Fetal Response Research Articles

Physical activity throughout pregnancy is key to preventing chronic disease.

According to The Developmental Origins of Health and Disease theory, the intrauterine environment of the developing fetus may impact later life physiology, including susceptibility to chronic disease conditions. Maternal exposures during pregnancy can affect the intrauterine environment and result in fetal programming for chronic diseases through changes in the structure or function of specific organs. Negative maternal exposures, such as poor nutrition intake, have been shown to increase the risk for later life chronic diseases. On the contrary, healthful behaviors, such as physical activity, may have a positive and protective effect against chronic disease risk. This narrative review summarizes literature to discuss the potential preventative role prenatal physical activity may have on prevalent chronic diseases: obesity, type 2 diabetes, and cardiovascular disease. We describe the natural physiological response to pregnancy that may increase the risk for complications and consequently later life disease for both mother and baby. We then present evidence highlighting the role prenatal exercise may have in preventing pregnancy complications and downstream chronic disease development, as well as proposing potential mechanisms that may explain the protective maternal and fetal physiological response to exercise. As the prevalence of these non-communicable diseases increase globally, intervening during pregnancy with an effective exercise intervention may be the key to preventing chronic disease risk in more than one generation.

Current status of fertility preservation for women with collagen disease undergoing gonadotoxic therapy in Nagasaki University Hospital

Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1β). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome. However, the role of inflammasome activation and pyroptosis in HBC pathophysiology remains unclear. HBCs isolated from human term placentas were treated with or without LPS or ATP, alone or in combination. Treatment of HBCs with both LPS and ATP induced the rapid secretion of high levels of IL-1β and at the same time, cell death associated with nuclear condensation and cellular swelling. HBC treatment with both LPS and ATP induced caspase-1 activation, gasdermin D (GSDMD) cleavage, which mediates pyroptosis, and IL-1β processing. Caspase-1 activation, GSDMD cleavage, IL-1β processing, and IL-1β secretion were all significantly reduced following NLRP3 knockdown; inhibition of caspase-1; and inhibition of P2X7, the receptor that mediates K+ efflux. Together, our data indicate that LPS and ATP treatment stimulated NLRP3 inflammasome activation and pyroptosis in HBCs leading to the rapid release of IL-1β. Since the localization of HBCs confers a unique ability to influence microbial-associated placental and fetal inflammation, these studies suggest a key role for the inflammasome and pyroptosis in mediating HBC driven inflammation.

A Review on the Effects of Melatonin on Fetal Protection during Pregnancy with Intrauterine Inflammation

Intrauterine inflammation is defined as the inflammation of the chorion, amnion, and placenta. Untreated inflammation increases the risk of fetal inflammatory response syndrome, which may result in multiorgan diseases involving the brain, cardiovascular system, lung, eye, and intestine. Therefore, controlling inflammation is critical in pregnant women to reduce the risk of diseases. However, there are no safe and effective anti-inflammatory drugs for administration during pregnancy. Although the primary function of melatonin is to control circadian rhythms, it has protective effects against cellular insults occurring from hypoxia, oxidative stress, and inflammation. While animal studies support the effective and safe role of melatonin in improving pregnancy-related morbidities, it leaves plenty of opportunities for clinical studies investigating its anti-inflammatory, antioxidant, and protective effects against insults induced by intrauterine inflammation. Therefore, it will be worthwhile to investigate antenatal supplementation of melatonin in pregnant women with intrauterine inflammation to reduce the incidence of associated comorbidities.

