Michael H. Dahan

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG

STUDY QUESTION Is severe early ovarian hyperstimulation syndrome (OHSS) completely prevented with the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol? SUMMARY ANSWER Severe early OHSS can occur even after the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol. WHAT IS KNOWN ALREADY Prior studies including over 200 women who received the GnRH agonist trigger and 1500 hCG luteal rescue protocol have reported complete prevention of severe early OHSS. Only a few late OHSS cases have been reported and it has been suggested that this protocol can be safely applied to any women under risk. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included all women who were at high risk of OHSS and were given the GnRH agonist trigger plus hCG luteal rescue protocol between December 2008 and August 2012 in the two participating centers. PARTICIPANTS/MATERIALS, SETTING, METHODS There were 23 women with a mean estradiol level of 4891 ± 2214 pg/ml and a mean number of >12 mm follicles of 20 ± 6 on the day of ovulation triggering. OHSS was categorized according to the Golan criteria. MAIN RESULTS AND THE ROLE OF CHANCE Overall 6 of the 23 (26%) women developed severe OHSS. Five women had severe early OHSS requiring ascites drainage and hospitalization and three of these women did not undergo embryo transfer. The number of follicles measuring 10-14 mm on the day of triggering was significantly different between women who developed severe early OHSS and those who did not. LIMITATIONS, REASONS FOR CAUTION The small number of women with severe early OHSS may have prevented identification of other significant risk factors. WIDER IMPLICATIONS OF THE FINDINGS Although the GnRH agonist plus 1500 IU hCG luteal rescue protocol significantly decreases the risk of severe OHSS, this life threatening complication can still occur in high-risk patients. It would be prudent to avoid hCG luteal rescue and freeze all embryos for future transfer in such women particularly when there are ≥18 follicles with 10-14 mm diameters even with few larger follicles.

Relationship of GnRH‐stimulated LH release to episodic LH secretion and baseline endocrine‐metabolic measures in women with polycystic ovary syndrome

background and objective  In polycystic ovary syndrome (PCOS) inappropriate gonadotrophin secretion is characterized by increased pulse frequency and amplitude, elevated 24‐h mean serum concentrations, and greater responses to GnRH. While the mechanism(s) responsible for this increased release of LH are not well understood, enhanced LH secretion has been attributed to increased pituitary sensitivity to GnRH and feedback influences from circulating steroid hormones. To address these considerations, we conducted a study to examine the relationships between GnRH‐stimulated LH responses, episodic gonadotrophin secretion, and baseline measurements of endocrine‐metabolic function in PCOS.

Risk of surgery after use of potassium chloride for treatment of tubal heterotopic pregnancy.

BACKGROUND: Spontaneous heterotopic pregnancies are rare, but with assisted reproductive techniques the incidence may approach 1:100. With the widespread use of transvaginal ultrasonography, physicians have attempted treatment of heterotopic pregnancies with minimally invasive procedures such as transvaginal guided potassium chloride (KCl) injection. However, there are few data on the success of this treatment. CASE: A 30-year-old primigravida presented with a desired pregnancy and was found to have a tubal pregnancy in addition to an intrauterine pregnancy. Ultrasound-guided KCl injection into the heterotopic pregnancy was complicated by abdominal pain, surgical abdomen, and hemoperitoneum requiring salpingectomy. CONCLUSION: A review of the literature revealed that 55% of tubal heterotopic pregnancies treated by KCl injection required subsequent salpingectomy. This raises concerns about the advisability of this treatment.

Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation

OBJECTIVE To evaluate the pregnancy rate, ovarian responsiveness, and endometrial thickness in infertility patients with a history of methotrexate exposure who subsequently underwent controlled ovarian stimulation. DESIGN Retrospective cohort study. SETTING University reproductive endocrinology and infertility program. SUBJECT(S) Forty-eight women with infertility undergoing ovarian stimulation after receiving methotrexate treatment for ectopic gestation. INTERVENTION(S) Methotrexate administration and controlled ovarian stimulation. MAIN OUTCOME MEASURE(S) Pregnancy rate, cycle day 3 FSH levels, number of oocytes retrieved, and endometrial thickness. RESULT(S) The cumulative intrauterine pregnancy rate achieved with controlled ovarian stimulation at 2 years after methotrexate exposure was 43%, with a mean time to conceive of 181 days. Thirty-five patients with similar fertility treatments pre- and post-methotrexate were identified. Within this group, when an IVF cycle occurred within 180 days of methotrexate exposure, a significant decline in oocytes retrieved was observed. Cycles performed later than 180 days after methotrexate exposure did not exhibit a decrease in oocyte production. Endometrial development was similar at all time points examined. CONCLUSION(S) These findings suggest a time-limited and reversible impact of methotrexate on oocyte yield. If confirmed by larger clinical series and/or animal data, these results may impact the management of ectopic gestation in the patient with a history of infertility or the timing of subsequent treatments.

