Maternal Adaptation Research Articles

PMON253 The Ghrelin/Leap-2 ratio might be associated with physiologic changes in maternal weight during different stages of pregnancy

Abstract Ghrelin is an orexigenic gastric peptide hormone implicated in pleiotropic functions, playing an important role in the regulation of food intake and homeostatic body weight regulation mediated through the growth hormone secretagogue receptor (GHSR). Recently, the liver and small intestine–derived peptide liver enriched antimicrobial peptide-2 (LEAP-2) was characterized to acts as an endogenous GHSR antagonist and blunts the orexigenic action of ghrelin. On the other hand, physiologic maternal weight gain during each trimester of pregnancy might be associated primarily with the developing fetus and the maternal energy requirements. This study aimed to determine serum LEAP-2 levels and Ghrelin/Leap-2 ratio in pregnant women at each trimester of gestation and three months postpartum. We conducted a nested study within an observational prospective cohort study. Twenty five healthy women were longitudinally studied during the first, second and third trimester of pregnancy and three months postpartum. Additionally, twenty healthy non – pregnant women were studied during the follicular a luteal phase of the menstrual cycle. Biochemical and hormonal laboratory measurements were performed during the early morning hours (07: 00-08: 00 hours) following an overnight fast (9: 00-10: 00 hours). Human serum Ghrelin (MBS283919) and LEAP-2 (MBS917663) levels were determined using the commercially available ELISA kits and the ratio between circulating Ghrelin and Leap-2 (Ghrelin/Leap-2) levels was calculated. The clinical and biochemical parameters in the studied population of pregnant women and non – pregnant women were described. In healthy pregnant women, circulating Ghrelin levels decreased significantly in the third trimester of gestation (p<0.05). Also, serum Ghrelin levels are markedly increased after delivery and reaching the levels from first trimester of pregnancy (p>0.05). Additionally, in healthy pregnant women, a significant decrease was observed in serum LEAP-2 concentrations from second to third trimesters of pregnancy (p<0.05). In addition, serum LEAP-2 levels were significantly increased after delivery and returned to the levels of the first trimester of gestation. The Ghrelin/Leap-2 ratio increases significantly during pregnancy and reaches its peak in the second and third trimester of gestation in healthy pregnant women (p<0.05). In conclusion, this study provides the first evidence that Ghrelin/Leap-2 ratio increase steadily during pregnancy reaching their peak in the second and third trimester of pregnancy. Additionally, the findings of this study suggest that Ghrelin/Leap-2 ratio might play an important role in maternal physiology adaptation of weight gain during pregnancy. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Genomic imprinting and maternal adaptations to pregnancy

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Placental proteome in late‑onset of fetal growth restriction.

Fetal growth restriction (FGR) occurs when the fetus does not reach its genetically programmed intrauterine potential for growth and affects ~5–10% of pregnancies. This condition is one of the leading causes of perinatal mortality and morbidity associated with obstetric and neonatal complications. Placental dysfunction in FGR causes an impairment in the transfer of nutrients and oxygen from the mother to the developing fetus. Maternal adaptations to placental insufficiency may also play a role in the pathophysiology of FGR. The present study aimed to compare the proteome of the placentas of 18 women with the physiological course of pregnancy and eutrophic fetus [estimated fetal weight (EFW) >10th percentile; control group] and 18 women with late FGR (EFW <10th percentile) diagnosed after 32 weeks of pregnancy, according to the Delphi consensus (study group). The U. Mann-Whitney test was used to compare two independent groups. The R. Spearman correlation coefficient significance test was used to assess the existence of a relationship between the analyzed measurable parameters. P<0.05 was considered to indicate a statistically significant difference. The tests showed the presence of 356 different proteins which were responsible for the regulation of gene transcription control, inhibiting the activity of proteolytic enzymes, regulation of trophoblast proliferation and angiogenesis and inflammatory response. In the FGR placental proteome, other detected proteins were mostly involved in response to oxidative stress, cellular oxidation and detoxication, apoptosis, hemostatic and catabolic processes, energy transduction protein interactions, cell proliferation, differentiation and intracellular signaling. The present study used chromatographic mass-spectrometry to compare the placental proteome profiles in pregnancies complicated by late-onset FGR and normal pregnancy. Comparative analysis of proteomes from normal and FGR placentas showed significant differences. Further research is needed to clarify maternal and fetal adaptations to FGR.

