Metabolic regulation of preimplantation embryo development in vivo and in vitro: Molecular mechanisms and insights.

Understanding of embryonic development has led to the clinical application of Assisted Reproductive technologies (ART), with the resulting birth of millions of children. Recent developments in metabolomics, proteomics, and transcriptomics have brought to light new insights into embryonic growth dynamics, with implications spanning reproductive medicine, stem cell research, and regenerative medicine. The review explores the key metabolic processes and molecular pathways active during preimplantation embryo development, including PI3K-Akt, mTOR, AMPK, Wnt/β-catenin, TGF-β, Notch and Jak-Stat signaling pathways.

The effect of fertility treatment and socioeconomic status on neonatal and post-neonatal mortality in the United States.

Objective: To determine the association between fertility treatment, socioeconomic status (SES), and neonatal and post-neonatal mortality.

Study Design: Retrospective cohort study of all births (19,350,344) and infant deaths from 2014-2018 in the United States. The exposure was mode of conception-spontaneous vs fertility treatment.

Overweight or obesity in children born after assisted reproductive technologies in Denmark: A population-based cohort study.

Background: The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility.

Culture conditions in the IVF laboratory: state of the ART and possible new directions.

In the last four decades, the assisted reproductive technology (ART) field has witnessed advances, resulting in improving pregnancy rates and diminishing complications, in particular reduced incidence of multiple births. These improvements are secondary to advanced knowledge on embryonic physiology and metabolism, resulting in the ability to design new and improved culture conditions. Indeed, the incubator represents only a surrogate of the oviduct and uterus, and the culture conditions are only imitating the physiological environment of the female reproductive tract.

Fertility treatment increases the risk of preterm birth independent of multiple gestations.

Objective: To investigate the complex interplay between fertility treatment, multiple gestations, and prematurity.

Design: Retrospective cohort study linking the national Center for Disease Control and Prevention infant birth and death data from 2014 to 2018.

Setting: National database from Center of Disease Control and Prevention.

Can Cryopreservation in Assisted Reproductive Technology (ART) Induce Epigenetic Changes to Gametes and Embryos?

Since the birth of Louise Brown in 1978, more than nine million children have been conceived using assisted reproductive technologies (ARTs). While the great majority of children are healthy, there are concerns about the potential epigenetic consequences of gametes and embryo manipulation. In fact, during the preimplantation period, major waves of epigenetic reprogramming occur.

Metabolomic Profile of Children Conceived With Medically Assisted Technologies.

Context: Assisted reproductive technologies (ART) and non-in vitro fertilization fertility treatments (NIFT) are treatments for infertility. These technologies may have long-term health effects in children such as increased hypertension, glucose intolerance, and hypertriglyceridemia. Few studies have compared children born following ART and NIFT to those conceived spontaneously by subfertile couples.

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production.

In vitro fertilization (IVF) has resulted in the birth of over 8 million children. Although most IVF-conceived children are healthy, several studies suggest an increased risk of altered growth rate, cardiovascular dysfunction, and glucose intolerance in this population compared to naturally conceived children. However, a clear understanding of how embryonic metabolism is affected by culture condition and how embryos reprogram their metabolism is unknown.

Micro-scale probing of the Rat's oviduct detects its viscoelastic property needed for creating a biologically relevant substrate for In-Vitro- Fertilization.

Techniques used in assisted reproductive technology such as In-Vitro- Fertilization (IVF) process, often only replicate the biomechanical environment for embryo. Despite its importance, the biomechanics of the Oviduct tissue that is usually called Fallopian Tube in Human, the natural site of fertilization, has not been replicated nor sufficiently studied. This work studies the time-independent and time-dependent biomechanics of the oviduct tissue by realizing a viscoelastic model that accurately fit on the experimental indentation data collected on the mucosal epithelial lining of the oviduct tissue of rats.

Ovulation induction is associated with altered growth but with preservation of normal metabolic function in murine offspring.

Objective: To study the effects of ovulation induction on mouse postnatal health, with a focus on growth pattern and glucose tolerance. To study the effect of ovulation induction on DNA methylation, we took advantage of the agouti viable yellow (A) mouse.

Design: Animal study.

Effectiveness and safety of intrauterine insemination vs. assisted reproductive technology: emulating a target trial using an observational database of administrative claims.

Objective: To compare the effectiveness and safety of 1 cycle of assisted reproductive technology (ART) vs. 3 cycles of intrauterine insemination (IUI).

Design: Target trial emulation using observational data.

Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.

Study Question: What are the comparative pregnancy outcomes in women who receive up to six consecutive cycles of ovulation induction with letrozole versus clomiphene citrate?