Clinical definition paper on in vitro maturation of human oocytes

In vitro maturation (IVM) of human oocytes is a reproductive technique which has been practiced for 25 years and is gaining popularity. However, the techniques used for IVM differ substantially across clinics and they result in extremely variable pregnancy rates, partially due to some of these differences in protocols. Such differences include the use in some cycles of hCG triggering prior to oocyte retrieval and the use of a few days of gonadotrophin treatment to support moderate follicle growth. Other important factors are patient selection (including those with polycystic ovaries or decreased ovarian reserve), the number of embryos transferred and cleavage-stage embryo or blastocyst transfer. There are also substantial differences of opinion among clinicians regarding IVM and what it implies. Due to the large variation in protocols, a decision was made to write this paper in an attempt to introduce uniformity when comparing treatments and outcomes of IVM. A clinical definition of IVM was developed: The retrieval of oocytes from small and intermediate sized follicles in an ovary before the largest follicle has surpassed 13 mm in mean diameter. The use of short gonadotrophin stimulation should be acknowledged. However, it should be stated that metaphase II oocytes also have the potential to be collected at that time in the cycles associated with either hCG or GnRH agonist priming. Many feel this is not IVM because some mature oocytes are retrieved, therefore, we recommend renaming this procedure either natural cycle IVF or modified natural cycle IVF (if gonadotrophin stimulation is given) with early triggering, combined with IVM The percentage as well as the absolute number of mature oocytes at retrieval should be indicated. The use of these titles will allow transparency when comparing results of IVM cycles.

A comparison of biochemical pregnancy rates between women who underwent IVF and fertile controls who conceived spontaneously

STUDY QUESTION Does IVF affect the biochemical pregnancy rate? SUMMARY ANSWER The likelihood of an early pregnancy loss may be lower and is certainly not higher in IVF cycles when compared with published rates of biochemical pregnancy in fertile women ≤42 years old. WHAT IS KNOWN ALREADY The use of gonadotrophins to stimulate multi-folliculogenesis alters endometrial expression of genes and proteins, compared with unstimulated cycles. Exogenous estrogen and progesterone taken for endometrial preparation in frozen embryo transfer cycles, also cause changes in endometrial gene and protein expression .These endometrial alterations may compromise the ability of embryos to develop once implanted, possibly increasing the biochemical pregnancy rate. STUDY DESIGN, SIZE, DURATION This is a retrospective study, involving 1636 fresh and 188 frozen, single embryo transfer (SET) IVF cycles performed between August 2008 and December 2012. The biochemical pregnancy rate of the 1824 combined IVF and frozen cycles were compared with fertile controls, derived from the three prospective studies in the medical literature that evaluate this rate. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects ≤42-years old, who underwent a SET, as part of a fresh or thawed IVF cycle were considered for inclusion. Each subject is represented only once. The biochemical pregnancy rates were compared with those of historical standard, fertile populations with spontaneous conceptions. MAIN RESULTS AND THE ROLE OF CHANCE The pregnancy rates per transfer for fresh and frozen IVF cycles were similar at 39 and 40%, respectively. There was also no significant difference in the likelihood of pregnancy outcomes (clinical, biochemical and ectopic pregnancy) between fresh IVF and frozen cycles (85.4 versus 85.6%, 13.8 versus 14.8%, 0.5 versus 0%, P = 0.82). However, pregnancy rates decreased in older patients when compared with younger ones P < 0.0001. The biochemical pregnancy rate for fresh and frozen IVF cycles combined was 13.8% of all pregnancies. IVF and frozen cycles were combined as the IVF group treated with hormones for further comparison with the fertile control group. The biochemical pregnancy rate (14%) in the IVF group was lower than the rate based on the total fertile group (18%), P = 0.01 and differed significantly from the rate in two out of the three studies used to establish the normative rate. The age ranges of the IVF and fertile controls were 21-42 years. The mean age in the IVF population was 34.8 years, as compared with 29 years, 29, 4 years and 30.6 years (Zinaman) in the three published studies (mean: 29.4 years). LIMITATIONS, REASONS FOR CAUTION This is a retrospective study and it was impossible to recruit an in-house biochemical pregnancy control population. WIDER IMPLICATIONS OF THE FINDINGS Lower early pregnancy wastage after IVF may be due to the opportunity to select the embryo for transfer. This finding should be confirmed in further studies but supports the idea that embryo selection is an important step. STUDY FUNDING/COMPETING INTERESTS None.

