Imprinting disorders in children conceived with assisted reproductive technology in Sweden.

OBJECTIVE: To assess whether the use of assisted reproductive technology for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility. DESIGN: A nationwide register-based cohort study. SUBJECTS: All liveborn singletons in Sweden (N = 2 084 127) between 1997-2017 with follow-up to December 31, 2018. EXPOSURE: The use of specific methods implemented in the assisted reproductive technology MAIN OUTCOME MEASURES: The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Prader-Willi/Silver-Russell syndrome, Beckwith-Wiedemann syndrome, and central precocious puberty. The Cox model combined with inverse probability treatment weights were used to estimate weighted hazard ratio (wHR) with 95% confidence interval (CI), accounting for multiple confounders. RESULTS: A total of 1044 children were diagnosed with the disorders of interest, and 52 of them were conceived with assisted reproductive technology. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived with ART compared to all other children (HR 1.84, 95% CI: 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR 1.50, 95% CI: 0.97-2.32), but remained also in the weighted comparison restricted to children of couples with known infertility (wHR 1.52, 95% CI: 1.05-2.21). For the specific diagnoses of Prader-Willi/Silver-Russell syndrome and Beckwith-Wiedemann syndrome, compared to children of couples with known infertility, children conceived with assisted reproductive technology showed a small excess risk, which could not be distinguished from the null (wHR 1.56 [95% CI: 0.93-2.62] and 1.80 [95% CI: 0.99-3.28], respectively). Further subgroup analysis showed that the combined use of intra-cytoplasmic sperm injection and cryopreserved embryos was associated with higher risk of both Prader-Willi/Silver-Russell syndrome (wHR 4.60, 95% CI: 1.72-12.28) and Beckwith-Wiedemann syndrome (wHR 6.69, 95% CI: 2.09-21.45). The number of central precocious puberty cases in children conceived with assisted reproductive technology was too small (N=3) to make any meaningful inference. CONCLUSION: The combined use of intra-cytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of Prader-Willi/Silver-Russell syndrome and Beckwith-Wiedemann syndrome in children, independent of parental factors related to infertlity.

Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia.

Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes.

Obstetric and Perinatal Outcomes of Singleton Births Following Single- vs Double-Embryo Transfer in Sweden.

Importance: Pregnancies resulting from assisted reproductive technology are associated with an increased risk of adverse perinatal outcomes compared with those following natural conception. Previous studies have shown an association of pregnancies resulting from transfer of multiple embryos with these negative findings. Objective: To determine the risk for adverse outcomes in singletons conceived through assisted reproduction using double-embryo transfer (DET) vs single-embryo transfer (SET). Design, Setting, and Participants: This cohort study used data from women who achieved singleton deliveries after SET or DET in Sweden between 2007 and 2017 as recorded in the National Quality Registry for Assisted Reproduction. All embryo transfers, at cleavage or blastocyst stage, replaced in fresh or frozen treatment cycles were included. Data on obstetric and neonatal outcomes were retrieved by linkage to the National Medical Birth Register. Naturally conceived singletons were included as a reference group. Data were analyzed between September 2021 and August 2022. Exposures: Double-embryo transfer leading to singleton birth. Main Outcomes and Measures: Relative risk ratios or odds ratios (ORs) and absolute risk differences (ARDs) in percentage points with 95% CIs were calculated for obstetric and perinatal outcomes in singleton births conceived using DET vs SET. Results: Among 1 115 863 singleton births, 30 713 singletons were born after SET and 5123 after DET. A higher risk of neonatal death was found in singletons after DET vs SET (OR, 2.67 [95% CI, 1.28-5.55]; ARD, 0.2 percentage points [95% CI, 0.0-0.4 percentage points]). In frozen embryo transfers, DET was associated with a higher risk of low birth weight (OR, 1.64 [95% CI, 1.19-2.25]; ARD, 2.0 percentage points [95% CI, 0.5-3.5 percentage points]). Among blastocyst transfers, DET was associated with very preterm birth (relative risk ratio, 2.64 [95% CI, 1.50-4.63]; ARD, 1.8 percentage points [95% CI, 0.3-3.4 percentage points]) and low birth weight (OR, 1.83 [95% CI, 1.29-2.60]; ARD, 3.2 percentage points [95% CI, 0.9-5.5 percentage points]). Conclusions and Relevance: These results indicate a higher risk of adverse outcomes following DET, even when the result is a singleton birth, vs singletons born after SET. Adverse outcomes were mainly observed in singletons following DET using frozen embryos and blastocysts.

Profiling the Influence of Gene Variants Related to Folate-Mediated One-Carbon Metabolism on the Outcome of In Vitro Fertilization (IVF) with Donor Oocytes in Recipients Receiving Folic Acid Fortification.

Nutritional status and gene polymorphisms of one-carbon metabolism confer a well-known interaction that in pregnant women may affect embryo viability and the health of the newborn. Folate metabolism directly impacts nucleotide synthesis and methylation, which is of increasing interest in the reproductive medicine field. Studies assessing the genetic influence of folate metabolism on IVF treatments have currently been performed in women using their own oocytes. Most of these patients seeking to have a child or undergoing IVF treatments are advised to preventively intake folate supplies that restore known metabolic imbalances, but the treatments could lead to the promotion of specific enzymes in specific women, depending on their genetic variance. In the present study, we assess the influence of candidate gene variants related to folate metabolism, such as Serine Hydroxymethyltransferase 1 SHMT1 (rs1979276 and rs1979277), Betaine-Homocysteine S-Methyltransferase BHMT (rs3733890), Methionine synthase reductase MTRR (rs1801394), Methylenetetrahydrofolate reductase MTHFR (rs1801131 and rs1801133), methionine synthase MTR (rs12749581), ATP Binding Cassette Subfamily B Member 1 ABCB1 (rs1045642) and folate receptor alpha FOLR1 (rs2071010) on the success of IVF treatment performed in women being recipients of donated oocytes. The implication of such gene variants seems to have no direct impact on pregnancy consecution after IVF; however, several gene variants could influence pregnancy loss events or pregnancy maintenance, as consequence of folic acid fortification.

Exploring the Developmental Potential of Human Germinal Vesicle Oocytes Aiming at Fertility Preservation: Can We Increase the Yields of Competent Oocytes through IVM Combined with Vitrification?

The rescue in vitro maturation (rIVM) of germinal vesicle oocytes (GVs) has been proposed to improve the total number of mature oocytes in women undergoing fertility preservation. Currently, there is no consensus about the clinical utility of this practice, and heterogeneity in the protocols used may influence the final outcomes. This study investigated the developmental potential of mature metaphase II (MII) human oocytes obtained from GVs after rIVM and the impact of applying vitrification at different timepoints either before or after rIVM. After randomization, oocytes were assigned to undergo rIVM and thereafter vitrification or intracytoplasmic sperm injection (ICSI), or to undergo direct vitrification-warming and thereafter rIVM and ICSI. The likelihood of obtaining MII oocytes was just slightly higher in the fresh rIVM group compared to the vitrification-warming-rIVM group. When comparing fresh rIVM that underwent subsequently ICSI, the fertilization and developmental rates up to the blastocyst stage were seen to be reduced in both groups that underwent vitrification either before or after rIVM. Although some blastocysts were obtained in the fresh rIVM-ICSI group, the efficacy of these methods was low overall, suggesting that the further development of protocols for IVM conducted early after denudation is needed to improve the final results of rIVM aiming at fertility preservation.