Should the modified natural cycle protocol for frozen embryo transfer be modified? A prospective case series proof of concept study.

OBJECTIVE: Modified natural cycles for frozen embryo transfer utilize an ovulation trigger which assists in embryo transfer scheduling and simplifies cycle monitoring. There have been conflicting results with this protocol and modifications may be sought. We wanted to ascertain whether a modified natural protocol for frozen embryo transfer without triggered ovulation but with luteal progesterone support disconnecting the timing of embryo transfer from the timing of the LH surge can achieve a high pregnancy rate. STUDY DESIGN: Candidates for frozen embryo transfer of 48-h cleavage cell embryos were recruited from May 2016 to April 2018. The patients were monitored for endometrial growth, follicle formation and estradiol, progesterone, and LH hormone levels. After meeting the predetermined criteria, embryo transfer was scheduled. The patients began progesterone treatment 48 h before embryo transfer, regardless of identification of the LH surge if ovulation had not commenced. The predetermined primary outcome was the biochemical pregnancy rate while the secondary outcome included the clinical pregnancy rate and the ongoing pregnancy rate. Patients were monitored to the eighth week of pregnancy, but data was collected from the medical records to provide the live birth rate as well. RESULTS: Fifty-six women were screened. Eleven women declined or did not meet the inclusion criteria. Three had anovulatory cycles and were excluded. Forty-two women were included in the statistical analysis. The implantation rate was 42.9 % [95 %CI 29.3 %-56.4 %). Of the 42 participants, 25 (59.5 %) conceived [95 % CI 44.0 %-75 %]. Two pregnancies ended in first trimester miscarriage leaving 23 (54.7 %) ongoing pregnancies [95 % CI 39.1 %-70.5 %]. One patient experienced a late abortion such that the live birth rate was 22 of 42 patients or 52.4 % [95 % CI 36.4 %-68.0 %]. CONCLUSION: The proposed modified natural protocol which utilizes progesterone luteal support but does not trigger ovulation, maintains a high pregnancy rate while providing flexibility regarding the day of transfer disconnected from the day of the LH surge. This was a prospective, proof of concept study. This protocol may be suitable for smaller or public in-vitro fertility units whose resources are limited and facilities are not available daily. The high pregnancy and live birth rate that we found provides confidence that this protocol can be part of the armament of protocols the clinician may offer to his patients. Larger studies should confirm these findings.

Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.

BACKGROUND: In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger. METHODS: We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015. RESULTS: Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section. CONCLUSION: Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency.

Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.

Empty follicle syndrome: successful treatment in a recurrent case and review of the literature.

Empty follicle syndrome is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. It is a rare condition of obscure etiology. A patient with primary infertility who underwent seven assisted reproductive technique cycles is described. In spite of a satisfactory ovarian response, aspiration yielded no oocytes in four cycles and 1-4 low quality oocytes in three cycles. In the index treatment cycle, ovulation was triggered using GnRH agonist 40 h prior to ovum pickup and hCG was added 6 h after the first trigger. Eighteen oocytes were recovered, of which 16 were mature and were inseminated by ICSI. Two embryos were transferred 48 h after aspiration and nine embryos were cryopreserved. The patient conceived and delivered a healthy boy at 38 weeks of gestation. The literature is reviewed and possible etiologies and treatment options of this enigmatic syndrome are suggested.

GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data.

BACKGROUND: Cancer survival rates in young women are improving due to progress in treatment. This includes aggressive chemotherapy, a treatment that often poses a threat to fertility. GnRH agonists were proposed as ovarian protectors during gonadotoxic therapies. This study was undertaken in order to determine the clinical evidence concerning this issue. METHODS: The medical literature was searched for studies that reported on ovarian function after the administration of GnRH agonists concomitant with chemotherapy. Twelve studies met the predetermined selection criteria. RESULTS: Data on ovarian function were obtained for 579 women who received chemotherapy. Among 345 women who received GnRH agonist co-treatment, ovarian function was preserved in 91% and 9% had premature ovarian failure. In 234 women who did not receive GnRH agonist co-treatment, ovarian function was preserved in 41% and failed in 59%. Only two of the studies were randomized. The control and the GnRH agonist groups differed in several important characteristics: the follow-up times were not equal, different treatment protocols were utilized and end-points were poorly defined and inconsistent between the studies. CONCLUSIONS: The effectiveness of GnRH agonists as fertility-preserving agents is debatable. A thorough literature search has found insufficient evidence to show that GnRH agonist co-treatment is effective in protecting the ovary from the damage of chemotherapy. A large randomized controlled trial with adequate follow-up is needed.