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.

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.

Development of human white matter pathways in utero over the second and third trimester.

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

Maternal Diet Influences Fetal Growth but Not Fetal Kidney Volume in an Australian Indigenous Pregnancy Cohort.

Suboptimal nutrition during pregnancy is recognised as a significant modifiable determinant in the development of chronic disease in offspring in later life. The current study aimed: (i) to assess the dietary intakes of pregnant Indigenous Australian women against national recommendations and (ii) to investigate the associations between maternal nutrition during pregnancy and the growth of the offspring, including kidney development in late gestation in the Gomeroi gaaynggal cohort (n = 103). Maternal dietary intake in the third trimester was assessed using the Australian Eating Survey Food Frequency Questionnaire. Estimated fetal weight (EFW) and kidney size were obtained by ultrasound. Birth weight was retrieved from hospital birth records. Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the nutrient reference values (NRVs) were zinc (75.7%) and folate (57.3%), whereas iron was the lowest. Only four people achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. Sodium and saturated fat intake exceeded recommended levels and diet quality was low, with a median score of 28 out of 73 points. After adjusting for smoking and pre-pregnancy body mass index, only maternal intake of retinol equivalents and the proportion of energy from nutrient-dense or energy-dense, nutrient-poor (EDNP) foods were associated with fetal growth. EFW decreased by 0.13 g and birth weight decreased by 0.24 g for every µg increase in maternal dietary retinol intake. Interestingly, EFW, but not actual birth weight, was positively associated with percentage energy from nutrient dense foods and negatively associated with percentage energy from EDNP foods. Dietary supplement usage was associated with increased birthweight, most significantly iron and folate supplementation. Current dietary intakes of pregnant Australian women from this cohort do not align with national guidelines. Furthermore, current findings show that maternal retinol intake and diet composition during pregnancy can influence fetal growth, but not fetal kidney growth in late gestation. Strategies that aim to support and optimise nutrient intakes of Indigenous pregnant women are urgently needed. Future studies with long-term follow-up of the children in the current cohort to assess renal damage and blood pressure are imperative.

Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health.

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research "road forward" to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.

Association of Maternal Prepregnancy Body Mass Index With Fetal Growth and Neonatal Thalamic Brain Connectivity Among Adolescent and Young Women.

Importance: Higher maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is associated with adverse long-term outcomes for offspring, including obesity, poorer cognitive and social abilities, and increased risk of psychiatric disorders. Less clear is whether higher maternal BMI disrupts fetal growth and brain development. Objective: To investigate the association of maternal prepregnancy BMI with fetal growth and neonatal functional connectivity. Design, Setting, and Participants: This prospective longitudinal cohort study was conducted from 2012 to 2017. Participants included nulliparous pregnant adolescent and young adult women, aged 14 to 19 years who were recruited in the second trimester through Columbia University Irving Medical Center and Weill Cornell Medical College. Women received routine prenatal care and had no major health problems at the time of recruitment. Data were analyzed from January 2018 to March 2020. Exposures: Maternal prepregnancy BMI. Main Outcomes and Measures: The main outcomes were fetal growth, measured as estimated fetal weight, and neonatal functional connectivity, measured using magnetic resonance imaging. Prepregnancy BMI and fetal ultrasonographic measurements were obtained from electronic health record review. Resting-state brain imaging data were acquired in infants within the first month of postnatal life. Functional connectivity was measured using intrinsic functional distribution and seed-based methods. Results: Among 129 women recruited, 105 had ultrasonographic data from at least 2 points and were included in analyses. The mean (SD) age at delivery was 17.82 (1.31) years. Maternal prepregnancy BMI was positively associated with the slope of estimated fetal weight (ß = 0.668; 95% CI, 0.163 to 1.175; P = .01) but not with fetal head circumference (ß = -0.004; 95% CI, -0.024 to 0.016; P = .70). In a subsample of 45 infants with magnetic resonance imaging data, maternal prepregnancy BMI was positively correlated with global connectivity in the left thalamus. Using this thalamic region as a seed, higher maternal BMI was associated with greater local thalamic (both hemispheres) and lower frontothalamic connectivity. Conclusions and Relevance: These results suggest that maternal prepregnancy BMI was associated with the development of regulation of body weight and thalamic functional brain connectivity in offspring even during fetal development.

