David E. Reichman

Pregnancy outcomes in unicornuate uteri: a review

OBJECTIVE To elucidate the impact of unicornuate uteri on pregnancy outcomes as evidenced by historical and contemporary studies. DESIGN Publications related to unicornuate uterus were identified through MEDLINE and other bibliographic databases. SETTING Literature review in an academic research environment. PATIENT(S) Premenopausal women with confirmed unicornuate uterus based on surgical or radiological evidence who were undergoing gynecologic and obstetrical care. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Rates of ectopic pregnancy, miscarriage, preterm delivery, intrauterine fetal demise, and live birth. RESULT(S) Our review revealed 20 studies of varying size and design that had commented on pregnancy outcomes in unicornuate uteri. These studies ranged in date from 1953 to 2006 and from a sample size of one to 55 patients. In total, we examined 290 women with unicornuate uterus reported in the literature. Of those patients, 175 conceived, to carry a total of 468 pregnancies. Incidence data in the literature reveal that unicornuate uterus occurs in 1:4020 women in the general population; the anomaly, however, is significantly more common in infertile women, as in women with repeated poor outcomes. Our review revealed rates of 2.7% ectopic pregnancy, 24.3% first trimester abortion,9.7% second trimester abortion, 20.1% preterm delivery, 3.8% intrauterine fetal demise, and 51.5%live birth [corrected]. CONCLUSION(S) Unicornuate uterus is a Mullerian anomaly with prognostic implications for poorer outcomes during pregnancy. The rates of adverse outcomes have likely been historically overestimated. Although it is unclear whether interventions before conception or early in pregnancy such as resection of the rudimentary horn and prophylactic cervical cerclage decidedly improve obstetrical outcomes, current practice suggests that such interventions may be helpful. Women presenting with a history of this anomaly should be considered high-risk obstetrical patients.

Congenital uterine anomalies affecting reproduction

The following review seeks to summarise the current data regarding reproductive outcomes associated with congenital uterine anomalies. Such malformations originate from adverse embryologic events ranging from agenesis to lateral and vertical fusion defects. Associated renal anomalies are common both for the symmetric and asymmetric malformations. While fertility is minimally impacted upon by müllerian anomalies in most cases, such malformations have historically been associated with poor obstetric outcomes such as recurrent miscarriage, second trimester loss, preterm delivery, malpresentation and intrauterine foetal demise (IUFD). The following review delineates the existing literature regarding such outcomes and indicates therapies, where applicable, to optimise the care of such patients.

Value of antimüllerian hormone as a prognostic indicator of in vitro fertilization outcome

OBJECTIVE To determine the predictive attributes of antimüllerian hormone (AMH) in terms of oocyte yield, cycle cancellation, and pregnancy outcomes. DESIGN Retrospective cohort. SETTING Academic center. PATIENT(S) All patients initiating IVF at the Weill-Cornell Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine from April 2010 through January 2013. INTERVENTION(S) In vitro fertilization without preimplantation genetic testing. MAIN OUTCOME MEASURE(S) Number of oocytes retrieved, cycle cancellation, clinical and ongoing pregnancy, implantation, and miscarriage rates. RESULT(S) Antimüllerian hormone was positively correlated with number of eggs retrieved. Number of oocytes retrieved increased with increasing AMH within each age group and diminished slightly within AMH groupings as age increased. Overall, AMH was significantly correlated with risk of cycle cancellation, with an area under the curve (AUC) of 0.74. Patients with undetectable AMH had a 13.3-fold increased risk of cancellation as compared with patients with an AMH >2.0 ng/mL. Antimüllerian hormone had an AUC of 0.83 for prediction of three or fewer oocytes; undetectable AMH exhibited sensitivity and specificity of 21.1% and 98.2%, respectively, for three or fewer oocytes retrieved. Antimüllerian hormone was less predictive of pregnancy, with AUCs ranging from 0.55 to 0.65. Even with undetectable AMH, 23.5% of patients <40 years old achieved live birth after transfer. CONCLUSION(S) Antimüllerian hormone is a fairly robust metric for the prediction of cancellation and how many oocytes may be retrieved after stimulation but is a relatively poor test for prediction of pregnancy after any given treatment cycle. Patients with extremely low levels of AMH still can achieve reasonable treatment outcomes and should not be precluded from attempting IVF solely on the basis of an AMH value.