Lactation from the inside out: Maternal homeorhetic gastrointestinal adaptations regulating energy and nutrient flow into milk production

Lactation invokes homeorhetic processes to ramp up and supply milk synthesis components to fulfil nutritional, immunological and microbiological requirements of developing offspring, overseen by complex neuroendocrine networks. The maternal gut meets these intense metabolic demands, supported by hyperphagia and rapid adjustments to process larger food quantities. Enteroplasticity describes an inherent ability of the gastrointestinal tract to harness metabolic and structural adaptations that increase nutrient absorption. Most shifts in response to increased demands are transitory and by secreting milk, the continuous energetic drain out of the maternal body avoids development of pathological metabolic diseases. Lactation has various positive benefits for long-term maternal health but many females do not lactate for long post pregnancy and younger women are increasingly pre-disposed to excessive body mass and/or metabolic complications prior to reproducing. Inadvertently invoking intestinal adaptations to harvest and store excess nutrients has negative health implications with increased risks for both mother and offspring.

Adaptation of the gut holobiont to malnutrition during mouse pregnancy depends on the type of nutritional adversity

Malnutrition can influence maternal physiology and programme offspring development. Yet, in pregnancy, little is known about how dietary challenges that influence maternal phenotype affect gut structure and function. Emerging evidence suggests that interactions between the environment, multidrug resistance (MDR) transporters and microbes may influence maternal adaptation to pregnancy and regulate fetoplacental development. We hypothesized that the gut holobiont (host and microbes) during pregnancy adapts differently to suboptimal maternal diets, evidenced by changes in the gut microenvironment, morphology, and expression of key protective MDR transporters during pregnancy. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD) 5.5–18.5, or fed 60% high fat diet (HF) for 8 weeks before and during pregnancy. At GD18.5, maternal small intestinal (SI) architecture (H&E), proliferation (Ki67), P-glycoprotein (P-gp - encoded by Abcb1a/b) and breast cancer resistance protein (BCRP/Abcg2) MDR transporter expression and levels of pro-inflammatory biomarkers were assessed. Circulating inflammatory biomarkers and maternal caecal microbiome composition (G3 PhyloChipTM) were measured. MDR transporter expression was also assessed in fetal gut. HF diet increased maternal SI crypt depth and proinflammatory load, and decreased SI expression of Abcb1a mRNA, whilst UN increased SI villi proliferation and Abcb1a, but decreased Abcg2, mRNA expression. There were significant associations between Abcb1a and Abcg2 mRNA levels with relative abundance of specific microbial taxa. Using a systems physiology approach we report that common nutritional adversities provoke adaptations in the pregnancy holobiont in mice, and reveal new mechanisms that could influence reproductive outcomes and fetal development.

Maternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation

During lactation, the maternal physiology adapts to bear the nutritional requirements of the offspring. The exocrine and endocrine pancreas are central to nutrient handling, promoting digestion and metabolism. In concert with prolactin, insulin is a determinant factor for milk synthesis. The investigation of the pancreas during lactation has been scattered over several periods. The investigations that laid the foundation of lactating pancreatic physiology and glucose homeostasis were conducted in the decades of 1970–1980. With the development of molecular biology, newer studies have revealed the molecular mechanisms involved in the endocrine pancreas during breastfeeding. There has been a surge of information recently about unexpected changes in the pancreas at the end of the lactation period and after weaning. In this review, we aim to gather information on the changes in the pancreas and glucose homeostasis during and after lactation and discuss the outcomes derived from the current discoveries.

Peri-conceptional exposure to ambient air pollution increases risk of gestational diabetes among pregnant participants in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study

