pregnancy than those who had undergone salpingectomies. Interestingly, there was no difference noted in younger patients without a history of infertility or tubal disease. McLaren et al. (3) retrospectively analyzed 48 IVF cycles after MTX treatment for EP and identified a statistically