Summary Answer: The risks of pregnancy, livebirth, multiple gestation, preterm birth, neonatal intensive care unit (NICU) admission and congenital malformations were higher for letrozole compared with clomiphene in participants with polycystic ovarian syndrome (PCOS), though no treatment differences were observed in those with unexplained infertility.

What Is Known Already: Randomized trials have reported higher pregnancy and livebirth rates for letrozole versus clomiphene among individuals with PCOS, but no differences among those with unexplained infertility. None of these trials were designed to study maternal or neonatal complications.

DNA methylation profile of liver of mice conceived by fertilization.

Offspring generated by in vitro fertilization (IVF) are believed to be healthy but display a possible predisposition to chronic diseases, like hypertension and glucose intolerance. Since epigenetic changes are believed to underlie such phenotype, this study aimed at describing global DNA methylation changes in the liver of adult mice generated by natural mating (FB group) or by IVF. Embryos were generated by IVF or natural mating.

Outcomes of Very Preterm Infants Conceived with Assisted Reproductive Technologies.

Objective: To compare mortality and early respiratory outcomes of very preterm infants conceived via assisted reproductive technology (ART) vs spontaneously.

Study Design: We identified inborn infants (July 2014-July 2019) with gestational age <32 weeks (n = 439); 54 cases were ART conceived. Spontaneously conceived controls (n = 103) were matched by multiple gestation status and gestational age.

Effect of culture conditions and method of conception on mouse live birth rate.

Objective: To understand in a mouse model whether there are differences in the decidua and live birth rate after transfer of blastocysts generated by in vitro fertilization (IVF) or by superovulation with spontaneous mating into unstimulated recipients.

Design: Animal experiment.

Setting: University-affiliated tertiary hospital.

Sex-specific epigenetic profile of inner cell mass of mice conceived in vivo or by IVF.

The preimplantation stage of development is exquisitely sensitive to environmental stresses, and changes occurring during this developmental phase may have long-term health effects. Animal studies indicate that IVF offspring display metabolic alterations, including hypertension, glucose intolerance and cardiac hypertrophy, often in a sexual dimorphic fashion. The detailed nature of epigenetic changes following in-vitro culture is, however, unknown.

The Effect of Prenatal Treatments on Offspring Events in the Presence of Competing Events: An Application to a Randomized Trial of Fertility Therapies.

When studying the effect of a prenatal treatment on events in the offspring, failure to produce a live birth is a competing event for events in the offspring. A common approach to handle this competing event is reporting both the treatment-specific probabilities of live births and of the event of interest among live births. However, when the treatment affects the competing event, the latter probability cannot be interpreted as the causal effect among live births.

Pre-Implantation Mouse Embryos Cultured In Vitro under Different Oxygen Concentrations Show Altered Ultrastructures.

Assisted Reproductive Technologies routinely utilize different culture media and oxygen (O) concentrations to culture human embryos. Overall, embryos cultured under physiological O tension (5%) have improved development compared to embryos cultured under atmospheric O conditions (20%). The mechanisms responsible for this remain unclear.

Outcomes of pulmonary vascular disease in infants conceived with non-IVF fertility treatment and assisted reproductive technologies at 1 year of age.

Background: Assisted reproductive technologies (ARTs) have been associated with the development of endothelial dysfunction.

Objective: To determine potential differences in outcomes associated with pulmonary vascular disease in infants born to mothers receiving any infertility treatment including ART and non-IVF fertility treatments (NIFTs).

Design/methods: The sample was derived from an administrative database containing detailed information on infant and maternal characteristics for live-born infants in California (2007-2012) with gestational age (GA) 22 to 44 weeks.

Transitioning from Infertility-Based (ART 1.0) to Elective (ART 2.0) Use of Assisted Reproductive Technologies and the DOHaD Hypothesis: Do We Need to Change Consenting?

The use of assisted reproductive technologies (ARTs) has increased significantly in recent years. While this is partially due to improved access for infertile patients, another contribution to the growth of ART utilization is represented by individuals without infertility, who electively chose to freeze their gametes and embryos for future use, before ever attempting conception spontaneously. Overall, the safety of ART for parents and children is well described and the risks are modest.

Oxygen concentration alters mitochondrial structure and function in in vitro fertilized preimplantation mouse embryos.

Study Question: Does the oxygen concentration in the culture medium [either physiologic (5%) or atmospheric (20%)] affect mitochondrial ultrastructure and function in preimplantation mouse embryos generated by IVF?

Summary Answer: Embryos cultured in 20% oxygen show increased mitochondrial abnormalities compared to embryos cultured in 5% oxygen.

What Is Known Already: ART are widely used and have resulted in the birth of more than 8 million children. A variety of media and oxygen concentrations are used to culture embryos.