Background: Exposures to air pollution potentially disrupt maternal metabolic adaptation during pregnancy. However, influences of preconception and prenatal exposures to ambient air pollution on gestational diabetes mellitus (GDM) remain unclear, and even less is known about sensitive windows for these exposures’ effect on GDM. Methods: In 617 pregnant participants enrolled the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, we estimated daily levels of ambient particulate matter (PM₁₀; PM₂.₅), nitrogen dioxide (NO₂), ozone (O₃) using spatial interpolation. GDM was ascertained from medical records by physician diagnosis or defined as abnormally high glucose challenge and tolerance test results. We used distributed lag models (DLM) with Poisson regression to identify sensitive exposure windows by estimating weekly associations of exposures from pre-conception week (PcW) 12 to gestational week (GW) 24 with GDM risk, adjusting for maternal and meteorological factors. Analyses were additionally stratified by median prenatal Perceived Stress Scale (PSS, 14), median pre-pregnancy body mass index (BMI, 27.5 kg/m²), median age (28 years), and newborn sex to explore differential susceptibility to exposure effects. Results: Sixty (9.7%) participants were diagnosed with GDM. We identified sensitive peri-conceptional exposure windows for PM₂.₅, PM₁₀, and NO₂ ranging from PcW5 to GW3 associated with increased GDM risk. An IQR increase in each pollutant was associated with 5% (95%CI: 3.3-6.7%), 6% (5.9-7.4%), and 11% (9.3-12.2%) increased GDM risk, respectively. In stratified analyses, effects of PM₁₀ and NO₂ in the identified sensitive windows were greater among those &amp;#x2265;28 years old, with BMI&amp;#x2265;27.5 kg/m², or with PSS&amp;#x2265;14. Conclusions: Peri-conception exposures to ambient air pollutants were associated with increased risk of GDM. Stronger effects in the identified sensitive windows were seen in participants who were older, had higher BMI, or higher perceived stress. Keywords: air pollution, gestational diabetes, sensitive window, susceptibility, perceived stress, preconception

Maternal Right Ventricular and Left Atrial Function in Uncomplicated Twin Pregnancies: A Longitudinal Study.

Objective: The knowledge regarding maternal cardiovascular hemodynamic adaptation in twin pregnancies is incomplete. We performed a longitudinal investigation of maternal right ventricular (RV) and left atrial (LA) function in a cohort of uncomplicated twin pregnancies compared to singleton pregnancies. Study design: Healthy women with uncomplicated twin pregnancies were prospectively enrolled and assessed by transthoracic echocardiography at 10–15 weeks’ (w) gestation (T1), 19-26 w gestation (T2), and 30–38 w gestation (T3). Subjects with uneventful singleton pregnancies were selected as controls at the same gestational ages. Cardiac findings were compared to those of women with uneventful singleton gestations. RV systolic and diastolic functions were assessed by conventional echocardiography (FAC, TAPSE, sPAP, E, A, DT) and tissue Doppler imaging (TDI) (E’, A’, S’, IVA, IVCT, IVRT, ET, MPI), and LA dimensions were calculated. Speckle-tracking imaging was also applied to evaluate RV global longitudinal strain and LA 2D strains (at LV end-systole (LAS) and at atrial contraction (LAA)). Results: Overall, 30 uncomplicated twin and 30 uncomplicated singleton pregnancies were included. Regarding maternal RV function in twins, all the parameters (FAC, TAPSE, sPAP, E, A, E/A, DT, E/E’, IVA, IVCT, MPI and 2D longitudinal strain) were almost stable throughout gestation, with the exception of the TDI findings (E’ decreased from T1 to T3 (p = 0.03), while E’/A’ increased from T1 to T2 and then decreased (p = 0.01); A’ and basal S’ increased (p = 0.04 and p = 0.03, respectively), while IVRT and ET significantly decreased (p = 0.009 and p = 0.007, respectively)). These findings were similar to those found for singleton pregnancies. LA dimensions significantly increased throughout gestation in both twins and singletons (p < 0.001), without intergroup difference. LA strains did not vary during either twin or singleton pregnancies, except for LAA in T1, which was higher among twins than among singletons. Conclusion: Maternal RV and LA function in uncomplicated twin pregnancies does not seem to undergo more significant changes than in singletons, being characterized by similar findings in RV systolic and diastolic functions, as well as LA dimensions and strains.

Effectiveness of mindfulness-based intervention in the improvement of maternal role adaptation among first time mothers: A randomized controlled trial

Background and purposeMindfulness-based intervention (MBI) has been suggested as a method to alleviate mental health difficulties during the perinatal period. However, few studies have examined its use in improving maternal role adaptation. This study aimed to investigate the effectiveness of mindfulness in maternal role adaptation among first-time mothers. Materials and methodsThis randomized controlled trial study was performed on 40 first-time mothers who were randomly assigned into experimental (n = 20) and control (n = 20) groups. Research instruments included a demographic questionnaire and a validated Maternal Role Adaptation Questionnaire (MRAQ). In addition to receiving routine care, mothers in the experimental group attended eight 90-min sessions of mindfulness-based intervention. The control group, however, received only routine care. Both groups completed MRAQ before intervention, and immediately, one month, and two months after it. ResultsAfter intervention, there was a significant increase in the mean scores of MRAQ and its seven domains in the experimental group at all three follow-up intervals (P < 0.001). These domains included “support and strengthening of the couples’ relationships”, “hardship and dissatisfaction”, “mother-infant attachment”, “stress and anxiety”, “emotional growth”, “functionality” and “social adaptation development”. ConclusionThe intervention implemented in this study could be effective in promoting maternal role adaptation.