Effect of Vitamin D Status during Pregnancy on Infant Neurodevelopment: The ECLIPSES Study.

Vitamin D status during pregnancy is involved in numerous physiological processes, including brain development. In this study, we assess the association between vitamin D status during pregnancy and infant neurodevelopment (cognitive, language, and motor skills). From an initial sample of 793 women (mean age 30.6) recruited before the 12th week of pregnancy, 422 mother-infant pairs were followed up to a postpartum visit. Vitamin D levels were assessed in the first and third trimesters of pregnancy, and socio-demographic, nutritional, and psychological variables were collected. At 40 days postpartum, the Bayley Scales of Infant Development-III were administered to the infants and several obstetrical data were recorded. Independently from several confounding factors, deficient vitamin D levels in the first trimester of pregnancy (<30 nmol/L) predicted a worse performance in cognitive and language skills. Language performance worsened with lower vitamin D levels (<20 nmol/L). In the third trimester, this highly deficient level was also associated with lower motor skills. Vitamin D deficiency was therefore associated with worse neurodevelopmental outcomes. More studies are needed to determine specific recommendations with regard to vitamin D supplementation during pregnancy in order to promote an optimal course for pregnancy and optimal infant neurodevelopment.

Nutrition and growth in children.

The well-balanced nourishment during "the first 1000 days," the period between conception (day 18) and the age of two years, is quite important for two main reasons. Firstly, the nutritive requirement is high due to the rapid physiological growth and functional development. Then, this period is characterized by extreme susceptibility to external stimuli such as inadequate maternal and infant nutritional status which they can interfere with the different stages of the development process leading to short and long-term consequences for health. Linear growth and brain development are particularly impaired from not sufficient nutrition. In consideration of the irreversible damage of malnutrition, especially on developing brain, an adequate nutrition during the first 1000 days of life is paramount. The aim of this review was to overview the latest scientific evidences on the relationship between nutrition and growth, focusing on nutritional requirements during the first 1000 days, and the impact of inadequate nutrition on brain development and linear growth.

Prenatal developmental toxicity study of an alkaloid-free Ageratum conyzoides extract powder in rats by oral administration.

A prenatal developmental toxicological study was conducted to evaluate the safety of an alkaloid-free Ageratum conyzoides extract powder administration on pregnant female Wistar rats and on the development of the conceptus in accordance with OECD test guideline (no. 414). Pyrrolizidine alkaloids (PAs) naturally present in A. conyzoides have been shown to induce toxicity in past studies, particularly towards hepatic cells. Therefore our test item preparation of A.conyzoides extract (aerial part of the plant) consisted of the removal of PAs. There were no treatment related adverse effects found during maternal examinations (body weights, food consumption, numbers of pregnant and non-pregnant female rats, endocrine evaluation, gravid uterine weights, and number of corpora lutea), maternal/fetal examinations (numbers of implantation sites, pre-and post-implantation loss (%), dead and live fetuses (%), resorption sites), or fetal examinations (litter size and weights, number of fetuses, sex ratio, or external, visceral, and skeletal variations and malformations) in the Ageratum conyzoides extract powder groups at doses of 500, 1000 and 2000 mg/kw bw/day compared to vehicle control group. The no observed adverse effect level (NOAEL) determined for both maternal and developmental toxicity was 2000 mg/kg bw/day, which was the highest dose tested.

The enigmatic fetal subplate compartment forms an early tangential cortical nexus and provides the framework for construction of cortical connectivity.

