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Background: Up to 25-35% of women receive antibiotics (ABX) during pregnancy, but little is known about the consequences on a key mucosal interface such as the mammary gland, and on the development of the neonatal gut's microbiota and IgA. We hypothesize that prenatal ABX negatively affect the immune functionality of mammary gland, the composition of breast milk microbiota, the development of neonatal fecal microbiota and the abundance of neonatal fecal IgA., Methods: Case-control translational cohort study on women and neonates in the presence or absence (N = 41 + 41 pairs) of exposure to prenatal ABX for at least 7 consecutive days after 32 weeks of gestation., Results: We will evaluate IgA concentration in breast milk and in neonatal feces up to one year after delivery. We will also evaluate clinical parameters, neurodevelopment and the composition of the IgA-coated and uncoated fractions of breast milk and fecal microbiota by means of magnetic-activated cell sorting (MACS) coupled with shotgun metagenomics. Finally, we will measure the concentration of the chemokine CCL28 on maternal serum and breast milk, as a marker of activity of the entero-mammary pathway., Conclusions: Our results might support a data-driven evaluation of breast milk immune function in women exposed to prenatal ABX., Impact: Breast milk IgA and microbiota are critical to determine the positive effects of breastfeeding in infants. This research protocol will investigate breast milk IgA, microbiota, and the IgA + / IgA - fractions of neonatal fecal microbiota upon exposure to prenatal antibiotics. Fecal IgA and microbiota in infants exposed or not exposed to prenatal antibiotics will be analyzed up to 1 year after birth. This research will clarify the impact of prenatal antibiotics on the immune function of breast milk. This, in turn, might support the selective evaluation of breast milk IgA/microbiota in mothers exposed to prenatal antibiotics, or in donor human milk., Competing Interests: Competing interests: The authors declare no competing interests. Consent statement: Written informed consent will be obtained from enrolled women and the fathers of enrolled neonates., (© 2025. The Author(s).)

Background: Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment., Methods: Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years., Results: TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005)., Conclusions: FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk., Impact: Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Amino acid placental delivery is reduced in human intrauterine growth-restricted (IUGR) fetuses, and the activity of placental amino transporters has been consistently shown to be decreased in in vitro studies. We hypothesized lower placental expression and localization of sodium-coupled neutral amino acid transporter 2 (SNAT2 (also known as SLC38A2)), altered levels of intron-1 methylation, and altered distribution of single-nucleotide polymorphisms in human IUGR vs. normal pregnancies., Methods: We studied 88 IUGR and 84 control placentas from singleton pregnancies at elective caesarean section. SNAT2 expression was investigated by real-time PCR and immunohistochemistry. Intron-1 methylation levels were analyzed by pyrosequencing, and single-nucleotide polymorphism distribution was analyzed by allelic discrimination., Results: mRNA levels were significantly decreased in IUGR placentas with reduced umbilical blood flows. Syncytiotrophoblast immunostaining was lower in IUGR placentas than in control placentas. Methylation levels were steadily low in both IUGR and control placentas. SNP genotype and allele frequencies did not differ between the two groups., Conclusion: This is the first study investigating SNAT2 expression and regulation mechanisms in human IUGR placentas. We confirm previous results obtained in rats and cell cultures that support the fundamental role of SNAT2 in fetal growth and well-being, as well as a possible role of oxygen levels in regulating SNAT2 expression, indicating the relevance of hypoxia in IUGR.

The aim of this study was to evaluate maternal and fetal lipid profile in intrauterine growth restriction (IUGR) pregnancies with and without preeclampsia (PE). Thirteen normal pregnancies studied during the third trimester (control M) and 29 at elective cesarean section (control CS) were compared with 18 pregnancies complicated by IUGR (IUGR only) and with seven pregnancies complicated by both IUGR and PE (IUGR-PE). Total plasma fatty acids, triglycerides, cholesterol, and nonesterified fatty acids (NEFA) were determined in maternal and fetal plasma. Nutritional intake was analyzed. IUGR only mothers had lower percentage of linoleic acid (LA) and higher arachidonic acid (AA) than controls, partly explained by higher AA dietary intake. Higher levels of NEFA were observed both in IUGR only and in IUGR-PE mothers whereas triglyceride levels were increased in IUGR-PE mothers only. In IUGR-PE fetuses, LA and AA were significantly decreased, whereas triglyceride and NEFA concentrations were significantly increased compared with normal fetuses. In conclusion, IUGR only is associated with altered fatty acids profile not completely accounted by dietary changes. We hypothesize that the differences observed in IUGR with PE for triglycerides and other lipids could be related to a difference in maternal phenotype.