Comparison of complication rates and pain scores after transvaginal ultrasound–guided oocyte pickup procedures for in vitro maturation and in vitro fertilization cycles

OBJECTIVE To compare complication rates and pain scores after oocyte pickup (OPU) in in vitro maturation (IVM) and IVF cycles. DESIGN Retrospective cohort study. SETTING University-affiliated ART center. PATIENT(S) One hundred eighty-eight IVM and 188 IVF OPUs. INTERVENTION(S) IVM OPUs were done using a 19-gauge single-lumen needle, and IVF OPUs were done using a 17-gauge single- or 16-gauge double-lumen needles. MAIN OUTCOME MEASURE(S) Duration of OPU, complication rates, and pain scores during the OPU procedure. RESULT(S) IVM OPU took significantly more time than IVF OPU (22 vs. 15 minutes). Two women in the IVM and four in the IVF group experienced bleeding from the vaginal wall or ovary. None of them required hospitalization, transfusion, or an operative intervention. One patient in each group had pelvic infection. Severe post-OPU abdominal pain occurred in one patient in the IVM group and five patients in the IVF group. No differences were found between pain scores in the IVF and IVM groups (3.4 vs. 3.8). CONCLUSION(S) Although IVM OPU requires more punctures per ovary, it is well tolerated and does not seem to be associated with a higher complication rate than IVF OPU.

The evaluation of pre and post processing semen analysis parameters at the time of intrauterine insemination in couples diagnosed with male factor infertility and pregnancy rates based on stimulation agent. A retrospective cohort study.

OBJECTIVE To identify pre or post processing semen analysis parameters that may be predictive of successful pregnancy in couples with male factor infertility undergoing intra uterine insemination (IUI). To evaluate the pregnancy rate based on ovulation inducing agent in couples with male factor infertility per the 2010 world health organization criteria treated with IUI. STUDY DESIGN This retrospective study was performed at Stanford University medical center. All couples with male factor infertility fitting inclusion criteria were included over a 2 year period of time. 147 couples with male factor infertility were included and 356 IUIs were analyzed. All subjects in this study had Kruger strict analysis >4% normal forms. Logistic regression analysis was used to control for confounding effects and multiplicity. RESULTS The overall pregnancy rate was 5.3%. No parameter in either the pre or post analysis predicted pregnancy. Furthermore, it was found that natural cycle and letrazole treatment had similar pregnancy rates (3% and 3%) p=ns. Similar outcomes were also observed between clomiphene citrate and gonadotropin stimulated cycles (7.5% and 6.0%) p=ns. CONCLUSIONS Total motile sperm count which has been found to be a predictor of pregnancy when evaluated in isolation, may be due to a confounding effect. These low pregnancy rates should be considered when deciding whether to suggest IUI and when selecting a protocol for ovulation induction for couples with male factor infertility.

Spindle examination in unfertilized eggs using the polarization microscope can assist rescue ICSI

Rescue ICSI can induce a high rate of 3 pronuclei (PN) formation from double insemination in eggs already fertilized by IVF but lacking signs of normal pronuclear formation. This study was performed to determine whether the number of 3PN embryos could be reduced by using the polarization microscope for rescue intracytoplasmic sperm injection (ICSI). As a study group, after conventional insemination, 81 unfertilized mature oocytes from 11 couples were checked for the number of spindles using the polarization microscope. One spindle (82.7%) or two spindles (17.3%) were observed in this group. Rescue ICSI was only performed on the unfertilized oocytes showing one spindle. In the control group, 87 mature oocytes which lacked visualization of any fertilization signs were selected for rescue ICSI and none of them underwent observation of the spindle. After rescue ICSI, the normal fertilization rate in the study group was significantly higher than in the control (68.7% versus 43.7%; P=0.0032). The rate of 3PN or 4PN embryos was significantly decreased in the study group with one spindle compared with the group without observation of the spindle (4.5% versus 26.4%; P=0.0004).

Programming ovulation using estrogens for patients to time intercourse.

BACKGROUND: A woman wishing to conceive may be separated from her spouse at the time of ovulation. Moreover, some orthodox Jewish women have a unique problem when they are unable to initiate intercourse before ovulation. They are prohibited from participating in sexual relations from the start of menstruation until 7 days after the end of flow when they go to the ritual bath (mikveh). CASES: Two orthodox Jewish women who ovulated before restarting intercourse were treated with oral estrogens to delay ovulation. CONCLUSION: Women separated from their husbands at the time of ovulation and Jewish women who ovulate before ritual cleansing can effectively use oral estrogens to program ovulation.