Chronic Abruption Oligohydramnios Sequence

Abruption is a significant cause of both maternal morbidity and neonatal morbidity and mortality, particularly when it occurs preterm. Women with chronic abruption experience relatively light, chronic, intermittent bleeding. They are at risk of developing clinical manifestations of ischemic placental disease over time, such as oligohydramnios (termed chronic abruption-oligohydramnios sequence [CAOS]), fetal growth restriction, and preeclampsia. They are also at risk of preterm prelabor rupture of membranes. CAOS is manifested by chronic bleeding, placental insufficiency, and oligohydramnios. Oligohydramnios is presumably due to hypoxic fetal response and decreased urine output. At 22 weeks, 3 days gestation, the patient was seen in our maternal fetal medicine (MFM) clinic as a consultation from another hospital about an hour away. Her personal life had been very difficult: She was going through a divorce, had two other children whose father was not involved, had an unplanned pregnancy, her brother had just committed suicide, and her father was missing for more than 3 months. Not only was she at risk for having a severely premature newborn to care for, but she had many personal obstacles that our team had to consider to make a prolonged hospital stay work for her and her family. Our MFM clinic discussed the plan with the patient: hospitalization at 23 weeks with bedrest until the planned birth at 34 weeks. Our multidisciplinary team (MFM, neonatology, NICU nurses, labor nurses, a social worker, a psychiatrist, dietary, family patient experience specialist) developed a comprehensive, holistic care plan that enabled us to not only provide quality maternal and fetal care but also provide her family with care during her 10-week stay at our facility. Her baby was born at 33 weeks, 1 day gestation, just a little more than 10 weeks after arriving on our unit. A multidisciplinary team provided this patient with the best possible outcome. Our unit also did our best to provide this long-term patient with continuity of care by assigning a group of nurses who knew her well and could provide consistent and supportive care related to her specific needs.

Hypoxic modulation of fetal vascular MLCK abundance, localization, and function.

Changes in vascular contractility are among the most important physiological effects of acute and chronic fetal hypoxia. Given the essential role of myosin light-chain kinase (MLCK) in smooth muscle contractility and its heterogeneous distribution, this study explores the hypothesis that subcellular changes in MLCK distribution contribute to hypoxic modulation of fetal carotid artery contractility. Relative to common carotid arteries from normoxic term fetal lambs (FN), carotids from fetal lambs gestated at high altitude (3,802 m) (FH) exhibited depressed contractility without changes in MLCK mRNA or protein abundance. Patterns of confocal colocalization of MLCK with α-actin and 20-kDa regulatory myosin light chain (MLC20) enabled calculation of subcellular MLCK fractions: 1) colocalized with the contractile apparatus, 2) colocalized with α-actin distant from the contractile apparatus, and 3) not colocalized with α-actin. Chronic hypoxia did not affect MLCK abundance in the contractile fraction, despite a concurrent decrease in contractility. Organ culture for 72 h under 1% O2 decreased total MLCK abundance in FN and FH carotid arteries, but decreased the contractile MLCK abundance only in FH carotid arteries. Correspondingly, culture under 1% O2 depressed contractility more in FH than FN carotid arteries. In addition, hypoxia appeared to attenuate ubiquitin-independent proteasomal degradation of MLCK, as reported for other proteins. In aggregate, these results demonstrate that the combination of chronic hypoxia followed by hypoxic culture can induce MLCK translocation among at least three subcellular fractions with possible influences on contractility, indicating that changes in MLCK distribution are a significant component of fetal vascular responses to hypoxia.

Perinatal outcome after persistence of abnormal umbilical artery Doppler indices in the growth-restricted fetus following betamethasone administration

Background An optimal approach for providing sufficient antenatal surveillance for fetal growth restriction (FGR) has yet to be elucidated. Moreover, there is scant literature on the fetal response to betamethasone and its effect on fetal Dopplers. Objective To compare persistence of umbilical artery Doppler abnormalities after corticosteroid administration and adverse perinatal outcome in growth restricted fetuses. Methods Retrospective cohort study (2008–2018) of singleton gestations with FGR (EFW <10th percentile) and umbilical artery Doppler abnormalities (absent or reversed end diastolic velocity) between 24 and 34 weeks of gestation at two institutions. Included patients had Dopplers performed before betamethasone administration and again within 1 week. Excluded were multiple gestations, chromosomal abnormalities, fetal anomalies, or missing outcome information. Pregnancies with persistently abnormal Dopplers were compared with those in which an improvement of Dopplers was noted. The primary outcome was a composite that consisted of indicated preterm birth <32 weeks, 1 or 5 min APGAR score <7, intrauterine fetal demise, and neonatal demise. Secondary outcomes included length of NICU stay, ventilator support, gestational age at delivery, interval between steroids and delivery, and birth weight. Results Fifty-three FGR pregnancies met inclusion criteria. Umbilical artery Dopplers improved after steroids in 32% (n = 17). No difference in the frequency of the primary outcome was observed between the persistently abnormal Doppler and improved Doppler groups (72.2% vs. 70.6%, respectively), and there was no difference in any of the secondary outcomes. Conclusions Perinatal outcomes in FGR pregnancies were not affected by improved versus persistently abnormal umbilical artery Dopplers after betamethasone administration.