Prenatal health behaviours as predictors of human placental lactogen levels.

Placental lactogen (hPL) is a key hormone of pregnancy responsible for inducing maternal adaptations critical for a successful pregnancy. Low levels of placental lactogen have been associated with lower birth weight as well as symptoms of maternal depression and anxiety. Lower placental lactogen has been reported in women with higher body mass index (BMI) but it is unclear whether prenatal health behaviours predict hPL levels or if hPL is associated with infant weight outcomes. This study utilised data from the longitudinal Grown in Wales cohort, based in South Wales. Participants were recruited at the pre-surgical appointment for an elective caesarean section. This study incorporates data from recruitment, post-delivery and a 12 month follow-up. Measures of maternal serum hPL were available for 248 participants. Analysis included unadjusted and adjusted linear and binary regression. Unadjusted, prenatal smoking and a Health Conscious dietary pattern were associated with hPL levels, however this was lost on adjustment for BMI at booking, Welsh Index of Multiple Deprivation (WIMD) score and placental weight. When stratified by maternal BMI at booking, a Health Conscious dietary pattern remained associated with increased hPL levels in women with a healthy BMI (p=.024, B=.59. 95% CI=.08,1.11) following adjustment for WIMD score and placental weight. When adjusted for a wide range of confounders, maternal hPL was also associated with increased custom birthweight centiles (CBWC) (p=.014, B=1.64. 95% CI=.33,2.94) and increased odds of large for gestational age deliveries (p=<.001, Exp(B)=1.42. 95% CI=1.17,1.72). This study identified that consuming a Health Conscious dietary pattern in pregnancy was associated with increased hPL, within women of a healthy BMI. Moreover, higher hPL levels were associated with increased CBWC and increased odds of delivering a large for gestational age infant. This improves the current limited evidence surrounding the nature of hPL in these areas.

Maternal Left Ventricular Function in Uncomplicated Twin Pregnancies: A Speckle-Tracking Imaging Longitudinal Study.

Objective: The knowledge of maternal cardiovascular hemodynamic adaptation in twin pregnancies is incomplete. We aimed to longitudinally investigate maternal left ventricular (LV) function in uncomplicated twin pregnancies. Methods: 30 healthy and uncomplicated twin pregnant women and 30 controls with normal singleton pregnancies were prospectively enrolled to undergo transthoracic echocardiography at 10–15 week’s gestation (w) (T1), 19–26 w (T2) and 30–38 w (T3). LV dimensions and volumes, as well as LV ejection fraction (LVEF), mass (LVM) and diastolic parameters (at transmitral pulsed wave Doppler and mitral annular plane tissue Doppler), were calculated. Speckle-tracking imaging was also applied to evaluate LV global longitudinal (GLS), radial and circumferential 2D strains. Results: During twin pregnancy, maternal LV dimensions, volumes and LVM had an increasing trend from T1 to T3, similar to singletons, while LVEF remained stable. There was LV remodeling/hypertrophy in 50% of women at T2 and T3 in both groups. Diastolic function had a worsening trend from T1 to T3 with no differences between twins and singletons, except for higher LV filling pressure (i.e., E/E′) at T2 in twins. Two-dimensional strains did not vary during gestation in either group, except for a linear trend to increase (i.e., worsen) GLS in singletons. Radial and circumferential 2D strains were impaired in about half of the women at each trimester, while GLS was altered in one-fourth/one-third of them in both groups. Conclusion: Maternal LV geometry, dimensions and function are significantly impaired during twin pregnancies, in particular in the second half of gestation, with no significant differences compared to singletons.

Placental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction

Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease.

Study of the Ghrelin/LEAP-2 Ratio in Humans and Rats during Different Phases of Pregnancy.