Fertility preservation using controlled ovarian hyperstimulation and oocyte cryopreservation in a premenarcheal female with myelodysplastic syndrome

OBJECTIVE To report the first case of fertility preservation in a premenarcheal female by use of controlled ovarian hyperstimulation and oocyte cryopreservation. DESIGN Case report. SETTING Reproductive endocrinology and infertility unit of a tertiary care university-based medical center. PATIENT(S) A 13-year-old premenarcheal female with Tanner stage 3 breast development and Tanner stage 1 pubic hair diagnosed with myelodysplastic syndrome, referred by her medical oncologist for fertility preservation before undergoing a potentially sterilizing antineoplastic therapy. INTERVENTION(S) Evaluation of ovarian reserve, ovarian stimulation, transvaginal oocyte aspiration, in vitro maturation of immature oocytes, and oocyte cryopreservation. MAIN OUTCOME MEASURE(S) Cryopreservation of mature oocytes. RESULT(S) Successful controlled ovarian hyperstimulation allowed for the cryopreservation of 18 mature oocytes before the patients gonadotoxic treatment. The oocyte retrieval and cryopreservation did not delay the patients planned chemotherapy. CONCLUSION(S) Ovarian stimulation and oocyte cryopreservation can be successfully performed in premenarcheal/peripubertal patients, thus providing a viable alternative to ovarian tissue freezing for fertility preservation in the pediatric population.

Fertility in patients with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is the most frequently encountered genetic steroid disorder affecting fertility. Steroid hormones play a crucial role in sexual development and reproductive function; patients with either 21- hydroxylase or 11β-hydroxylase deficiency thus face immense challenges to their fertility. Given the relevance of CAH in reproductive medicine as well as the diagnostic challenges posed by the phenotypic overlap with polycystic ovary syndrome, we review the reproductive pahophysiology of both classic and nonclassic CAH and present contemporary treatment options.

Incidence and development of zygotes exhibiting abnormal pronuclear disposition after identification of two pronuclei at the fertilization check

OBJECTIVE To determine the incidence, developmental potential, and clinical implications of embryos having one pronucleus (1PN) or three pronuclei (3PN) at early cleavage, despite exhibiting 2PN at the fertilization check. DESIGN Retrospective cohort study. SETTING Hospital-based academic medical center. PATIENT(S) All IVF cycles from January 2006 through May 2008 having 2PN zygotes that subsequently transitioned to 1PN or 3PN before cleavage, matched to cycles having 2PN zygotes progressing to cleavage without intervening abnormal pronuclear disposition. INTERVENTION(S) Standard IVF protocol. MAIN OUTCOME MEASURE(S) Incidence, day 3 development, and implantation rates of 2PN zygotes transitioning to 1PN and 3PN states before cleavage, compared with normal embryos. RESULT(S) The incidences of 1PN and 3PN zygotes were 2.9% and 0.4%, respectively. Both types of abnormal zygote showed slower day 3 cleavage, although only the 1PNs exhibited higher fragmentation and asymmetry compared with controls. The 1PN zygotes had a 6.4% implantation rate and viable pregnancy rate of 1.3%. Of the nine 3PN zygotes transferred, none implanted. CONCLUSION(S) Two-pronuclear zygotes transitioning through 1PN or 3PN states tend to develop into poorer-quality embryos than 2PN control zygotes. Patients should be counseled regarding the very low likelihood of viable pregnancy after transfer of these abnormally developing zygotes.

