First-trimester fetal size, accelerated growth in utero, and child neurodevelopment in a cohort study.

BACKGROUND: Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children's neurodevelopment remains to be assessed. This study aimed to explore the association between first-trimester fetal size and children's neurodevelopment and to examine whether intrauterine accelerated growth could compensate for the detrimental effects of first-trimester restricted growth on childhood neurodevelopment. METHODS: The participants were from a birth cohort enrolled from March 2014 to March 2019 in Wuhan, China. A total of 2058 fetuses with crown to rump length (CRL) (a proxy of first-trimester fetal size) measurements in the first trimester and neurodevelopmental assessment at age 2 years were included. We measured the first-trimester CRL and defined three fetal growth patterns based on the growth rate of estimated fetal weight from mid to late pregnancy. The neurodevelopment was assessed using the Bayley Scales of Infant Development of China Revision at 2 years. RESULTS: Each unit (a Z score) increase of first-trimester CRL was associated with increased scores in mental developmental index (MDI) (adjusted beta estimate = 1.19, (95% CI: 0.42, 1.95), P = 0.03) and psychomotor developmental index (PDI) (adjusted beta estimate = 1.36, (95% CI: 0.46, 2.26), P < 0.01) at age 2 years, respectively. No significant association was observed between fetal growth rate and PDI. For children with restricted first-trimester fetal size (the lowest tertile of first-trimester CRL), those with "intrauterine accelerated growth" pattern (higher growth rates) had significantly higher MDI (adjusted beta estimate = 6.14, (95% CI: 3.80, 8.49), P < 0.001) but indistinguishable PDI compared to those with "intrauterine faltering growth" pattern (lower growth rates). Main limitations of this study included potential misclassification of gestational age due to recall bias of the last menstrual period and residual confounding. CONCLUSIONS: The current study suggests that restricted first-trimester fetal size is associated with mental and psychomotor developmental delay in childhood. However, in children with restricted first-trimester fetal size, intrauterine accelerated growth was associated with improved mental development but had little effect on psychomotor development. Additional studies are needed to validate the results in diverse populations.

Developmental Windows for Effects of Choline and Folate on Excitatory and Inhibitory Neurotransmission During Human Gestation.

Choline and folate are critical nutrients for fetal brain development, but the timing of their influence during gestation has not been previously characterized. At different periods during gestation, choline stimulation of α7-nicotinic receptors facilitates conversion of γ-aminobutyric acid (GABA) receptors from excitatory to inhibitory and recruitment of GluR1-R2 receptors for faster excitatory responses to glutamate. The outcome of the fetal development of inhibition and excitation was assessed in 159 newborns by P50 cerebral auditory-evoked responses. Paired stimuli, S1, S2, were presented 500 msec apart. Higher P50 amplitude in response to S1 (P50S1microV) assesses excitation, and lower P50S2microV assesses inhibition in this paired-stimulus paradigm. Development of inhibition was related solely to maternal choline plasma concentration and folate supplementation at 16 weeks' gestation. Development of excitation was related only to maternal choline at 28 weeks. Higher maternal choline concentrations later in gestation did not compensate for earlier lower concentrations. At 4 years of age, increased behavior problems on the Child Behavior Checklist 1½-5yrs were related to both newborn inhibition and excitation. Incomplete development of inhibition and excitation associated with lower choline and folate during relatively brief periods of gestation thus has enduring effects on child development.

Autophagy and Exocytosis of Lipofuscin Into the Basolateral Extracellular Space of Human Retinal Pigment Epithelium From Fetal Development to Adolescence.