Placental epigenetic clocks: relations with in-utero exposures, ancestry, and fetal growth

Placental aging is a normal physiologic phenomenon during pregnancy. However, premature aging of the placenta can lead to decreased functional capacity of the placenta and obstetric complications including preeclampsia, pre-term birth, still birth and fetal growth restriction. Routine methods used in aging studies such as histopathological examination of the placenta and telomerase homeostasis markers may not detect aging alterations that are subtle and caused by senescence-independent DNA damage. The field of biological aging has recently been revolutionized by molecular methods that estimate the “biological clock” of a tissue with high accuracy using DNA methylation markers. This talk will introduce ongoing work based on the concept of epigenetic age acceleration in placenta, demonstrating its relationship with genetic ancestry, maternal cardiometabolic risk factors, and in-utero exposures. In addition, data will be presented illustrating the potential that epigenetic aging of the placenta may be one of the mechanisms underlying sexually-biased fetal growth responses to adverse exposures. Lastly, the talk will outline potential research directions for facilitating the utility of placental epigenetic clocks for gaining novel insights on placental origins of pregnancy outcomes and childhood diseases, and for the discovery of biomarkers as indicators of high-risk pregnancy.

Genome‐wide postnatal changes in immunity following fetal inflammatory response

The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, <28weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. DATABASES: EGAS00001003635 (EGA); PXD011626 (PRIDE).

Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation.

The fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na+/H+ exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular signal transduction and thus influence NF-kB activation. Accordingly, NHERF1 has been reported to enhance proinflammatory cytokine release and amplify inflammation in a NF-kB-dependent fashion in different cell types. The objective of this study was to examine the role of NHERF1 in regulating fetal membrane inflammation during PTB. We evaluated the levels of NHERF1 in human fetal membranes from term labor (TL), term not in labor (TNIL), and PTB and in a CD1 mouse model of PTB induced by lipopolysaccharide (LPS). Additionally, primary cultures of fetal membrane cells were treated with LPS, and NHERF1 expression and cytokine production were evaluated. Gene silencing methods using small interfering RNA targeting NHERF1 were used to determine the functional relevance of NHERF1 in primary cultures. NHERF1 expression was significantly (p < 0.001) higher in TL and PTB membranes compared to TNIL membranes, and this coincided with enhanced (p < 0.01) interleukin (IL)-6 and IL-8 expression levels. LPS-treated animals delivering PTB had increased levels of NHERF1, IL-6, and IL-8 compared to phosphate-buffered saline (PBS; control) animals. Silencing of NHERF1 expression resulted in a significant reduction in NF-kB activation and IL-6 and IL-8 production as well as increased IL-10 production. In conclusion, downregulation of NHERF1 increased anti-inflammatory IL-10, and reducing NHERF1 expression could be a potential therapeutic strategy to reduce the risk of infection/inflammation associated with PTB.

The placenta as the window to congenital heart disease.

There is an increasing recognition that structural abnormalities and functional changes in the placenta can have deleterious effects on the development of the fetal heart. This article reviews the role of the placenta and the potential impact of placental insufficiency on fetuses with congenital heart disease. The fetal heart and the placenta are directly linked because they develop concurrently with shared regulatory and signaling pathways. Placental disease is more common in pregnancies carrying a fetus with congenital heart disease and the fetal response to placental insufficiency may lead to the postnatal persistence of cardiac remodeling. The mechanisms underlying this placental-fetal axis of interaction potentially include genetic factors, oxidative stress, chronic hypoxia, and/or angiogenic imbalance. The maternal-placental-fetal circulation is critical to advancing our understanding of congenital heart disease. We must first expand our ability to detect, image, and quantify placental insufficiency and dysfunction in utero. Elucidating the modifiable factors involved in these pathways is an exciting opportunity for future research, which may enable us to improve outcomes in patients with congenital heart disease.

