Live-Birth Outcomes Among Women With Infertility and Anti-Müllerian Hormone Levels of 0.3 ng/mL or Lower.

OBJECTIVE: To estimate the live-birth rate per in vitro fertilization (IVF) cycle and after cumulative infertility treatment among patients with anti-müllerian hormone (AMH) levels of 0.3 ng/mL or lower. METHODS: We conducted a retrospective cohort study at a single academic center of patients with infertility and AMH levels of 0.3 ng/mL or lower who initiated one or more IVF cycles (2013-2019). Exclusion criteria included prior chemotherapy, hormonal contraceptive use within 3 months of AMH level measurement, and severe male factor infertility. Patients were stratified by Society for Assisted Reproductive Technology (SART) age group. The primary outcome was live-birth rate per IVF cycle. Live-birth outcomes were compared with the 2018 SART National Summary Report for live births per single intended oocyte retrieval, with proportion difference (PD) and 95% CI reported. RESULTS: A total of 978 patients were included. The median (interquartile range) number of cycles initiated was 2 (1-3). With the first initiated cycle, the live-birth rate for those with AMH levels of 0.3 ng/mL or lower was significantly lower in each age category compared with the SART live-birth rate per single initiated cycle (younger than 35 years: 26.2% vs 55.6%, PD 29.4%, 95% CI 20.9-37.9%; 35-37 years: 15.9% vs 40.8%, PD 24.9%, 95% CI 19.0-30.9%; 38-40 years: 12.6% vs 26.8%, PD 14.3%, 95% CI 10.2-18.3%; 41-42 years: 4.7% vs 13.4%, PD 8.7%, 95% CI 5.9-11.6%; older than 42 years: 1.2% vs 4.1%, PD 2.9%, 95% CI 1.5-4.3%). In patients aged 35-37, 38-40, 41-42, and older than 42 years, the cumulative live-birth rate after up to three initiated cycles was comparable with the SART live-birth rate per single initiated cycle but remained significantly lower in patients younger than age 35 years (PD 16.8%, 95% CI 7.3-26.2%). After all treatments were included (cumulative IVF, ovulation induction, and unassisted cycles), live-birth rates were similar to SART live-birth rates per single initiated cycle in all age groups. CONCLUSION: Compared with national outcomes, patients with AMH levels of 0.3 ng/mL or lower had a significantly lower chance of live birth after their first initiated cycle. However, the cumulative live-birth rate after up to three initiated cycles was comparable with national live-birth outcomes per single initiated cycle in patients aged 35 years or older. In patients younger than age 35 years, only when all IVF and non-IVF treatment cycles were included did the cumulative live-birth rate become comparable with the national rate per single IVF cycle.

p53 and reproduction.

Tumor protein 53 (TP53) and its related family of p63 and p73 are tumor suppressor genes that regulate cellular activity to enhance longevity. p53 binds to specific response elements in DNA, modulating the transcription of genes that govern the major defenses against tumor growth. Additional members of the p53 family are involved with male and female germ cell survival. Although the majority of studies have focused on p53 as a tumor suppressor gene, little is known about its function in normal cellular processes. Polymorphisms of TP53 codon 72 that alter activity levels have been studied with respect to implantation in both the murine and human models. TP53 codon 72 (arginine) exhibits higher rates of apoptosis and leukemia inhibitory factor expression, whereas the C allele (proline) reduces leukemia inhibitory factor expression. Here, we review the role of p53 and the family of p53 proteins, along with the potential effect of p53 polymorphisms on reproduction.

Preimplantation genetic screening: who benefits?