Risk factors for a suboptimal response to gonadotropin-releasing hormone agonist trigger during in vitro fertilization cycles

OBJECTIVE To identify risk factors for a suboptimal response to gonadotropin-releasing hormone (GnRH) agonist trigger in in vitro fertilization (IVF) cycles. DESIGN Retrospective cohort study. SETTING Academic medical center. PATIENT(S) All 424 patients undergoing fresh IVF cycles (n = 500) between August 2007 and June 2013 in whom a GnRH agonist was used as all or part of the ovulation trigger. INTERVENTION(S) GnRH-antagonist-based IVF cycles triggered with leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. MAIN OUTCOME MEASURE(S) Suboptimal response to GnRH-agonist trigger, as defined by a serum luteinizing hormone (LH) level <15 mIU/mL on the morning after trigger. RESULT(S) The rate of suboptimal response to the GnRH-agonist trigger was 5.2%. Patients with a suboptimal hormone response had lower follicle-stimulating hormone (<0.1 vs. 3.48) and LH (<0.1 vs. 2.51) levels on day 2 of the cycle start, lower LH (0.109 vs. 0.596) on the day of trigger, and required longer stimulation and more gonadotropins than those with an adequate response. Suboptimal responders were also more likely to have irregular menses and be on long-term oral contraception. Patients with an undetectable LH on the day of trigger had a 25% chance of a suboptimal LH surge. In our study cohort, limiting the use of the GnRH-agonist trigger alone to patients with a trigger day LH ≥0.5 would have reduced the rate of suboptimal response from 5.2% to 0.2%. CONCLUSION(S) Long-term hormonal contraception use is an independent risk factor for suboptimal response to GnRH-agonist trigger. Patients with very low endogenous serum LH levels on the day of LH trigger are at increased risk for a suboptimal GnRH-agonist trigger response. Understanding the at-risk phenotype and using trigger day LH as a marker for increased risk of suboptimal GnRH-agonist trigger response can be helpful for individualizing treatment and selecting a safe and efficacious trigger medication for patients undergoing IVF.

Morphologic grading of euploid blastocysts influences implantation and ongoing pregnancy rates

OBJECTIVE To determine whether blastocyst grading can predict pregnancy outcomes in the frozen-thawed embryo transfer (FET) of euploid blastocysts. DESIGN Retrospective cohort study. SETTING Academic medical center. PATIENT(S) Women who underwent FET of euploid embryo(s) between January 2013 and December 2015, with blastocysts were divided into four groups based on their morphologic grading before cryopreservation: excellent (≥3AA), good (3-6AB, 3-6BA, 1-2AA), average (3-6BB, 3-6AC, 3-6CA, 1-2AB, 1-2BA), and poor (1-6BC, 1-6CB, 1-6CC, 1-2BB). INTERVENTION(S) FET. MAIN OUTCOMES MEASURE(S) Ongoing pregnancy rate (OPR). RESULT(S) A total of 417 FET cycles (477 embryos) were included. Excellent-quality embryos (n = 38) yielded a statistically significantly higher OPR than poor-quality embryos (n = 106) (84.2% vs. 35.8%; adjusted odds ratio 11.0; 95% confidence interval, 3.8-32.1) and average-quality embryos (n = 197) (84.2% vs. 55.8%; adjusted odds ratio 4.8; 95% confidence interval, 1.7-13.3). Good-quality embryos (n = 76) were associated with a statistically significantly higher OPR than poor-quality embryos (61.8% vs. 35.8%). These odds ratios were adjusted for patients age, body mass index, number of transferred embryos, type of frozen cycle, peak endometrial thickness, day of trophectoderm biopsy (5 or 6), and total number of euploid embryos for each patient. An inner cell mass grade of A yielded a statistically significantly higher OPR than ICM grade C (76.2% vs. 13.5%) or grade B (76.2% vs. 53.6%) after controlling for all confounders. CONCLUSION(S) Contrary to prior published studies, the current data suggest that blastocyst morphologic grading and particularly inner cell mass grade is a useful predictor of OPR per euploid embryo. Morphologic grading should be used to help in the selection among euploid blastocysts.

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.

Mayer-Rokitansky-Küster-Hauser syndrome: fertility counseling and treatment

To date, no literature has focused on the counseling of patients with Mayer-Rokitansky-Küster-Hauser syndrome as relates to their unique fertility challenges. This article is presented as a guide to practitioners in the counseling of patients with varying Mayer-Rokitansky-Küster-Hauser phenotypes regarding individual reproductive potential.