V. Gunnala

In vitro fertilization versus conversion to intrauterine insemination in the setting of three or fewer follicles: how should patients proceed when follicular response falls short of expectation?

OBJECTIVE To determine whether in vitro fertilization (IVF) cycles with suboptimal response should be converted to intrauterine insemination (IUI) or proceed to oocyte retrieval (OR). DESIGN Retrospective cohort. SETTING Academic medical center. PATIENT(S) All patients initiating IVF from January 2004 through December 2011. INTERVENTION(S) OR versus conversion to IUI. MAIN OUTCOME MEASURE(S) A total of 1,098 patients were identified whose IVF cycles were characterized by recruitment of three or fewer follicles, excluding patients with bilateral tubal disease or severe male factor. Cycles with three follicles were defined as those with three follicles ≥ 14 mm with no fourth follicle ≥ 10 mm. Cycles with two or fewer follicles were similarly defined. Outcomes were compared for patients proceeding with OR (n = 624) versus converting to IUI (n = 474). Age-adjusted relative risks for pregnancy were calculated, stratifying for number of follicles. RESULT(S) The likelihood of retrieving at least one mature oocyte (82.9% vs. 94.8% vs. 96.2%), having at least one zygote (61.9% vs. 76.8% vs. 84.2%), and undergoing transfer (57.1% vs. 73.0% vs. 83.3%) increased significantly with increasing follicle number. Patients with three or fewer follicles were 2.6 times more likely to achieve a live birth with IVF versus IUI (9.3% vs. 3.4%). This benefit was only apparent when at least two follicles were present. No benefit was gained by performing OR in the setting of one follicle. CONCLUSION(S) IVF compared with IUI presents superior pregnancy rates in the setting of two or more follicles. Assisted reproduction programs may benefit their patients by pursuing IVF in this scenario.

Oocyte vitrification for elective fertility preservation: the past, present, and future

Purpose of review Oocyte cryopreservation is no longer experimental and one of its rapidly growing indications is elective fertility preservation. Currently there is no sufficient evidence to support its practice and therefore its place in IVF remains uncertain. Recent findings Vitrification has superior post-thaw survival and fertilization outcomes compared with oocytes that were frozen with the slow-freeze technique. Oocyte vitrification produces similar IVF outcomes compared with fresh oocytes and is not associated with further obstetrical or perinatal morbidity. Undergoing elective oocyte cryopreservation between ages 35 and 37 will optimize live birth rates as well as cost effectiveness from mathematical models. Summary In women who delay child bearing, elective oocyte cryopreservation in the mid 30s may be beneficial in terms of live birth rates and cost effectiveness. Prospective studies of women who have undergone oocyte cryopreservation and are now attempting conception are needed before official recommendations can be made regarding elective egg freezing.

Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women ≥43 years old?

OBJECTIVE To determine the number of cleavage-stage embryos that can be safely transferred in women ≥43 years old. DESIGN Retrospective cohort. SETTING Academic medical center. PATIENT(S) All patients ≥43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012. INTERVENTION(S) In vitro fertilization. MAIN OUTCOME MEASURE(S) A total of 567 cycles in 464 patients aged 43-45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred. RESULT(S) Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos. CONCLUSION(S) Transferring five or more day 3 embryos may be a safe option for patients ≥43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional embryo(s) for transfer or the inherently better prognosis of such patients remains to be determined.

Sliding scale HCG trigger yields equivalent pregnancy outcomes and reduces ovarian hyperstimulation syndrome: Analysis of 10,427 IVF-ICSI cycles

Objective To evaluate pregnancy outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS) using a sliding scale hCG protocol to trigger oocyte maturity and establish a threshold level of serum b-hCG associated with optimal oocyte maturity. Design Retrospective cohort. Setting Academic medical center. Patients Fresh IVF cycles from 9/2004–12/2011. Intervention 10,427 fresh IVF-ICSI cycles met inclusion criteria. hCG was administered according to E2 level at trigger: 10,000IU vs. 5,000IU vs. 4,000IU vs. 3,300IU vs. dual trigger (2mg leuprolide acetate + 1,500IU hCG). Serum absorption of hCG was assessed according to dose and BMI. Main outcome measures Oocyte maturity was analyzed according to post-trigger serum b-hCG. Fertilization, clinical pregnancy, live birth and OHSS rates were examined by hCG trigger dose. Results Post-trigger serum b-hCG 20–30, 30–40, and 40–50 mIU/mL was associated with reduced oocyte maturity as compared b-hCG >50 (67.8% vs. 71.4% vs. 73.3% vs. 78.9%, respectively, P<0.05). b-hCG 20–50 mIU/mL was associated with a 40.1% reduction in live birth (OR 0.59, 95% CI 0.41–0.87). No differences in IVF outcomes per retrieval were seen for varying doses of hCG or dual trigger when controlling for patient age. The incidence of moderate to severe OHSS was 0.13% (n = 14) and severe OHSS was 0.03% (n = 4) of cycles. Conclusions Moderate stimulation with sliding scale hCG at trigger and fresh transfer is associated with low rates of OHSS and favorable pregnancy rates. Doses as low as 3,300IU alone or dual trigger with 1,500IU are sufficient to facilitate oocyte maturity.