OBJECTIVE: To compare IVF outcomes between women undergoing frozen transfers of blastocysts verified as euploid by preimplantation genetic screening (PGS) with patients undergoing fresh nonbiopsied blastocyst transfers. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): All patients undergoing IVF-PGS cycles between January 2010 and November 2014 were included (n = 274). Patients were compared with a control group consisting of all fresh blastocyst transfers that occurred during the same period (n = 863). INTERVENTION(S): Patients underwent IVF-PGS with 24-chromosome screening. Patients with euploid embryos had transfer of one to two embryos in a subsequent frozen ET cycle. MAIN OUTCOME MEASURE(S): Implantation, clinical intrauterine gestation (CIG), miscarriage, biochemical pregnancy (BC), and live birth (LB) rates were compared. RESULT(S): Odds ratios (ORs) were estimated for outcomes in women undergoing PGS versus controls. Among patients ≤37 years old, there were no differences in CIG and LB rates for single (adjusted ORs [aORs], 1.20 [95 %confidence interval {CI}, 0.66-2.21]; 1.21 [95% CI, 0.66-2.2]) and double ETs (aORs, 1.09 [95% CI, 0.54-2.18]; 0.87 [95% CI, 0.44-1.7]). BC and miscarriage rates were also similar. For patients >37 years old, CIG and LB rates were increased for single (aORs, 3.86 [95% CI, 1.25-11.9]; 8.2 [95% CI, 2.28-29.5]) and double ETs (aORs, 9.91 [95% CI, 2.0-49.6]; 8.67 [95% CI, 2.08-36.2]) with no difference in BC and miscarriage rates. A per-retrieval analysis of the >37 group failed to demonstrate any difference in CIG or LB rates. CONCLUSION(S): Among patients ≤37, IVF-PGS does not improve CIG, LB, and miscarriage rates. IVF-PGS in women >37 improved CIG and LB rates. However, per cycle, the PGS advantage in this age group does not persist.

The effect of 5α-reductase-2 deficiency on human fertility.

A most interesting and intriguing male disorder of sexual differentiation is due to 5α-reductase-2 isoenzyme deficiency. These male infants are born with ambiguous external genitalia due to a deficiency in their ability to catalyze the conversion of T to dihydrotestosterone. Dihydrotestosterone is a potent androgen responsible for differentiation of the urogenital sinus and genital tubercle into the external genitalia, urethra, and prostate. Affected males are born with a clitoral-like phallus, bifid scrotum, hypospadias, blind shallow vaginal pouch from incomplete closure of the urogenital sinus, and a rudimentary prostate. At puberty, the surge in mainly T production prompts virilization, causing most boys to choose gender reassignment to male. Fertility is a challenge for affected men for several reasons. Uncorrected cryptorchidism is associated with low sperm production, and there is evidence of defective transformation of spermatogonia into spermatocytes. The underdeveloped prostate and consequent low semen volumes affect sperm transport. In addition, semen may not liquefy due to a lack of prostate-specific antigen. In the present review, we discuss the 5α-reductase-2 deficiency syndrome and its impact on human fertility.

Regulation of female reproduction by p53 and its family members.

Tumor suppressor p53 is crucial for embryonic implantation through transcriptional up-regulation of uterine leukemia inhibitory factor (LIF). This article reports that p53 and estrogen receptor α were activated in endometrial tissues during implantation to coordinately regulate LIF production. By using human p53 knockin (Hupki) mice carrying a single nucleotide polymorphism (SNP) at codon 72 (arginine/proline), the arginine allele was demonstrated to produce higher uterine LIF levels during implantation than the proline allele. In humans, the diversity of haplotypes of the p53 gene has decreased during evolution, because the arginine allele, existing in only a subset of haplotypes, is under positive selection. This observation is consistent with previous results showing that the proline allele is enriched in patients undergoing in vitro fertilization (IVF). Studies with p63- and p73-knockout mice have demonstrated the involvement of p63 and p73 in female reproduction and their roles in egg formation and apoptosis (p63) and spindle checkpoint (p73) in female mice. Here, the role of p63 and p73 in human reproduction was investigated. Selected alleles of SNPs in p63 and p73 genes were enriched in IVF patients. These findings demonstrate that the p53 family members are involved in several steps to regulate female reproduction in mice and humans.

The first successful paternity through in vitro fertilization-intracytoplasmic sperm injection with a man homozygous for the 5α-reductase-2 gene mutation.

OBJECTIVE: To report a case of successful paternity from a male homozygous for 5α-reductase-2 deficiency. DESIGN: Case report. SETTING: Academic center, division of reproductive endocrinology. PATIENT(S): A 45-year-old Dominican man and his 32-year-old wife. INTERVENTION(S): In vitro fertilization and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): Viable twin gestation. CONCLUSION(S): Men homozygous for 5α-reductase-2 deficiency can achieve biologic paternity through in vitro fertilization with intracytoplasmic sperm injection despite severely abnormal semen parameters.

Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans.

