William Buckett

Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection.

OBJECTIVE: To compare obstetric outcome and congenital abnormalities in pregnancies conceived after in vitro maturation (IVM), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) with those in spontaneously conceived controls. METHODS: Data were collected from the McGill Obstetrics and Neonatal Database (MOND). All children were examined and classified in a standard manner. Final data were reviewed 12 months after delivery. Pregnancies by IVM, IVF, and ICSI were compared with those of age- and parity-matched controls. Congenital abnormality, gestational age, birth weight, Apgar scores, cord pH, growth restriction, pregnancy complications, mode of delivery, and multiple pregnancy were compared. RESULTS: A total of 432 children were born from 344 pregnancies after assisted reproductive technology (ART) during the study period (IVM 55, IVF 217, ICSI 160). The observed odds ratios (ORs) for any congenital abnormality were 1.42 (95% confidence interval [CI] 0.52–3.91) for IVM, 1.21 (95% CI 0.63–2.62) for IVF, and 1.69 (95% CI 0.88–3.26) for ICSI. Twin pregnancy (IVM 21%, IVF 20%, ICSI 17%) and triplet pregnancy (IVM 5%, IVF 3%, ICSI 3%) were higher than those in controls (1.7% twins and 0% triplets) (P<.001). Cesarean delivery rates were higher after ART, even in singleton pregnancies (IVM 39%, IVF 36%, ICSI 36%; controls: 26.3%) (P<.05). Apgar scores, cord pH, growth restriction, and pregnancy complications were comparable in all groups. CONCLUSION: All ART pregnancies are associated with an increased risk of multiple pregnancy, cesarean delivery, and congenital abnormality. Compared with IVF and ICSI, IVM is not associated with any additional risk. LEVEL OF EVIDENCE: II

In-vitro maturation of human oocytes

Immature human oocytes can be matured and fertilized in vitro. However, subsequent embryonic development is different when the immature oocytes are retrieved in different situations. Exposure to the LH surge in vivo may be important for the oocytes to acquire the competence for maturation and subsequent embryonic development. The size of the follicles may also be an important feature for subsequent embryonic development. However, the developmental competence of oocytes derived from small antral follicles does not seem to be adversely affected by the presence of a dominant follicle. Oocyte maturation in vitro is profoundly affected by culture conditions. Gonadotrophins are required for oocyte maturation in vivo, but any requirement in vitro is still unclear. Recent clinical results from in-vitro matured (IVM) human oocytes are promising, although further research remains to be done in order to address the mechanisms of oocyte maturation and to improve culture conditions and also the implantation rate of embryos generated from IVM oocytes.

Priming with human chorionic gonadotropin before retrieval of immature oocytes in women with infertility due to the polycystic ovary syndrome.

To the Editor: Women who have infertility due to anovulation in association with the polycystic ovary syndrome are particularly difficult to treat. A substantial proportion have no response to the ...

Obstetric outcomes following vitrification of in vitro and in vivo matured oocytes

OBJECTIVE To evaluate obstetric outcomes with oocyte vitrification after ovarian stimulation (OS) and in vitro maturation (IVM) of immature oocytes. DESIGN A prospective trial from October 2003 to April 2007. SETTING University-based medical center. PATIENT(S) OS group: 38 patients undergoing intrauterine insemination who overresponded to OS. IVM group: 20 patients who had previous unsuccessful intrauterine insemination. INTERVENTION(S) Mature oocyte retrieval following OS. Immature oocyte retrieval and IVM. Oocyte vitrification, thawing, insemination, and transfer of the resulting embryos. MAIN OUTCOME MEASURE(S) Live-birth rates and obstetric outcomes. RESULT(S) The OS group was superior to the IVM group in terms of oocyte survival (81.4 +/- 22.6% vs. 67.5 +/- 26.1%), fertilization rate (75.6 +/- 22.5% vs. 64.2 +/- 19.9%), and cumulative embryo score (38.4 +/- 22.3 vs. 20.0 +/- 13.8). However, the differences in the implantation rate per embryo (19.1 +/- 25.8% vs. 9.6 +/- 24.1%), clinical pregnancy rate per cycle started (44.7%, vs. 20.0%), and live-birth rate per cycle started (39.5% vs. 20.0%) were not statistically significant. Twenty healthy babies were born in the OS group and four in the IVM group. CONCLUSION(S) Pregnancies achieved with vitrification of oocytes after OS and IVM treatments do not appear to be associated with adverse pregnancy outcomes. Vitrification of IVM oocytes represents a novel option for fertility preservation.

Live birth after vitrification of in vitro matured human oocytes

OBJECTIVE To report the first healthy live birth from immature oocytes retrieved in a natural menstrual cycle, followed by in vitro maturation (IVM) and cryopreservation of the oocytes by vitrification. DESIGN Case report. SETTING University-based tertiary medical center. PATIENT(S) A 27-year-old woman with tubal disease and polycystic ovaries. INTERVENTION(S) Immature oocytes were retrieved by transvaginal ultrasound guided follicle aspiration on day 13 of her natural menstrual cycle, matured in vitro and vitrified. The oocytes were thawed in a subsequent menstrual cycle, inseminated by intracytoplasmic sperm injection, and the resulting embryos transferred. MAIN OUTCOME MEASURE(S) Oocyte maturation and survival rates, pregnancy, and live birth. RESULT(S) One metaphase II and 18 germinal vesicle stage oocytes were collected; 16 out of 18 germinal vesicle oocytes matured, and a total of 17 oocytes were vitrified. After thawing, four IVM oocytes survived; three embryos were transferred. The woman went on to deliver a single healthy live baby at term. CONCLUSION(S) We provide proof-of-principle evidence that the novel fertility preservation strategy of immature oocyte retrieval, IVM, and vitrification of oocytes can lead to successful pregnancy and healthy live birth.

