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.

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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.

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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 (β − 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 β − 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.

Study question Does oolemma area change before the 2-cell stage? Is oolemma area associated with fertilization rate, embryo usage rate and preimplantation embryo development? Summary answer Oolemma area is associated with preimplantation embryo development, the odds of fertilizing and developing into a used or discarded embryo. What is known already Current morphological grading systems are based on embryo morphology and omit oocyte morphology. Fertilization and embryo potential are largely determined by the maturation and quality of the oocyte. Oocyte quality correlates to morphology, and the very early stages of embryo development are critical to changes in oocyte size. Larger oocyte size associates with higher quality blastocyst. This suggests that oocyte size can be a morphological marker of preimplantation embryo quality and assisted reproductive treatment (ART) outcomes. Study design, size, duration This study is embedded in the Rotterdam Periconceptional Cohort, an ongoing prospective tertiary hospital-based birth cohort study. From May 2017 to July 2020, a subcohort of 378 women that underwent ART was included comprising of 124 pregnancies after in vitro fertilization (IVF) and 254 after intracytoplasmic sperm injection (ICSI). Participants/materials, setting, methods Health, lifestyle and treatment factors were collected from detailed self-reported questionnaires and medical records. Oolemma area was measured at the time of fertilization (t0), pronuclear appearance (tPNa) and fading (tPNf). Oolemma area trajectories (slope surface t0-tPNf) were calculated with linear regression. Fertilization rate, embryo usage rate, and embryo morphokinetics were analyzed in association with oolemma area and trajectories. Analyses were performed with linear mixed models, mixed effects logistic regression, and adjusted for relevant confounders. Main results and the role of chance Oolemma area decreased from t0 to tPNf for oocytes that developed into both used or discarded embryos. Oolemma area at t0 was strongly associated with the rate of area shrinking, as larger oolemma areas had faster shrinking rates (Bshrinking -12.55 µm²/hour, 95%CI -14.55; -10.55, p &lt; 0.001). Oocytes that resulted in a usable embryo were larger and reached tPNf faster than oocytes that resulted in a discarded embryo (tPNf 9855±595 µm2 vs 9690±721 µm2, p &lt; 0.001, 24.4±3.6 h vs 26.5±5.8 h, p &lt; 0.001). Oolemma area at tPNf did not differ between ICSI and IVF oocytes, however ICSI oocytes reached tPNf faster than IVF oocytes (23.6±3.2h and 25.9±3.8h, p &lt; 0.001, respectively). In ICSI only, larger oolemma area showed lower odds of a successful fertilization (t0 OR 0.57, 95%CI 0.48; 0.67, p &lt; 0.001), but higher odds of being cryopreserved or transferred (tPNf OR 1.66, 95%CI 1.33; 2.08, p &lt; 0.001). For IVF and ICSI, larger oolemma area at tPNF was associated with faster preimplantation development up to the morula stage (t7 B -1.41, 95%CI -2.18; -0.63, p &lt; 0.001). Oolemma area shrinking rate was not associated with embryo morphokinetics. Limitations, reasons for caution Small number of embryos measured at the blastocyst stage, and oolemma area measurements were not possible at t0 and tPNa for IVF oocytes. Wider implications of the findings Oolemma area is a suggested morphological marker for oocyte competence and an early marker for the success of fertilization and embryo development. The relevance of oolemma area as predictor of ART success requires further research. Cryopreservation and PCOS, which influence oocyte size, could be studied in association with oolemma area. Trial registration number not applicable