The most prominent transient compartment of the primate fetal cortex is the deep, cell-sparse, synapse-containing subplate compartment (SPC). The developmental role of the SPC and its extraordinary size in humans remain enigmatic. This paper evaluates evidence on the development and connectivity of the SPC and discusses its role in the pathogenesis of neurodevelopmental disorders. A synthesis of data shows that the subplate becomes a prominent compartment by its expansion from the deep cortical plate (CP), appearing well-delineated on MR scans and forming a tangential nexus across the hemisphere, consisting of an extracellular matrix, randomly distributed postmigratory neurons, multiple branches of thalamic and long corticocortical axons. The SPC generates early spontaneous non-synaptic and synaptic activity and mediates cortical response upon thalamic stimulation. The subplate nexus provides large-scale interareal connectivity possibly underlying fMR resting-state activity, before corticocortical pathways are established. In late fetal phase, when synapses appear within the CP, transient the SPC coexists with permanent circuitry. The histogenetic role of the SPC is to provide interactive milieu and capacity for guidance, sorting, "waiting" and target selection of thalamocortical and corticocortical pathways. The new evolutionary role of the SPC and its remnant white matter neurons is linked to the increasing number of associative pathways in the human neocortex. These roles attributed to the SPC are regulated using a spatiotemporal gene expression during critical periods, when pathogenic factors may disturb vulnerable circuitry of the SPC, causing neurodevelopmental cognitive circuitry disorders.

In vivo: maternal betaine supplementation normalized fetal growth in diabetic pregnancy.

PURPOSE: Diabetes alters maternal metabolism and can lead to aberrant fetal growth. In addition to insulin treatment, nutritional diet interventions are recommended for promoting fetal health against diabetes-induced adverse effects. Therefore, we conducted an in vivo study to investigate betaine efficacy on fetal development against maternal diabetes. METHODS: Thirty-two dams were divided into four equal groups: control (C), betaine supplementation (BS), diabetic pregnancy (DP) and diabetic pregnancy plus betaine supplementation (DP + BS). Fasting blood sugar (FBS) and body weight (BW) were monitored during pregnancy. After physiological delivery, dams glycated hemoglobin (HbA1c) concentrations were measured, followed by fetal development indices including litter size (LS), neonatal weight (NW) and crown-rump (CR). Also, maternal oxidative status was assessed by evaluating glutathione (GSH) content, glutathione peroxidase (GSH-Px) and catalase (CAT) activities, and malondialdehyde (MDA) concentration in the erythrocytes. RESULTS: Betaine supplementation significantly alleviated FBS and tended to recover BW loss. It also significantly decreased HbA1c values in dams of DP + BS compared to DP group. Normalized fetal indices such as LS, NW and CR under betaine supplementation were associated with a significant increase in GSH content and GSH-Px activity, as well as decreased MDA concentrations in erythrocytes of dams in the DP + BS versus the DP group, indicating improved redox balance in the dams. CONCLUSION: We indicated for the first time that betaine supplementation improved the maternal glucose metabolism and redox balance associated with normalized fetal growth. Nevertheless, further studies are required to investigate the mechanisms through which betaine protects fetal growth in diabetic pregnancy.

The Effect of Interactions between Folic Acid Supplementation and One Carbon Metabolism Gene Variants on Small-for-Gestational-Age Births in the Screening for Pregnancy Endpoints (SCOPE) Cohort Study.