Intrauterine growth restriction (IUGR) is associated with reduced placental supply of nutrients to the fetus. Lipoprotein lipase (LPL) mediates the hydrolysis of triglycerides from maternal lipoproteins to obtain fatty acids. Here, we tested the hypothesis that placental LPL gene expression level is altered in pregnancies complicated by IUGR. To this purpose, 28 IUGR fetuses were identified during pregnancy and divided in two groups: 7 M-IUGR ["mild" IUGR, with normal umbilical artery pulsatility index (PI)] and 21 S-IUGR ("severe" IUGR, with abnormal PI). Moreover, 10 out of 28 IUGR pregnancies were associated with preeclampsia. Controls were 19 normal pregnancies delivering appropriate for gestational age (AGA) fetuses. Relative real-time quantification of LPL was carried out in RNA from placental chorionic villi by the DeltaDeltaCt method, using beta-actin as normalizing gene. Placental LPL mRNA expression levels were significantly higher in IUGR than in AGA. In particular, significantly higher values were observed in S-IUGR, independent from the concomitant association with preeclampsia. No significant relationship was observed between placental LPL mRNA expression levels or gestational age. In conclusion, placental LPL mRNA gene expression is increased in severe IUGR, characterized by enhanced vascular placental resistances and alterations of placental nutrient transport.

The placenta is essential to nutrition before birth. Recent work has shown that a range of clearly defined alterations can be found in the placentas of infants with intrauterine growth restriction (IUGR). In the mouse, a placental specific knockout of a single imprinted gene, encoding IGF-2, results in one pattern of alterations in placenta structure and function which leads to IUGR. We speculate that the alterations in the human placenta can also be grouped into patterns, or phenotypes, that are associated with specific patterns of fetal growth. Identifying the placental phenotypes of different fetal growth patterns will improve the ability of clinicians to recognize high-risk patients, of laboratory scientists to disentangle the complexities of IUGR, and of public health teams to target interventions aimed at ameliorating the long-term adverse effects of inadequate intrauterine growth.

Fetuses with intrauterine growth restriction (IUGR) are at increased risk of death and disease during neonatal, pediatric, and adult life. Postnatal deficits in essential fatty acids have been associated with the neural and vascular complications of premature neonates. We studied whether fetal-maternal fatty acid relationships are already impaired in utero in IUGR fetuses. Fetal (F) and maternal (M) fatty acid profiles were determined in utero in 11 normal [appropriate for gestational age (AGA)] and in 10 IUGR fetuses by fetal blood sampling (FBS) between 19 and 39 wk. Total plasma fatty acid concentrations were significantly higher in M than in F of both AGA (M: 2.03 +/- 0.53 mg/mL; F: 0.64 +/- 0.29 mg/mL; p < 0.001) and IUGR (M: 2.16 +/- 0.59 mg/mL; F: 0.73 +/- 0.17 mg/mL; p < 0.001). The F/M ratio was significantly higher for linoleic acid (AGA: 0.36 +/- 0.09; IUGR: 0.52 +/- 0.12; p < 0.01) and significantly lower for the long-chain polyunsaturated fatty acid docosahexaenoic acid (AGA: 1.94 +/- 0.32; IUGR: 1.25 +/- 0.19; p < 0.05) and arachidonic acid (AGA: 2.35 +/- 0.35%; IUGR: 2.04 +/- 0.3%; p < 0.05) in IUGR compared with AGA pregnancies. The differences observed in the relative amounts but not in total plasma concentrations of fatty acid fetal-maternal relationships in pregnancies associated with IUGR could be related to inadequate transplacental supply as well as to a fetal lack of the enzymes necessary for elaboration of these metabolically relevant conditionally essential fatty acids. These differences might have a role in determining the biochemical environment leading to the neural and vascular complications associated with IUGR.

Fetal growth and development are dependent upon the adequate provision of oxygen and substrates from the maternal circulation. The need for amino acids is related to protein synthesis, interconversion to other substrates, and oxidation. Amino acids cross the placenta by active transport systems, and their concentrations in the fetus are higher than in the mother. In addition, most amino acids are extensively metabolized within the placenta, and, for some nonessential amino acids, placental synthesis has been demonstrated in chronically catheterized fetal lambs. Interorgan cycling between the fetal liver and placenta has been hypothesized for nonessential amino acids like glycine and serine. Amino acids are oxidized within the fetal tissues, particularly in liver and muscle, with differences between amino acids and in relation to metabolic state. In human pregnancies, maternal-fetal transfer rates have been investigated in vivo by stable isotope methodologies performed at fetal blood sampling. The transfer rate of nonessential amino acids like glycine is significantly lower than for essential amino acids like leucine, confirming glycine synthesis in the fetoplacental unit also in human pregnancies. Moreover, when a steady state model is applied, the fetal-maternal ratio for [1-(13)C]leucine is significantly reduced in pregnancies associated with intrauterine growth restriction, reflecting a decrease in leucine placental transfer and/or an increase in protein catabolism in the fetoplacental unit. This reduction is proportional to the degree of severity of intrauterine growth restriction but is significant also in those intrauterine growth-restricted fetuses with normal oxygenation and acid-base status.

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6+/-0.6 ng/mL; p<0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p<0.001) and fetal weight (p<0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p<0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p<0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p<0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.

