Human oocyte area is associated with preimplantation embryo usage and early embryo development: the Rotterdam Periconception Cohort.

PURPOSE: To investigate the association between oocyte area and fertilization rate, embryo usage, and preimplantation embryo development in order to establish if oocyte area can be a marker for optimal early embryo development. METHODS: From 2017 to 2020, 378 couples with an indication for IVF (n = 124) or ICSI (n = 254) were included preconceptionally in the Rotterdam Periconception Cohort. Resulting oocytes (n = 2810) were fertilized and submitted to time-lapse embryo culture. Oocyte area was measured at the moment of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf). Fertilization rate, embryo usage and quality, and embryo morphokinetics from 2-cell stage to expanded blastocyst stage (t2-tEB) were used as outcome measures in association with oocyte area. Oocytes were termed "used" if they were fertilized and embryo development resulted in transfer or cryopreservation, and otherwise termed "discarded". Analyses were adjusted for relevant confounders. RESULTS: Oocyte area decreased from t0 to tPNf after IVF and ICSI, and oocytes with larger area shrank faster (ß - 12.6 µm2/h, 95%CI - 14.6; - 10.5, p < 0.001). Oocytes that resulted in a used embryo were larger at all time-points and reached tPNf faster than oocytes that fertilized but were discarded (oocyte area at tPNf in used 9864 ± 595 µm2 versus discarded 9679 ± 673 µm2, p < 0.001, tPNf in used 23.6 ± 3.2 h versus discarded 25.6 ± 5.9 h, p < 0.001). Larger oocytes had higher odds of being used (oocyte area at tPNf ORused 1.669, 95%CI 1.336; 2.085, p < 0.001), were associated with faster embryo development up to the morula stage (e.g., t9 ß - 0.131 min, 95%CI - 0.237; - 0.025, p = 0.016) and higher ICM quality. CONCLUSION: Oocyte area is an informative marker for the preimplantation development of the embryo, as a larger oocyte area is associated with higher quality, faster developing embryos, and higher chance of being used. Identifying determinants associated with oocyte and embryo viability and quality could contribute to improved preconception care and subsequently healthy pregnancies.

Maternal obesity during pregnancy leads to derangements in one-carbon metabolism and the gut microbiota: implications for fetal development and offspring wellbeing.

A healthy diet before and during pregnancy is beneficial in acquiring essential B vitamins involved in 1-carbon metabolism, and in maintaining a healthy gut microbiota. Each play important roles in fetal development, immune-system remodeling, and pregnancy-nutrient acquisition. Evidence shows that there is a reciprocal interaction between the one-carbon metabolism and the gut microbiota given that dietary intake of B vitamins has been shown to influence the composition of the gut microbiota, and certain gut bacteria also synthesize B vitamins. This reciprocal interaction contributes to the individual's overall availability of B vitamins and, therefore, should be maintained in a healthy state during pregnancy. There is an emerging consensus that obese pregnant women often have derangements in 1-carbon metabolism and gut dysbiosis owing to high intake of nutritiously poor foods and a chronic systemic inflammatory state. For example, low folate and vitamin B12 in obese women coincide with the decreased presence of B vitamin-producing bacteria and increased presence of inflammatory-associated bacteria from approximately mid-pregnancy. These alterations are risk factors for adverse pregnancy outcomes, impaired fetal development, and disruption of fetal growth and microbiota formation, which may lead to potential long-term offspring metabolic and neurologic disorders. Therefore, preconceptional and pregnant obese women may benefit from dietary and lifestyle counseling to improve their dietary nutrient intake, and from monitoring their B vitamin levels and gut microbiome by blood tests and microbiota stool samples. In addition, there is evidence that some probiotic bacteria have folate biosynthetic capacity and could be used to treat gut dysbiosis. Thus, their use as an intervention strategy for obese women holds potential and should be further investigated. Currently, there are many knowledge gaps concerning the relationship between one-carbon metabolism and the gut microbiota, and future research should focus on intervention strategies to counteract B vitamin deficiencies and gut dysbiosis in obese pregnant women, commencing with the use of probiotic and prebiotic supplements.

First Trimester Maternal Homocysteine and Embryonic and Fetal Growth: The Rotterdam Periconception Cohort.

Homocysteine is a marker for derangements in one-carbon metabolism. Elevated homocysteine may represent a causal link between poor maternal nutrition and impaired embryonic and fetal development. We sought to investigate associations between reference range maternal homocysteine and embryonic and fetal growth. We enrolled 1060 singleton pregnancies (555 natural and 505 in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) pregnancies) from November 2010 to December 2020. Embryonic and fetal body and head growth was assessed throughout pregnancy using three-dimensional ultrasound scans and virtual reality techniques. Homocysteine was negatively associated with first trimester embryonic growth in the included population (crown-rump length B −0.023 mm, 95% CI −0.038,−0.007, p = 0.004, embryonic volume B −0.011 cm3, 95% CI −0.018,−0.004, p = 0.003). After stratification for conception mode, this association remained in IVF/ICSI pregnancies with frozen embryo transfer (crown-rump length B −0.051 mm, 95% CI −0.081,−0.023, p < 0.001, embryonic volume B −0.024 cm3, 95% CI −0.039,−0.009, p = 0.001), but not in IVF/ICSI pregnancies with fresh embryo transfer and natural pregnancies. Homocysteine was not associated with longitudinal measurements of head growth in first trimester, nor with second and third trimester fetal growth. Homocysteine in the highest quartile (7.3−14.9 µmol/L) as opposed to the lowest (2.5−5.2 µmol/L) was associated with reduced birth weight in natural pregnancies only (B −51.98 g, 95% CI −88.13,−15.84, p = 0.005). In conclusion, high maternal homocysteine within the reference range is negatively associated with first trimester embryonic growth and birth weight, and the effects of homocysteine are dependent on conception mode.

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review.

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538-1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (<7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

Paternal programming of offspring health.

In recent years, a new focus of the Developmental Origins of Health and Disease hypothesis has emerged examining the potential role that paternal health may play in embryo development, fetal growth and long-term offspring health. While the association between male health and sperm quality has been studied in detail, our understanding of the long-term paternal effects on offspring health remains limited. As with studies aimed at understanding maternal programming, animal models are an essential tool with which to define the underlying mechanisms linking paternal health to post-fertilisation development and offspring well-being. Here, new insights into the genetic and epigenetic nature of the sperm, as well as the role seminal plasma plays in modulating the maternal reproductive environment, are demonstrating the significant role a father's wellbeing at the time of conception has for programming the health of his offspring. In this article we will outline the current understanding of the impact of male health on semen quality, reproductive fitness and post-fertilisation offspring development and explore the mechanisms underlying the paternal programming of offspring health.