Small-for-gestational-age (SGA) is associated with significant perinatal morbidity and mortality. Our aim was to investigate gene-nutrient interactions between maternal one-carbon single nucleotide polymorphisms (SNPs) and folic acid supplement (FAS) use, and their association with SGA. Nulliparous New Zealand women with singleton pregnancy were recruited as part of the Screening for Pregnancy Endpoints prospective cohort study. Data on FAS use was collected via face-to-face interview at 15 weeks' gestation; participants were followed prospectively and birth outcome data collected within 72 h of delivery. Participants were genotyped for MTHFR 677, MTHFR 1298, MTHFD1 1958, MTR 2756, MTRR 66 and TCN2 776 SNPs. Genotype data for at least one SNP was available for 1873 (93%) of eligible participants. Analysis showed a significant SNP-FAS interaction for MTHFR 1298 (p = 0.020), MTHFR 677 (p = 0.019) and TCN2 776 (p = 0.017) in relation to SGA: MTHFR 1298 CC variant non-FAS users had an increased likelihood [Odds Ratio (OR) = 2.91 (95% Confidence Interval (CI) = 1.52, 5.60] compared with wild-type (MTHFR 1298 AA) FAS users. MTHFR 677 variant allele carrier (MTHFR 677 CT + MTHFR 677 TT) non-FAS users had an increased likelihood [OR = 1.87 (95% CI = 1.21, 2.88)] compared to wild-type (MTHFR 677 CC) FAS users. TCN2 776 variant (TCN2 776 GG) non-FAS users had an increased likelihood [OR = 2.16 (95% CI = 1.26, 3.71)] compared with wild type homozygote + heterozygote (TCN2 776 CC + TCN2 776 CG) FAS users. No significant interactions were observed for MTHFD1 1958, MTR 2756 or MTRR 66 (p > 0.05). We observed an overall pattern of FAS attenuating differences in the likelihood of SGA seen between genotype groups in FAS non-users. Future research should focus on how intake of other one-carbon nutrients might mediate these gene-nutrient interactions.

Maternal choline and respiratory coronavirus effects on fetal brain development.

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 µM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.

Maternal diet high in Omega-3 fatty acids upregulate genes involved in neurotrophin signalling in fetal brain during pregnancy in C57BL/6 mice.

Neurotrophins play a critical role in the development, maintenance, and proper function of the brain. We investigated the effects of maternal diet high in omega (n)-3 polyunsaturated fatty acids (PUFA) on fatty acids composition and the gene expression of neurotrophins in fetal brain at different gestation stages. Female C57BL/6 mice (7-weeks old, n = 8/group) were fed a diet containing high, low or very low n-3 PUFA (9, 3 or 1% w/w, respectively), with an n-6:n-3 PUFA of 5:1, 20:1 and 40:1, respectively, for two weeks before mating and throughout pregnancy. Animals were sacrificed during pregnancy at gestation day 12.5 and 18.5 to determine placental and fetal-brain fatty acids composition. The gene expressions of endothelial lipase (EL) and plasma membrane fatty acid-binding protein (FABPpm) were measured in the placenta, while major facilitator superfamily domain-containing 2a (Mfsd2a), brain-derived neurotrophic factor (BDNF), tropomyosin-receptor kinase (TrK)-B, and cAMP response element-binding protein (CREB) were measured in fetal-brain, using qPCR. The protein expression of phosphorylated CREB (pCREB) was determined using ELISA. The high n-3 PUFA diet increased the mRNA expression of EL, FABPpm, and Mfsd2a at both gestation days, compared to other groups. Docosahexaenoic acid (DHA) and total n-3 PUFA were significantly higher in the high n-3 PUFA group, compared to the other groups at both gestation days. The high n-3 PUFA diet also increased the mRNA expressions of BDNF, TrKB and CREB, as well as the protein concentration of pCREB as gestation progressed, compared to the other groups. Our findings show for the first time that maternal diet high in n-3 PUFA increased the mRNA expression of Mfsd2a, which correlated with an increase in DHA accretion in the fetal-brain. A diet high in n-3 PUFA increased neurotrophin signalling in fetal-brain as gestation progressed, demonstrating the importance of n-3 PUFA during brain development.

Child Head Circumference and Placental MFSD2a Expression Are Associated to the Level of MFSD2a in Maternal Blood During Pregnancy.