Purpose: To undertake the first ultrastructural characterization of human retinal pigment epithelial (RPE) differentiation from fetal development to adolescence. Methods: Ten fetal eyes and three eyes aged six, nine, and 17 years were examined in the temporal retina adjacent to the optic nerve head by transmission electron microscopy. The area, number, and distribution of RPE organelles were quantified and interpreted within the context of adjacent photoreceptors, Bruch's membrane, and choriocapillaris maturation. Results: Between eight to 12 weeks' gestation (WG), pseudostratified columnar epithelia with apical tight junctions differentiate to a simple cuboidal epithelium with random distribution of melanosomes and mitochondria. Between 12 to 26 WG, cells enlarge and show long apical microvilli and apicolateral junctional complexes. Coinciding with eye opening at 26 WG, melanosomes migrate apically whereas mitochondria distribute to perinuclear regions, with the first appearance of phagosomes, complex granules, and basolateral extracellular space (BES) formation. Significantly, autophagy and heterophagy, as evidenced by organelle recycling, and the gold standard of ultrastructural evidence for autophagy of double-membrane autophagosomes and mitophagosomes were evident from 32 WG, followed by basal infoldings of RPE cell membrane at 36 WG. Lipofuscin formation and deposition into the BES evident at six years increased at 17 years. Conclusions: We provide compelling ultrastructural evidence that heterophagy and autophagy begins in the third trimester of human fetal development and that deposition of cellular byproducts into the extracellular space of RPE takes place via exocytosis. Transplanted RPE cells must also demonstrate the capacity to subserve autophagic and heterophagic functions for effective disease mitigation.

Comparative analysis of foetal and neonatal growth curves.

INTRODUCTION: Our aim was to determine which foetal or neonatal growth curves discriminate the probability of dying of newborns with low birth weight for their gestational age (small for gestational age, SGA) and sex (weight < 10th percentile) and to establish the curves that are presumably most useful for monitoring growth through age 10 years. MATERIAL AND METHODS: The analysis included every neonate (15 122) managed in our hospital (2013-2022) and all neonates born preterm before 32 weeks (6913) registered in the SEN1500 database (2019-2022). We considered most useful those curves with the highest likelihood ratio (LR) for dying with or without a history of SGA in each subgroup of gestational ages. Theoretically, the optimal curves for monitoring growth would be those with a higher R2 in the quantile regression formulas for the 50th percentile. RESULTS: The growth curves exhibiting the strongest association between SGA and hospital mortality are the Intergrowth fetal curves and the Fenton neonatal curves in infants born preterm before 32 weeks. However, the optimal curves for premature babies and neonates overall were those of Olsen and Intergrowth. The most useful curves to monitor anthropometric values alone until age 10 years of age are the longitudinal Intergrowth curves followed by the WHO standards, but if a single reference is desired from birth through age 10 years, the best option is the Fenton curves followed by the WHO standards. CONCLUSIONS: The Intergrowth reference provides the most discriminating foetal growth curves. In neonatal clinical practice, the optimal references are the Fenton followed by the WHO charts.

Fetal brain MRI atlases and datasets: A review.

Fetal brain development is a complex process involving different stages of growth and organization which are crucial for the development of brain circuits and neural connections. Fetal atlases and labeled datasets are promising tools to investigate prenatal brain development. They support the identification of atypical brain patterns, providing insights into potential early signs of clinical conditions. In a nutshell, prenatal brain imaging and post-processing via modern tools are a cutting-edge field that will significantly contribute to the advancement of our understanding of fetal development. In this work, we first provide terminological clarification for specific terms (i.e., "brain template" and "brain atlas"), highlighting potentially misleading interpretations related to inconsistent use of terms in the literature. We discuss the major structures and neurodevelopmental milestones characterizing fetal brain ontogenesis. Our main contribution is the systematic review of 18 prenatal brain atlases and 3 datasets. We also tangentially focus on clinical, research, and ethical implications of prenatal neuroimaging.

Development and growth of bovine calves demi-embryos.

The aim of this study was to investigate the growth and development of animals produced from demi-embryos and compare them with whole embryos from fetus to adult life. To achieve this, calves produced from fresh demi-embryos and whole embryos were individually transferred and monitored from 60 days of pregnancy until slaughter at 550 days. Ultrasound scans were conducted on fetuses at 60 and 90 days to evaluate the biparietal, abdominal, umbilical cord, orbital, and aorta diameters. Subsequently, morphological traits of newborn calves were measured at 0, 7, and 21 days (N = 18). Live weight was recorded at birth, weaning, and every 30 days thereafter until slaughter at 550 days. The growth curve of each group was modeled using logistic regression, and the factors of the respective functions were compared. As early as 60 days of pregnancy, ultrasound evaluations revealed no morphometric differences between fetuses produced from demi-embryos and those from whole embryos. This lack of differentiation persisted in the morphometric evaluations of newborns up to 21 days of age, as well as in live weight and the growth curve from birth to slaughter. Moreover, there were no significant differences between the groups in terms of rib eye area and fat thickness evolution. Consequently, individuals from demi-embryos exhibited no discernible disparities to those whole embryos in growth and development from 60 days of gestation, through birth, and into adulthood.