Robot-Assisted Myomectomy for Large Uterine Myomas: A Single Center Experience

Objective. To determine if robot-assisted myomectomy (RAM) is feasible for women with large uterine myomas. Methods. Retrospective review of one gynecologic surgeons RAM cases between May 2010 and July 2013. Large uterine myomas, defined as the largest myoma ≥9 cm by preoperative magnetic resonance imaging, was age- and time-matched to controls with the largest myoma <9 cm. Primary surgical outcomes compared were operative time and estimated blood loss (EBL). Results. 207 patients were included: 66 (32%) patients were in the ≥9 cm group, while 141 (68%) patients were in the <9 cm group. There was a statistically significant increase in the operative time (130 min versus 92 min) and EBL (100 mL versus 25 mL) for the ≥9 cm group compared to the <9 cm group. Ten (4.8%) patients had the largest myoma measuring ≥15 cm, and 11 (5.3%) patients had a specimen weight >900 gm, of which no major adverse outcomes were observed. All patients in the study cohort were discharged on the same day after surgery. Conclusion. RAM is a feasible surgical approach for patients with myomas ≥9 cm. Patients with large myomas undergoing RAM are also candidates for same-day discharge after surgery.

A rationale for biopsying embryos reaching the morula stage on Day 6 in women undergoing preimplantation genetic testing for aneuploidy

STUDY QUESTION Is there a benefit to assessing ploidy in delayed embryos reaching the morula stage on Day 6 of development? SUMMARY ANSWER Day-6 morulae should be considered for biopsy in women <40 years old undergoing preimplantation genetic testing for aneuploidy (PGT-A) because they are associated with acceptable, albeit reduced, euploidy and implantation rates (IRs). WHAT IS KNOWN ALREADY Embryo development and morphology have been shown to correlate with aneuploidy and pregnancy rates. During PGT-A cycles, embryos are biopsied if they reach the blastocyst stage by Day 5 or 6, whereas slow-developing embryos are typically deselected and discarded. Determining the viability of slow-developing embryos is particularly relevant for women undergoing PGT-A who have diminished ovarian reserve and a relatively low blastocyst yield. STUDY DESIGN, SIZE, DURATION This is a retrospective cohort study that was performed at an academic medical center. Patients who underwent IVF with PGT-A were reviewed for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 1615 cycles were reviewed. All cycles which involved a biopsy of a cavitating or compacted morula on Day 6 were included (n = 763). PGT-A was performed using array comparative genomic hybridization. The aneuploidy and implantation of morulae were compared to those of blastocysts originating from the same couples. MAIN RESULTS AND THE ROLE OF CHANCE The study included 763 cycles in which 1260 morulae and 3014 blastocysts were biopsied. Women were divided into four age groups (<35, 35-37, 38-39 and ≥40 years): the prevalence of aneuploidy was consistently lower among blastocysts (40.3, 50.8, 56 and 78.3%, respectively) than among compacted morulae (68.7, 75.5, 88.9 and 98.1%, respectively) and cavitating morulae (57, 66.4, 81 and 91.6%, respectively) throughout the different age groups (P < 0.001). Of note, the majority of compacted morulae (98.1%) and cavitating morulae (91.6%) were aneuploid in women aged ≥40 years. Compacted and cavitating morulae had significantly higher rates of complex aneuploidy, which involves ≥3 chromosomes, compared with blastocysts (P < 0.001). Furthermore, euploid morulae were associated with a significantly lower IR (28.2 versus 54.6%; P = 0.002) and live birth rate (23.1 versus 55.0%; P = 0.001) compared to euploid blastocysts. LIMITATIONS REASONS FOR CAUTION This study confirms that Day-6 morulae should not be discarded in young women undergoing PGT-A. However, a potential drawback of biopsying embryos at the morula stage is the inability to distinguish between inner cell mass and trophectoderm cell origin. The sample size of euploid morula transfer cycles in this study was limited. Thus, a larger cohort would be beneficial to validate the reassuring live birth and spontaneous abortion rates reported here. Furthermore, the reproducibility of our findings should be determined at different centers. WIDER IMPLICATIONS OF THE FINDINGS Although Day-6 morulae are associated with higher aneuploidy rates and lower IRs compared to blastocysts, they still yielded successful pregnancies. Therefore, testing Day-6 morulae should be considered, especially for women <40 years old who are undergoing PGT-A with a small cohort of available blastocysts for biopsy. STUDY FUNDING/COMPETING INTEREST(S) The authors have nothing to disclose. They received no specific funding for this work. TRIAL REGISTRATION NUMBER N/A.