Gestational diabetes mellitus (GDM) is a world-wide health challenge, which prevalence is expected to increase in parallel to the epidemic of obesity. Children born from GDM mothers have lower levels of docosahexaenoic acid (DHA) in cord blood, which might influence their neurodevelopment. Recently, the membrane transporter Major Family Super Domain 2a (MFSD2a) was associated with the selective transportation of DHA as lysophospholipids. The expression of the DHA membrane transporter MFSD2a is lower in GDM placentas, which could affect materno-fetal DHA transport. Humans with homozygous inactivating mutations in the MFSD2a gene present severe microcephaly and intellectual impairments. Herein, we intended to identify early blood biomarkers that may be of use during pregnancy to monitor the offspring development and the adequate nutritional interventions, such as nutritional supplementation, that may be selected to improve it. We evaluated MFSD2a expression in maternal blood at the third trimester of pregnancy, and its potential relationship with the expression of placental MFSD2a at delivery and child outcomes. Three groups of pregnant women were recruited: 25 controls, 23 GDM with dietary treatment, and 20 GDM with insulin treatment. Maternal and neonatal anthropometric and biochemical parameters were evaluated. MFSD2a was analyzed in placenta, blood and serum. MFSD2a protein expression in maternal blood was significantly lower in GDM groups and correlated with placental MFSD2a and Z-score neonatal head circumference during the first 6 months of life. The cord/maternal serum ratio of DHA, a solid indicator of materno-fetal DHA transport, was reduced in GDM groups and correlated with MFSD2a in maternal blood at the third trimester and in placenta at delivery. This indicates that altered MFSD2a levels in maternal blood during pregnancy might influence placental nutrient transport and fetal neurodevelopment. Furthermore, MFSD2a levels in maternal blood on the third trimester were inversely correlated to DHA in maternal serum lyso-PL. Thus, the level of MFSD2a in maternal blood could be used as a potential biomarker for the early detection of disturbances of MFSD2a expression during pregnancy and the subsequent consequences for the neurodevelopment of the child, as well as it may help to choose the optimal treatment approach for the affected subjects.

Student midwives' perception of the growth assessment protocol (GAP): Preparation for clinical practice.

Fetal growth restriction is a major complication of pregnancy and increases the risk of stillbirth. Midwives screen for fetal wellbeing by measuring the symphysis fundal height to detect growth restriction, which can present in a low risk pregnancy or occur late in gestational age. The detection, surveillance and onward referral of these pregnancies are the responsibility of all midwives. To prevent avoidable stillbirth due to restricted fetal growth and to ensure safe, evidence based practice, the Perinatal Institute developed the Growth Assessment Protocol (GAP). A qualitative study using semi-structured interviews was conducted to explore 2nd year student midwives' perception of the GAP training and its impact on their clinical practice. Data was analysed and four main themes were identified using interpretative phenomenological analysis. The findings from the study show that the participants viewed the GAP training as 'authentic' and commented on the alignment with contemporary practice for the detection and surveillance of at risk pregnancies. The findings suggest that GAP training for pre-registration student midwives has the potential to provide a sustainable workforce, prepared to meet the World Health Organisation's global strategy for eliminating avoidable stillbirth by 2030.

Mineral and bone physiology in the foetus, preterm and full-term neonates.

Mother is the major source of minerals in foetal life with placenta actively transporting against a concentration and electrochemical gradient. The foetal serum mineral concentration is thereby higher as compared to maternal values, which possibly help in its rapid accretion in developing bones and for counteracting postnatal fall in calcium levels at birth. Parathyroid hormone related peptide (PTHrP) and parathyroid hormone (PTH) play a major role in mineral physiology during foetal life with hormones like calcitriol, calcitonin, FGF-23 and sex steroids having minimal role. PTHrP and PTH also play a major role in endochondral bone formation and mineralization of skeleton. At the birth, as the cord is clamped, there is loss of active transport of minerals through placenta and the neonate has to rely on enteral intake of minerals to meet the demands of growing bones and metabolisms. The calcium levels fall after birth, reaching a nadir at 24-48 h and gradually rise to adult values over several days, probably resulting from a fall in PTHrP levels and hyporesponsiveness of parathyroid glands. As PTH and calcitriol levels increase postnatally, there is a rise in calcium levels with maturation in functioning of kidneys and intestines. However, there may be significant delay in intestinal maturation in preterm infants along with an increased demand for mineral accretion, which predispose them to osteopenia of prematurity.