Routine third-trimester ultrasound assessment for intrauterine growth restriction.

Intrauterine growth restriction significantly impacts perinatal outcomes. Undetected IUGR escalates the risk of adverse outcomes. Serial symphysis-fundal height measurement, a recommended strategy, is insufficient in detecting abnormal fetal growth. Routine third-trimester ultrasounds significantly improve detection rates compared with this approach, but direct high-quality evidence supporting enhanced perinatal outcomes from routine scanning is lacking. In assessing fetal growth, abdominal circumference alone performs comparably to estimated fetal weight. Hadlock formulas demonstrate accurate fetal weight estimation across diverse gestational ages and settings. When choosing growth charts, prescriptive standards (encompassing healthy pregnancies) should be prioritized over descriptive ones. Customized fetal standards may enhance antenatal IUGR detection, but conclusive high-quality evidence is elusive. Emerging observational data suggest that longitudinal fetal growth assessment could predict adverse outcomes better. However, direct randomized trial evidence supporting this remains insufficient.

Effects of umbilical vein flow on midbrain growth and cortical development in late onset fetal growth restricted fetuses: a prospective cross-sectional study.

OBJECTIVES: To investigate midbrain growth, including corpus callusum (CC) and cerebellar vermis (CV) and cortical development in late fetal growth restricted (FGR) subclassified according to the umbilical vein blood flow (UVBF) values. METHODS: This was a prospective study on singleton fetuses late FGR with abnormal placental cerebral ratio (PCR). FGR fetuses were further subdivided into normal (≥fifth centile) and abnormal (

Autopsy-Based Growth Charts May under-Detect Fetal Growth Restriction at Autopsy.

Background: Accurate identification of fetal growth restriction in fetal autopsy is critical for assessing causes of death. We examined the impact of using a chart derived from ultrasound measurements of healthy fetuses (World Health Organization fetal growth chart) versus a chart commonly used by pathologists (Archie et al.) derived from fetal autopsy-based populations in diagnosing small-for-gestational-age (SGA) birth in perinatal deaths. Study Design: We examined perinatal deaths that underwent autopsy at BC Women's Hospital, 2015-2021. Weight centiles were assigned using the ultrasound-based fetal growth chart for birthweight and autopsy-based growth chart for autopsy weight. Results: Among 352 fetuses, 30% were SGA based on the ultrasound-based fetal growth chart versus 17% using the autopsy-based growth chart (p < 0.001). Weight centiles were lower when using the ultrasound-based versus autopsy-based growth chart (median difference of 9 centiles [IQR 2, 20]). Conclusions: Autopsy-based growth charts may under-classify SGA status compared to ultrasound-based fetal growth charts.

Early life corticosteroid overexposure: Epigenetic and fetal origins of adult diseases.

The relationship between events occurring during intrauterine development and later-life predisposition to long-term disease, has been described. The fetus responds to excess intrauterine exposure to high levels of corticosteroids, modifying their physiological development and stopping their growth. Fetal exposure to elevated levels of either endogenous (alterations in fetal hypothalamic-pituitary-adrenal axis) or synthetic corticosteroids, is one model of early-life adversity; to developing adult disease. At the molecular level, there are transcriptional changes in metabolic and growth pathways. Epigenetic mechanisms participate in transgenerational inheritance, not genomic. Exposures that change 11ß-hydroxysteroid dehydrogenase type 2 enzyme methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol. More precise diagnosis and management of antenatal corticosteroids for preterm birth, would potentially decrease the risk of long-term adverse outcomes. More studies are needed to understand the potential roles of factors to alter fetal corticosteroid exposure. Long-term infant follow-up is required to determine whether methylation changes in placenta may represent useful biomarkers of later disease risk. This review, summarize recent advances in the programming of fetal effects of corticosteroid exposure, the role of corticosteroids in epigenetic gene regulation of placental 11ß-hydroxysteroid dehydrogenase type 2 enzyme expression and transgenerational effects.

Exploring the Influence of Fetal Sex on Heart Rate Dynamics Using Fetal Magnetocardiographic Recordings.