The aim of this study was to compare the fetal/maternal (F/M) leucine-enrichment ratio in normal (AGA) and intrauterine growth-restricted (IUGR) pregnancies at the time of fetal blood sampling (FBS). A maternal primed-constant infusion of L-[1-13C]-leucine was given in six AGA and 14 IUGR pregnancies, divided into three groups according to the pulsatility index (PI) of the umbilical artery and to fetal heart rate (FHR): group 1 (normal FHR and PI, four cases); group 2 (normal FHR and abnormal PI, five cases); and group 3 (abnormal FHR and PI, five cases). Maternal arterialized samples were taken at time zero and every 20 min for 125+/-7 min. Umbilical venous samples were obtained after 114+/-42 min of infusion. Under steady state conditions, there was a significant linear relationship between maternal leucine disposal rate and maternal leucine concentration. The comparison of fetal to maternal leucine enrichment showed a progressive dilution of the fetal enrichment relative to the mother between AGA and IUGR of group 1 (0.89 versus 0.78, p < 0.02), group 2 (0.71, p < 0.001), and group 3 (0.62, p < 0.001), and also among the three IUGR groups. The F/M leucine molar percent enrichment (MPE) ratio showed a positive correlation with the umbilical venous oxygen content and an inverse correlation with fetal lactate concentration. We conclude that the dilution in the fetal/maternal leucine-enrichment ratio correlates with the severity of growth restriction and reflects decreased transplacental leucine flux and/or increased protein breakdown within the fetoplacental compartments.

Primarily, our objectives were to compare system A amino acid transporter activity in the microvillous plasma membrane (MVM) of placentas from normally grown (appropriate for gestational age, AGA) and intrauterine growth-restricted (IUGR) fetuses delivered during the third trimester, as a whole and in relation to the severity of IUGR. Ten AGA and 16 IUGR pregnancies were studied at the time of elective cesarean section performed between 28 and 40 wk of gestation. Severity of IUGR pregnancies was assessed primarily by Doppler velocimetry and fetal heart rate monitoring. Placental MVM vesicles were prepared, and system A activity in these was measured. The transporter activity was significantly lower in IUGR compared with AGA pregnancies. Within the IUGR group system A activity was only significantly lower, compared with AGA, in cases that presented with a reduction in umbilical blood flow. We conclude that placental MVM system A activity is lower in IUGR compared with AGA pregnancies delivered during the third trimester. System A activity is related to the severity of IUGR.

L-[1-13C]Glycine and L-[1-13C]leucine were infused as a bolus into 12 pregnant patients carrying normal fetuses before fetal blood sampling at gestational ages ranging from 20 to 37 wk. Maternal venous samples were obtained every 2-3 min for 15 min after the bolus infusion. Fetal samples were obtained from the umbilical vein within 15 min of the bolus. Amino acid plasma enrichments (molar percent enrichment) were determined by gas chromatography-mass spectroscopy and their concentrations by ion exchange chromatography. The ratios of glycine and leucine transfer were assessed from fetal/maternal enrichment ratios for each amino acid. We now report that over the gestational age range of 20-37 wk, under relatively undisturbed fetomaternal conditions (fetal blood sampling), human placental glycine transfer is limited, with a glycine/leucine ratio = 0.16 +/- 0.02. We hypothesize that, in human pregnancies, the relative rates of in vivo transplancental transport of amino acids can be assessed indirectly utilizing fetal blood sampling and stable isotope methodology. The application of this approach to leucine and glycine demonstrates that the transfer of leucine is rapid (demonstrable in seconds), whereas that of glycine is more limited.

Lactate concentration and oxygen content were measured in 21 normal (AGA) and 34 intrauterine growth-retarded (IUGR) infants at the time of elective cesarean section. Maternal lactate and umbilical arterial and venous lactate concentrations were significantly higher in IUGR infants compared with AGA infants. However, when IUGR patients were subdivided according to pulsatility index (PI) measurements of the umbilical artery, no differences were detected between AGA and IUGR patients with PI less than 4 SD, whereas IUGR patients with PI greater than 4 SD had higher lactate concentrations in maternal arterial blood and umbilical arterial and venous blood from both other groups. There was a significant inverse linear relationship between umbilical arterial lactate concentration and umbilical venoarterial differences for both lactate concentrations and for lactate/oxygen quotients. These relationships were significantly different in IUGR fetuses with PI greater than 4 SD compared with AGA and IUGR fetuses with PI less than 4 SD. AGA and IUGR fetuses with PI less than 4 SD have arterial lactate concentrations less than 2 mM even at low oxygen concentrations (O2 content less than 2 mM, O2 saturations less than 20%). At comparable levels of oxygenation, IUGR fetuses with PI greater than 4 SD have a marked lactacidemia. The data suggest that coupling Doppler assessment of flow velocimetry with biochemical analyses of fetal blood can be useful in identifying a subset of IUGR human fetuses at risk of intrauterine hypoxia.