Calciotropic and phosphotropic hormones in fetal and neonatal bone development.

There are remarkable differences in bone and mineral metabolism between the fetus and adult. The fetal mineral supply is from active transport across the placenta. Calcium, phosphorus, and magnesium circulate at higher levels in the fetus compared to the mother. These high concentrations enable the skeleton to accrete required minerals before birth. Known key regulators in the adult include parathyroid hormone (PTH), calcitriol, fibroblast growth factor-23, calcitonin, and the sex steroids. But during fetal life, PTH plays a lesser role while the others appear to be unimportant. Instead, PTH-related protein (PTHrP) plays a critical role. After birth, serum calcium falls and phosphorus rises, which trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply while the kidneys reabsorb filtered minerals. This striking developmental switch is triggered by loss of the placenta, onset of breathing, and the drop in serum calcium.

Gestational vitamin D concentration and other risk factors versus fetal femur length.

Introduction: Vitamin D plays a crucial role in the development of healthy fetal bone tissue. Analysis of fetal bone parameters versus maternal vitamin D status is necessary to shed some light on the matter. The aim of the study was to investigate the relationship between maternal and cord vitamin D concentrations and other factors which might affect fetal bone development and femur length.Material and methods: The study included 94 term pregnancies, delivered at the Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw. Fetal femur length was measured during an ultrasound examination on admission to the delivery unit. Total 25(OH)D concentrations were measured in maternal and cord blood. Direct interview with a dietician was used to collect lifestyle and nutrition data. Multiple regression analysis was used for statistical analysis.Results: No statistically significant relationship was found between vitamin D concentrations and fetal femur length, either in maternal (p = .7709) or cord (p = .7751) blood samples, despite the fact that low vitamin D concentrations, which might indicate aberrations in fetal bone development, were detected in 50.0% of the mothers and 28.7% of the newborns. Also, no relationship was confirmed for the remaining parameters, including nutritional factors (calcium or caffeine intake, vitamin/mineral supplements).Conclusion: Low vitamin D concentrations during pregnancy and lifestyle factors had no negative associations with fetal femur length.

Prenatal exercise reverses high-fat-diet-induced placental alterations and alters male fetal hypothalamus during late gestation in rats†.

Maternal high-fat (HF) diet negatively affects maternal metabolism and placental function. This study aimed to determine whether gestational exercise prevents the effect of HF diet on placental amino acid transporter expression and nutrient-sensing signaling and the fetal response. Pregnant Sprague-Dawley rats were either fed with a CHOW (13.5% fat) or HF (60% fat) diet during gestation and further divided into two subgroups: voluntary exercised and sedentary. Placentae were collected on gestational day (GD) 14 and GD20, and male placentae were used in this study. We found that gestational exercise ameliorated the detrimental effects of HF diet on dams' adiposity, plasma leptin, and insulin concentrations. Maternal exercise did not influence fetoplacental growth but affected male fetal hypothalamic Leprb, Stat3, Insr, Agrp, and Pomc expressions on GD20. Maternal HF diet decreased placental labyrinth thickness and increased system A amino acid transporter SNAT2 expression, while these changes were normalized by exercise. The activation of placental mechanistic target of rapamycin complex 1/4E-BP1 and LepRb/STAT3 signaling might contribute to the increased placental SNAT2 expression in HF-fed dams, which were reversed by exercise on GD20. These data highlight that gestational exercise reverses HF-diet-induced placental alterations during late gestation without influencing fetal growth. However, maternal exercise altered fetal hypothalamic gene expression, which may affect long-term offspring health.