Fetal sex has been associated with different development trajectories that cause structural and functional differences between the sexes throughout gestation. Fetal magnetocardiography (fMCG) recordings from 123 participants (64 females and 59 males; one recording/participant) from a database consisting of low-risk pregnant women were analyzed to explore and compare fetal development trajectories of both sexes. The gestational age of the recordings ranged from 28 to 38 weeks. Linear metrics in both the time and frequency domains were applied to study fetal heart rate variability (fHRV) measures that reveal the dynamics of short- and long-term variability. Rates of linear change with GA in these metrics were analyzed using general linear model regressions with assessments for significantly different variances and GA regression slopes between the sexes. The fetal sexes were well balanced for GA and sleep state. None of the fHRV measures analyzed exhibited significant variance heterogeneity between the sexes, and none of them exhibited a significant sex-by-GA interaction. The absence of a statistically significant sex-by-GA interaction on all parameters resulted in none of the regression slope estimates being significantly different between the sexes. With high-precision fMCG recordings, we were able to explore the variation in fHRV parameters as it relates to fetal sex. The fMCG-based fHRV parameters did not show any significant difference in rates of change with gestational age between sexes. This study provides a framework for understanding normal development of the fetal autonomic nervous system, especially in the context of fetal sex.

Investigating the association of maternal heart rate variability with fetal birth weight.

Maternal heart rate (HR) was reported to affect birth weight and birth outcomes. Low birth weight constitutes a major health problem, and it is estimated that around 15% to 20% of births worldwide are low weight. In our previous study, we discussed the presence of similarities between maternal and fetal HRs, therefore, here, we propose to develop a parameter based on maternal and fetal HR variability (HRV) to divide data into two patterns to investigate the association of fetal birth weight with maternal HR and HRV. The parameter was derived from non-invasive records of maternal and fetal electrocardiograms (ECGs) that were collected from 78 subjects (age: 22 - 44 years old, gestational age (GA): 19 - 40 weeks). The HRV parameter was calculated by first evaluating the standard deviation (SD) of the number of R peaks occurring per 2 seconds (snRpp2s). Then, the difference between maternal and fetal snRpp2s (dmf) was calculated. The correlation between our derived parameter [dmf] with GA revealed a significant correlation that suggested the dmf's association with fetal development. The association analysis results between birthweight with maternal HR and HRV per pattern showed that significant negative correlations exist between them in one pattern. Still, the same correlations were not observed in the other pattern. This study's findings emphasise maternal health's role in fetal development assessment. In addition, this study highlights the importance of developing novel factors for properly assessing fetal development and birth outcomes.

[Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies].

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (ß=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (ß=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Role of Hormones During Gestation and Early Development: Pathways Involved in Developmental Programming.

Accumulating evidence suggests that an altered maternal milieu and environmental insults during the intrauterine and perinatal periods of life affect the developing organism, leading to detrimental long-term outcomes and often to adult pathologies through programming effects. Hormones, together with growth factors, play critical roles in the regulation of maternal-fetal and maternal-neonate interfaces, and alterations in any of them may lead to programming effects on the developing organism. In this chapter, we will review the role of sex steroids, thyroid hormones, and insulin-like growth factors, as crucial factors involved in physiological processes during pregnancy and lactation, and their role in developmental programming effects during fetal and early neonatal life. Also, we will consider epidemiological evidence and data from animal models of altered maternal hormonal environments and focus on the role of different tissues in the establishment of maternal and fetus/infant interaction. Finally, we will identify unresolved questions and discuss potential future research directions.

Human Placental Adaptive Changes in Response to Maternal Obesity: Sex Specificities.

Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. At the interface between the mother and the fetus, the placenta mediates the impact of the maternal environment on fetal development. Most of the literature presents data on the effects of maternal obesity on placental functions and does not exclude potentially confounding factors such as metabolic diseases (e.g., gestational diabetes). In this context, the focus of this review mainly lies on the impact of maternal obesity (in the absence of gestational diabetes) on (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome. Moreover, some of those placental changes in response to maternal obesity could be supported by fetal sex. A better understanding of sex-specific placental responses to maternal obesity seems to be crucial for improving pregnancy outcomes and the health of mothers and children.

RACK1 may participate in placental development at mid-gestation via regulating trophoblast cell proliferation and migration in pigs.