The Liver-Expressed Antimicrobial Peptide 2 (LEAP-2) has emerged as an endogenous GHS-R antagonist and blunts the orexigenic action of ghrelin. This study aimed to determine the Ghrelin/LEAP-2 ratio in humans and rats during pregnancy. In humans, we conducted a nested case-control study within an observational prospective cohort. Healthy and mild preeclamptic pregnant women were studied at each trimester of gestation and three months postpartum. In addition, a group of non-pregnant women was studied into the follicular and luteal phases of the menstrual cycle. Furthermore, Ghrelin/LEAP-2 ratio was investigated in non-pregnant rats and at different periods of rat pregnancy. Human and rat serum ghrelin and LEAP-2 levels were determined using the commercially available ELISA kits. The Ghrelin/LEAP-2 ratio peak around the second trimester of gestation in healthy pregnant women (p < 0.05). Additionally, there were no statistically significant differences in Ghrelin/LEAP-2 ratio between healthy and preeclamptic pregnant women at each trimester of gestation (p > 0.05). The Ghrelin/LEAP-2 ratio in pregnant rat reached the peak around mid-gestation with a similar pattern to the human pregnancy. LEAP-2 was visualized by immunohistochemistry in human term placenta and rat placentas on days 12, 16 and 21 of pregnancy. In conclusion, this study provides the first evidence of a Ghrelin/LEAP-2 ratio peak around the half-way point of pregnancy onwards during human and rat pregnancy, and it might be associated with increased rates of weight gain during pregnancy. Thus, this study suggests that LEAP-2 and Ghrelin/LEAP-2 ratio might play an important role in maternal physiology adaptation of weight gain during pregnancy.

Maternal well-being and family adaptation during COVID-19 in fragile X syndrome.

Mothers of children with fragile X syndrome are at increased risk of experiencing anxiety and depression due to potential genetic risk and to stress associated with parenting a child with significant behavioral, emotional, and educational support needs. During the initial shutdown and subsequent restrictions of the COVID-19 pandemic, mothers of children with fragile X reported experiencing elevated levels of anxiety and depression relative to their usual levels of well-being. Many indicated that the negative consequences of exposure to COVID-19 and related stressors, as well as the impacts of the pandemic on their family, directly affected their anxiety and depression. Mothers reported on specific sources of distress as well as potential sources of resilience and positive adaptation that occurred during the first year of the COVID-19 pandemic.

Human Chorionic Villous Differentiation and Placental Development.

In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases.

Ablation of PI3K-p110alpha Impairs Maternal Metabolic Adaptations to Pregnancy.

Pregnancy requires adaptations in maternal metabolism to support fetal growth. The phosphoinositol-3-kinase (PI3K) signalling pathway controls multiple biological processes and defects in this pathway are linked to metabolic disorders including insulin resistance and glucose intolerance in non-pregnant animals. However, relatively little is known about the contribution of PI3K signalling to the maternal metabolic adaptations during pregnancy. Using mice with partial inactivation of the PI3K isoform, p110α (due to a heterozygous dominant negative mutation; Pik3ca-D933A), the effects of impaired PI3K-p110α signalling on glucose and insulin handling were examined in the pregnant and non-pregnant states and related to the morphological, molecular, and mitochondrial changes in key metabolic organs. The results show that non-pregnant mice lacking PI3K-p110α are glucose intolerant but exhibit compensatory increases in pancreatic glucose-stimulated insulin release and adipose tissue mitochondrial respiratory capacity and fatty acid oxidation. However, in pregnancy, mutant mice failed to show the normal increment in glucose intolerance and pancreatic β-cell mass observed in wild-type pregnant dams and exhibited further enhanced adipose tissue mitochondrial respiratory capacity. These maladaptations in pregnant mutant mice were associated with fetal growth restriction. Hence, PI3K-p110α is a key regulator of metabolic adaptations that support fetal growth during normal pregnancy.

Effects of post-traumatic stress disorder on maternal adaptation and newborn perception in the postpartum period

ABSTRACT This study was carried out to determine the effects of posttraumatic stress disorder (PTSD) on maternal adaptation and newborn perception in postpartum primiparous mothers. The research was designed as descriptive and cross-sectional. A total of 378 mothers who were in postpartum 6-8 weeks were reached. Of the 378 mothers participating in the study, 97 (25.7%) scored above the posttraumatic stress scale cut-off point (≥ 33). After vaginal childbirth, primiparous mothers with PTSD in the postpartum period were found to have weaker maternal adaptation and newborn perception than mothers without (p < 0.001). It was determined that primiparous mothers with PTSD who have experienced traumatic birth have difficulty in adapting to motherhood and have problems in perceiving, accepting, and bonding with the newborn. Mothers in the postpartum period should be screened for PTS symptoms by home visits by health professionals to ensure that mothers receive the necessary psychological support and care.

