Mirjana Krstic

Parental microbiome composition and nutritional and metabolic status have been studied in relation to in vitro fertilization (IVF), but their contribution to recurrent implantation failure (RIF) remains uncertain. This narrative review examines maternal and paternal microbial profiles, nutrition, inflammation, oxidative stress, and epigenetic regulation, distinguishing human observational and interventional findings from animal experiments, in vitro studies, and proposed mechanisms. The literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science, covering publications from 2000 to 2026. Search concepts included “in vitro fertilization”, “recurrent implantation failure”, “reproductive tract microbiota”, “gut microbiome”, “parental nutrition”, “oxidative stress”, and “sperm epigenetics”. Associations between reproductive-tract microbial profiles and pregnancy outcomes vary across populations and analytical methods. Endometrial findings require particular caution because low microbial biomass increases susceptibility to contamination. Evidence linking parental gut microbiota to epigenetic programming of human preimplantation embryos remains indirect, and paternal gut–testis mechanisms are supported predominantly by experimental research. Randomized probiotic studies have produced inconsistent results and have not established a reproducible improvement in implantation or live birth across IVF populations. Nutritional adequacy and management of relevant metabolic disorders belong within established preconception care, whereas microbiome testing, targeted microbial manipulation, and proposed epigenetic interventions remain investigational for RIF. The available evidence supports further study of these relationships but does not establish parental dysbiosis as a cause of RIF or demonstrate that microbiome modification prevents implantation failure.

In vitro fertilization (IVF) often requires multiple cycles before successful implantation and live birth are achieved. Although embryo quality and technical factors have traditionally been emphasized, emerging evidence suggests that parental microbiome composition and nutritional status are important, but under-recognized, determinants of reproductive success. Dysbiosis of the vaginal and endometrial microbiota in women is associated with reduced implantation rates, chronic low-grade inflammation, and altered endometrial receptivity, while maternal gut microbiota imbalance may contribute to systemic metabolic inflammation, oxidative stress, and epigenetic modifications affecting early embryonic development. Paternal factors are increasingly rec-ognized as equally important, as altered gut microbiota, obesity, insulin resistance, and micronu-trient deficiencies may affect sperm DNA integrity, methylation patterns, and small noncoding RNA profiles, potentially influencing embryonic developmental programming. This review aims to evaluate the interconnected mechanisms linking parental microbiome composition, nutritional and metabolic status, inflammation, oxidative stress, and epigenetic regulation with assisted reproduction and recurrent IVF failure. A comprehensive literature search was performed using PubMed/MEDLINE, Scopus, and Web of Science, covering the period from 2000 to 2025, with predefined keywords and Medical Subject Headings related to in vitro fertilization, recurrent implantation failure, maternal gut microbiome, reproductive tract dysbiosis, paternal gut-testis axis, oxidative stress, sperm epigenetics, DNA methylation, short-chain fatty acids, and preconception nutritional optimization. We considered peer-reviewed articles published in English, including original research, meta-analyses, and high-impact reviews providing mechanistic and translational insights. The evidence indicates that parental dysbiosis and nutritional and metabolic im-balances may converge on inflammatory, oxidative, mitochondrial, and epigenetic pathways, creating a biological environment that compromises implantation and may influence early em-bryonic programming. Importantly, these potentially modifiable factors support preconception microbiome modulation, nutritional optimization, and metabolic conditioning for both partners before IVF. In conclusion, an integrated preconception approach addressing parental microbiome, nutritional, metabolic, inflammatory, and epigenetic factors may represent a promising strategy for improving reproductive outcomes and potentially supporting the long-term health of the offspring.

Pregnancy is characterized by progressive maternal hyperlipidemia, including increased triglycerides, total cholesterol, and low-density lipoprotein, with dynamic fluctuations in high-density lipoprotein. Excess maternal free fatty acids induce oxidative stress through reactive oxygen species, causing mitochondrial dysfunction, lipid peroxidation, activation of inflammatory pathways, and epigenetic remodeling in the placenta and fetal tissues. These molecular alterations impair placental lipid transport and nutrient sensing, leading to hypertrophy of fetal liver, myocardium, and adipose tissue, while disrupting neonatal glucose and lipid homeostasis and increasing susceptibility to perinatal complications and long-term metabolic disorders. This review aims to evaluate mechanistic pathways linking maternal lipid metabolism, oxidative stress, placental function, and fetal organ remodeling. Mechanistic and translational studies were identified through searches of PubMed, Scopus, the Cochrane Library, and Web of Science (2000–2025) using predefined keywords including lipid metabolism, free fatty acids, oxidative stress, placental lipid transport, epigenetics, DNA methylation, fetal programming, and perinatal outcomes. Evidence indicates that maternal lipid imbalance drives placental oxidative and epigenetic modifications, directly contributing to fetal organ hypertrophy and neonatal metabolic dysregulation. In conclusion, maternal dyslipidemia represents a modifiable determinant of fetal organ hypertrophy and long-term metabolic risk, supporting the clinical relevance of maternal lipid monitoring and targeted metabolic interventions during pregnancy.

Maternal nutrition and gut microbiome composition are central regulators of fetal development and perinatal outcomes, modulating immune signaling, oxidative balance, and epigenetic programming. The authors searched PubMed, Scopus, the Cochrane Library, and Web of Science for full-text, peer-reviewed articles published in English between 2010 and 2025, using keywords relevant to maternal diet, gut microbiome, epigenetic modifications, oxidative stress, reactive oxygen species (ROS), short-chain fatty acids (SCFAs), placental function, and perinatal outcomes. Selected studies provided detailed insights into how maternal dietary patterns and microbiome-derived metabolites influence placental function, fetal growth, and neonatal health. Integration of the microbiome, epigenetics, and nutritional factors reveals key molecular and metabolic networks that shape perinatal health. Targeted modulation of these networks provides a foundation for personalized strategies to improve neonatal outcomes.