High Serum IGF-1 Levels are Associated With Pregnancy Loss Following Frozen-Thawed Euploid Embryo Transfer Cycles

An elevated level of insulin growth factor (IGF-1) in rat uterine fluid has been shown to exert detrimental effects of embryo development possibly leading to an increase in pregnancy loss. Interestingly, the administration of somatostatin to rats undergoing superovulation reduced IGF-1 levels in uterine luminal fluid and thus reversed its deleterious effects on embryo development and increased the number of normal embryos. Therefore, we investigated whether serum levels of IGF-1 correlate with the incidence of pregnancy loss following IVF. To account for aneuploidy and the effect of hormonal supplementation on serum IGF levels, we only included natural frozen-thawed euploid embryo transfer (N-FET) cycles. Sera collected in the follicular phase (cycle day 10) were tested for levels of IGF-1, IGF-2, and IGF-binding protein 1 (IGFBP-1) using quantitative ELISA. A total of 156 N-FET cycles were included: 120 resulted in a live birth whereas 36 led to a first trimester pregnancy loss. Women with a pregnancy loss had significantly higher serum IGF-1 levels compared to those who achieved a live birth (18.0 ± 1.1 vs. 14.6 ± 0.7 ng/mL, respectively). The two groups had comparable serum IGF-2 and IGFBP-1 levels. There was no significant difference in maternal age, body mass index, gravidity, parity, number of prior miscarriages, peak endometrial thickness, or infertility diagnosis between the two groups. In conclusion, women undergoing euploid blastocyst transfer with elevated serum IGF-1 concentrations may be at increased risk of pregnancy loss. This may constitute a novel molecular explanation of pregnancy loss of euploid conceptus.

Unilateral pleural effusion as the sole clinical presentation of severe ovarian hyperstimulation syndrome: a systematic review

Abstract The pathophysiology of isolated pleural effusion in ovarian hyperstimulation syndrome (OHSS) is not well defined. The objective of the current review is to delineate the pathophysiology, risk factors, preventive measures, and therapeutic options of isolated pleural effusion in severe OHSS. Major databases were searched until June 2016. Studies evaluating women who presented with pleural effusion as the sole extra-ovarian manifestation of severe OHSS were included. Data were extracted from 24 articles encompassing 30 reported cases. Values were expressed as mean ± SEM. Patients were young (31.5 ± 0.8 years old) and 29.1% of them were diagnosed with polycystic ovary syndrome. All the patients received human chorionic gonadotropin to trigger oocyte maturation. Estradiol level was 3110 ± 330 pg/mL on the day of the ovulatory trigger. Dyspnea was the presenting symptom in 86.6% of the patients. Pleural effusion was predominantly on the right side (80%). Ninety percent of the patients underwent thoracentesis (4332 ± 769 mL): 66.7% exudate and 33.3% transudate. Fluid initially accumulates in the peritoneal cavity then enters the pleural space due to the pressure gradient through the thoracic duct and diaphragmatic defects, which are more common on the right side. The risk factors, prevention, and management, which are also discussed in this review, are similar to those of severe OHSS.

Abdominal ectopic pregnancy with undetectable serum β‐human chorionic gonadotropin 9 days following blastocyst transfer

With the availability of the highly sensitive β‐human chorionic gonadotropin (β‐hCG) assays, all pregnancies, including ectopic pregnancies (EP), are expected to have detectable serum β‐hCG at 4 weeks’ gestation or 9 days following blastocyst transfer. To our knowledge, this is the first report of a woman who underwent in vitro fertilization, had undetectable serum β‐hCG 9 days after blastocyst transfer, and was then diagnosed with a ruptured abdominal EP and intra‐abdominal bleeding 19 days later. This case highlights that the rise in serum β‐hCG might be delayed in abdominal EP compared to intrauterine pregnancy. This delay should raise the suspicion for EP, thus meriting close monitoring. Moreover, in the absence of menstruation, an undetectable serum β‐hCG 9 days post‐blastocyst transfer should prompt β‐hCG measurement in 2–3 days to avoid the misdiagnosis of an EP.