The tumor suppressor protein p53 plays an important role in maternal reproduction in mice through transcriptional regulation of leukemia inhibitory factor (LIF), a cytokine crucial for blastocyst implantation. To determine whether these observations could be extended to humans, a list of single-nucleotide polymorphisms (SNPs) in the p53 pathway that can modify the function of p53 was assembled and used to study their impact on human fertility. The p53 allele encoding proline at codon 72 (P72) was found to be significantly enriched over the allele encoding arginine (R72) among in vitro fertilization (IVF) patients. The P72 allele serves as a risk factor for implantation failure. LIF levels are significantly lower in cells with the P72 allele than in cells with the R72 allele, which may contribute to the decreased implantation and fertility associated with the P72 allele. Selected alleles in SNPs in LIF, Mdm2, Mdm4, and Hausp genes, each of which regulates p53 levels in cells, are also enriched in IVF patients. Interestingly, the role of these SNPs on fertility was much reduced or absent in patients older than 35 years of age, indicating that other functions may play a more important role in infertility in older women. The association of SNPs in the p53 pathway with human fertility suggests that p53 regulates the efficiency of human reproduction. These results also provide a plausible explanation for the evolutionary positive selection of some alleles in the p53 pathway and demonstrate the alleles in the p53 pathway as a good example of antagonistic pleiotropy.

Triploidy--the breakdown of monogamy between sperm and egg.

The advent of assisted reproductive technology (ART) has taught us a great deal about human fertilization patterns. Thirty years of experience with IVF and cultivation of early embryos has provided a unique view into the mechanisms of normal and aberrant human fertilization. Here we review the different types of triploidy following conventional in vitro fertilization and intracytoplasmic sperm injection, as well as the mechanisms giving rise to digynic and dispermic fertilization. Additionally, the role of the centrosome in triploidy, the genetic analysis of triploid embryos and the potential for therapeutic enucleation are explored. Lastly, we review our own clinical experience with human fertilization patterns following > 20,000 treatment cycles of assisted reproduction.

An analysis of transfusion practice and the role of intraoperative red blood cell salvage during cesarean delivery.

BACKGROUND: We sought to determine to what extent intraoperative salvaged red blood cells (RBC) might theoretically reduce exposure to appropriately transfused allogenic erythrocytes in Cesarean delivery patients. METHODS: Medical records of Cesarean delivery patients requiring blood transfusions from January 1, 1992 to June 30, 1996 and June 1, 1998 to June 30, 2003 were reviewed. For each patient, we calculated the number of allogenic RBC units that could have theoretically been avoided had intraoperative autotransfusion been performed, based upon estimated blood loss, preoperative hematocrit, and the amount of retrieved blood needed to yield a single RBC unit. RBC transfusion appropriateness was determined using the recommended guideline of transfusing RBCs if the hemoglobin is <7 gm/dL in a patient with continuing bleeding. RESULTS: A small percentage of Cesarean delivery patients (1.8%) received blood product transfusions. Of 207 patients receiving blood transfusions, salvaged erythrocytes could have theoretically decreased exposure to allogenic RBCs in 115 (55.6%) patients. Only 75.7% of these 115 patients were appropriately transfused with erythrocytes. CONCLUSION: Theoretically, based on best, average, and worst RBC salvage recovery calculations, 25.1%, 21.2%, or 14.5% of the appropriately transfused patients, respectively, could have completely avoided allogenic RBC transfusion.

Simultaneous bilateral ovarian torsion in the follicular phase after gonadotropin stimulation.

OBJECTIVE: To present and discuss the first report of follicular phase bilateral ovarian torsion following a cancelled IVF cycle. DESIGN: Case report. SETTING: University-based assisted reproductive technology program. PATIENT(S): A 41-year-old nulligravid patient on day 3 of her menses following a cancelled IVF cycle. INTERVENTION(S): Gonadotropin ovulation induction; laparoscopy with detorsion of left and right ovaries; aspiration of cysts. RESULT(S): Ovarian torsion resolved; follicular development in the following natural cycle. CONCLUSION(S): This is a unique case of simultaneous bilateral ovarian torsion following a cancelled IVF cycle and presenting in the ensuing follicular phase. Physicians should be aware of this unusual risk related to persistently enlarged ovaries in the cycle following gonadotropin stimulation. Furthermore, management of the infertility patient should be conservative and focused on ovarian preservation whenever feasible. Early surgical intervention can permit reperfusion and salvage of the affected adnexa.