Intrauterine growth restriction (IUGR) is a severe complication in swine production. Placental insufficiency is responsible for inadequate fetal growth, but the specific etiology of placental dysfunction-induced IUGR in pigs remains poorly understood. In this work, placenta samples supplying the lightest weight (LW) and mean weight (MW) pig fetuses in the litter at Day 65 (D65) of gestation were collected, and the relationship between fetal growth and placental morphologies and functions was investigated using histomorphological analysis, RNA sequencing, quantitative polymerase chain reaction, and in vitro experiment in LW and MW placentas. Results showed that the folded structure of the epithelial bilayer of LW placentas followed a poor and incomplete development compared with that of MW placentas. A total of 654 differentially expressed genes (DEGs) were screened out between the LW and MW placentas, and the gene encodes receptor for activated C kinase 1 (RACK1) was found to be downregulated in LW placentas. The DEGs were mainly enriched in translation, ribosome, protein synthesis, and mammalian target of rapamycin (mTOR) signaling pathway according to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In vitro experiments indicated that the decreased RACK1 in LW placentas may be involved in abnormal development of placental folds (PFs) by inhibiting the proliferation and migration of porcine trophoblast cells. Taken together, these results revealed that RACK1 may be a vital regulator in the development of PFs via regulating trophoblast cell proliferation and migration in pigs.

Effect of Musical Stimulation on Placental Programming and Neurodevelopment Outcome of Preterm Infants: A Systematic Review.

BACKGROUND: The fetal environment is modulated by the placenta, which integrates and transduces information from the maternal environment to the fetal developmental program and adapts rapidly to changes through epigenetic mechanisms that respond to internal (hereditary) and external (environmental and social) signals. Consequently, the fetus corrects the trajectory of own development. During the last trimester of gestation, plasticity shapes the fetal brain, and prematurity can alter the typical developmental trajectories. In this period, prevention through activity-inducing (e.g., music stimulation) interventions are currently tested. The purpose of this review is to describe the potentialities of music exposure on fetus, and on preterm newborns in the Neonatal Intensive Care Unit evaluating its influence on neurobehavioral development. METHODS: Databases were searched from 2010 to 2022 for studies investigating mechanisms of placental epigenetic regulation and effects of music exposure on the fetus and pre-term neonates. RESULTS: In this case, 28 selected papers were distributed into three research lines: studies on placental epigenetic regulation (13 papers), experimental studies of music stimulation on fetus or newborns (6 papers), and clinical studies on premature babies (9 papers). Placental epigenetic changes of the genes involved in the cortisol and serotonin response resulted associated with different neurobehavioral phenotypes in newborns. Prenatal music stimulation had positive effects on fetus, newborn, and pregnant mother while post-natal exposure affected the neurodevelopment of the preterm infants and parental interaction. CONCLUSIONS: The results testify the relevance of environmental stimuli for brain development during the pre- and perinatal periods and the beneficial effects of musical stimulation that can handle the fetal programming and the main neurobehavioral disorders.

Shared developmental pathways of the placenta and fetal heart.

Congenital heart defects (CHD) remain the most common class of birth defect worldwide, affecting 1 in every 110 live births. A host of clinical and morphological indicators of placental dysfunction are observed in pregnancies complicated by fetal CHD and, with the recent emergence of single-cell sequencing capabilities, the molecular and physiological associations between the embryonic heart and developing placenta are increasingly evident. In CHD pregnancies, a hostile intrauterine environment may negatively influence and alter fetal development. Placental maldevelopment and dysfunction creates this hostile in-utero environment and may manifest in the development of various subtypes of CHD, with downstream perfusion and flow-related alterations leading to yet further disruption in placental structure and function. The adverse in-utero environment of CHD-complicated pregnancies is well studied, however the specific etiological role that the placenta plays in CHD development remains unclear. Many mouse and rat models have been used to characterize the relationship between CHD and placental dysfunction, but these paradigms present substantial limitations in the assessment of both the heart and placenta. Improvements in non-invasive placental assessment can mitigate these limitations and drive human-specific investigation in relation to fetal and placental development. Here, we review the clinical, structural, and molecular relationships between CHD and placental dysfunction, the CHD subtype-dependence of these changes, and the future of Placenta-Heart axis modeling and investigation.