A meta-analysis of ultrasound-guided versus clinical touch embryo transfer.

OBJECTIVE To determine the relative efficacy of ultrasound-guided embryo transfer and embryo transfer by clinical touch alone. DESIGN Systematic review and meta-analysis of randomized, controlled trials comparing ultrasound-guided embryo transfer with embryo transfer by clinical touch alone. SETTING Infertility centers providing treatment with in vitro fertilization/embryo transfer. PATIENT(S) Women undergoing embryo transfer. INTERVENTION(S) Embryo transfer with or without transabdominal ultrasound guidance. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate and embryo implantation rate. RESULT(S) A total of eight prospective controlled trials were identified. Of these studies, four were nonrandomized or quasi-randomized and four were genuinely randomized. Meta-analysis demonstrated a significantly increased chance of clinical pregnancy following ultrasound-guided embryo transfer in all studies and in the genuinely randomized subgroup. The embryo implantation rate was also significantly increased following ultrasound-guided embryo transfer. CONCLUSION(S) Ultrasound-guided embryo transfer significantly increases the chance of clinical pregnancy and significantly increases the embryo implantation rate.

Pregnancies resulting from in vitro matured oocytes retrieved from patients with polycystic ovary syndrome after priming with human chorionic gonadotropin.

OBJECTIVE To describe pregnancies that resulted from in vitro matured oocytes derived from two unstimulated, anovulatory patients with polycystic ovary syndrome after priming with hCG before oocyte retrieval. DESIGN Case series. SETTING McGill Reproductive Center, Royal Victoria Hospital, McGill University. PATIENT(S) Two women with polycystic ovary syndrome. INTERVENTION(S) Progesterone induction of a withdrawal bleeding episode. The administration of subcutaneous hCG 36 hours before oocyte retrieval in a natural menstrual cycle. In vitro maturation of immature oocytes, fertilization, and ET. Luteal support with oral estrogen and progesterone. MAIN OUTCOME MEASURE(S) Pregnancy outcome. RESULT(S) Two clinical pregnancies were confirmed after oocyte maturation in vitro, fertilization with intracytoplasmic sperm injection, and ET. CONCLUSION(S) The administration of hCG 36 hours before harvesting of immature oocytes may improve the maturational and developmental competence of the oocytes and the pregnancy rates of unstimulated patients with polycystic ovary syndrome.

Comparison of in-vitro maturation cycles with and without in-vivo matured oocytes retrieved

This study compared the embryological characteristics and clinical outcome of in-vitro maturation (IVM) treatment cycles with and without in-vivo matured oocytes collected following human chorionic gonadotrophin (HCG) priming. The patients were administered 10,000 IU of HCG subcutaneously when endometrial thickness reached > or =6 mm and oocyte collection was performed 35-36 h after HCG administration. The clinical outcome and embryological aspects were analysed between IVM cycles with (group 1) and without (group 2) in-vivo matured oocytes. In group 1, three (range 1-12) in-vivo matured oocytes per patient were retrieved on average. The number of good quality embryos derived from in-vivo matured oocytes in group 1 was significantly higher than those derived from in-vitro matured oocytes in group 1 and group 2 (P < 0.05). However, there was no difference between the number of good quality embryos produced from in-vitro matured oocytes in the two groups. There were 12 clinical pregnancies (40.0%) in group 1, and seven pregnancies (23.3%) in group 2. These results suggest that IVM cycles with in-vivo matured oocytes resulted in a good clinical pregnancy rate, which could be explained by the superior quality of embryos derived from the in-vivo matured oocytes.

A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage

OBJECTIVE To estimate whether intravenous immunoglobulin (IVIG) improves the probability of a live birth in women with unexplained recurrent miscarriage (RM). DESIGN A computerized search in Medline, Embase, Central, Ovid Medline In-Process, and Other Non-Indexed Citations Databases and randomized controlled trial (RCT) registries was performed. Abstracts of the American Society of Reproductive Medicine and European Society of Human Reproduction and Embryology annual meetings and reference lists of identified reports were searched. SETTING None. PATIENT(S) Women with unexplained primary (without a prior live birth) or secondary (subsequent to a live birth) RM. INTERVENTION(S) IVIG or placebo control intervention. MAIN OUTCOME MEASURE(S) Live birth rate per randomized woman. RESULT(S) Six relevant RCTs were identified including 272 women with unexplained RM. The overall odds ratio for live birth is 0.92, with a 95% confidence interval of 0.55-1.54, indicating a lack of a treatment effect with IVIG. Similarly, IVIG was not found to be beneficial when women with primary and secondary RM were analyzed separately. CONCLUSION(S) A beneficial effect of IVIG in treatment of RM was not observed. Given the absence of a proven mechanism of action, and the lack of a diagnostic algorithm to identify patients who are likely to benefit from such treatment, IVIG administration for treatment of recurrent miscarriage is not justified outside the context of properly designed RCTs.

NLRP7 in the spectrum of reproductive wastage: rare non-synonymous variants confer genetic susceptibility to recurrent reproductive wastage

Background NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. Methods/Results All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1β and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. Conclusions The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.