Maternal gut microbiota Bifidobacterium promotes placental morphogenesis, nutrient transport and fetal growth in mice

The gut microbiota plays a central role in regulating host metabolism. While substantial progress has been made in discerning how the microbiota influences host functions post birth and beyond, little is known about how key members of the maternal gut microbiota can influence feto-placental growth. Notably, in pregnant women, Bifidobacterium represents a key beneficial microbiota genus, with levels observed to increase across pregnancy. Here, using germ-free and specific-pathogen-free mice, we demonstrate that the bacterium Bifidobacterium breve UCC2003 modulates maternal body adaptations, placental structure and nutrient transporter capacity, with implications for fetal metabolism and growth. Maternal and placental metabolome were affected by maternal gut microbiota (i.e. acetate, formate and carnitine). Histological analysis of the placenta confirmed that Bifidobacterium modifies placental structure via changes in Igf2P0, Dlk1, Mapk1 and Mapk14 expression. Additionally, B. breve UCC2003, acting through Slc2a1 and Fatp1-4 transporters, was shown to restore fetal glycaemia and fetal growth in association with changes in the fetal hepatic transcriptome. Our work emphasizes the importance of the maternal gut microbiota on feto-placental development and sets a foundation for future research towards the use of probiotics during pregnancy.

Placental Syndromes-A New Paradigm in Perinatology.

Placental syndromes include pregnancy loss, fetal growth restriction, preeclampsia, preterm delivery, premature rupture of membranes, placental abruption and intrauterine fetal demise. This paper discusses the common etiopathogenesis of those syndromes and the role of angiogenic biomarkers in their development. Pregnancy implantation, placental development and maternal adaptation are complex processes in which fetal and maternal cells interact. The syncytiotrophoblast, trophoblast, uterine natural killer cells and regulatory T cells interfere and interact in all the above-mentioned processes. The proper angioneogenesis and vasculogenesis of the placenta, as well as maternal circulatory adaptation, are dependent on angiogenic factor expression. Insufficient maternal immunotolerance, dysregulation in uterine natural killer or regulatory T cell function, syncytiotrophoblast and trophoblast ischemia and hypoxia or impaired balance in angiogenic factors are all related to the occurrence of placental syndromes. Differences in the time of impairment onset and its intensity and correlation with other dysfunctions result in the development of a specific syndrome. The clinical manifestations in the form of a combination of specific symptoms determine the diagnosis. However, they are just symptoms of an underlying complex trophoblast disorder.

Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats.

Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and proteinuria. We hypothesized that BN pregnancies would show renal functional, anatomical, or molecular features of preeclampsia. We used the Sprague-Dawley (CD) rat as a model of normal pregnancy. Pregnancy increased the glomerular filtration rate by 50% in CD rats and 12.2% in BN rats compared to non-pregnancy, and induced proteinuria only in BN rats. BN pregnancies showed a decrease in maternal plasma calcitriol levels, which correlated with renal downregulation of 1-alpha hydroxylase and upregulation of 24-hydroxylase. RNA sequencing revealed that pregnancy induced 297 differentially expressed genes (DEGs) in CD rats and 174 DEGs in BN rats, indicating a 70% increased response to pregnancy in CD compared to BN rats. Pregnancy induced activation of innate immune pathways such as ‘Role of Pattern Recognition Receptors’, and ‘Interferon signaling’ with interferon regulatory factor 7 as a common upregulated upstream factor in both rat strains. Comparison of rat strain transcriptomic profiles revealed 475 DEGs at non-pregnancy and 569 DEGs at pregnancy with 205 DEGs shared at non-pregnancy (36%), indicating that pregnancy interacted with rat strain in regulating 64% of the DEGs. Pathway analysis revealed that pregnancy induced a switch in renal transcriptomics in BN rats from ‘inhibition of renal damage’ to ‘acute phase reaction’, ‘recruitment of immune cells’ and ‘inhibition of 1,25-(OH)2-vitamin D synthesis’. Key upstream regulators included peroxisome-proliferator-activated receptor alpha (PPARA), platelet-derived growth factor B dimer (PDGF-BB), and NF-kB p65 (RELA). DNA methylome profiling by reduced representation bisulfite sequencing studies revealed that the DEGs did not correlate with changes in promoter methylation. In sum, BN rat kidneys respond to pregnancy-specific signals with an increase in pro-inflammatory gene networks and alteration of metabolic pathways including vitamin D deficiency in association with mild proteinuria and blunted GFR increase. However, the lack of glomerular endotheliosis and mild hypertension/proteinuria in pregnant BN rats limits the relevance of this rat strain for preeclampsia research.