Multi-region saliency-aware learning for cross-domain placenta image segmentation.

We propose a multi-region saliency-aware learning (MSL) method for cross-domain placenta image segmentation. Unlike most existing image-level transfer learning methods that fail to preserve the semantics of paired regions, our MSL incorporates the attention mechanism and a saliency constraint into the adversarial translation process, which can realize multi-region mappings in the semantic level. Specifically, the built-in attention module serves to detect the most discriminative semantic regions that the generator should focus on. Then we use the attention consistency as another guidance for retaining semantics after translation. Furthermore, we exploit the specially designed saliency-consistent constraint to enforce the semantic consistency by requiring the saliency regions unchanged. We conduct experiments using two real-world placenta datasets we have collected. We examine the efficacy of this approach in (1) segmentation and (2) prediction of the placental diagnoses of fetal and maternal inflammatory response (FIR, MIR). Experimental results show the superiority of the proposed approach over the state of the art.

Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45- TER119-Erythroid and Lymphoid Progenitors.

Summaryp32/C1qbp regulates mitochondrial protein synthesis and is essential for oxidative phosphorylation in mitochondria. Although dysfunction of p32/C1qbp impairs fetal development and immune responses, its role in hematopoietic differentiation remains unclear. Here, we found that mitochondrial dysfunction affected terminal differentiation of newly identified erythroid/B-lymphoid progenitors among CD45– Ter119– CD31– triple-negative cells (TNCs) in bone marrow. Hematopoietic cell-specific genetic deletion of p32/C1qbp (p32cKO) in mice caused anemia and B-lymphopenia without reduction of hematopoietic stem/progenitor cells. In addition, p32cKO mice were susceptible to hematopoietic stress with delayed recovery from anemia. p32/C1qbp-deficient CD51– TNCs exhibited impaired mitochondrial oxidation that consequently led to inactivation of mTORC1 signaling, which is essential for erythropoiesis. These findings uncover the importance of mitochondria, especially at the stage of TNCs during erythropoiesis, suggesting that dysregulation of mitochondrial protein synthesis is a cause of anemia and B-lymphopenia with an unknown pathology.

NLRP3 inflammasome function and pyroptotic cell death in human placental Hofbauer cells

Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1β). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome. However, the role of inflammasome activation and pyroptosis in HBC pathophysiology remains unclear. HBCs isolated from human term placentas were treated with or without LPS or ATP, alone or in combination. Treatment of HBCs with both LPS and ATP induced the rapid secretion of high levels of IL-1β and at the same time, cell death associated with nuclear condensation and cellular swelling. HBC treatment with both LPS and ATP induced caspase-1 activation, gasdermin D (GSDMD) cleavage, which mediates pyroptosis, and IL-1β processing. Caspase-1 activation, GSDMD cleavage, IL-1β processing, and IL-1β secretion were all significantly reduced following NLRP3 knockdown; inhibition of caspase-1; and inhibition of P2X7, the receptor that mediates K+ efflux. Together, our data indicate that LPS and ATP treatment stimulated NLRP3 inflammasome activation and pyroptosis in HBCs leading to the rapid release of IL-1β. Since the localization of HBCs confers a unique ability to influence microbial-associated placental and fetal inflammation, these studies suggest a key role for the inflammasome and pyroptosis in mediating HBC driven inflammation.

The metabolic and immunological characteristics of pregnant women with COVID-19 and their neonates.

Our aim was to investigate whether SARS-CoV-2 infection raised high risks of late pregnancy complications, and posed health problems in fetuses and neonates. We analyzed the data of COVID-19 pregnant women with COVID-19 during late pregnancy and their neonates. Eleven out of 16 (69%) pregnant women with COVID-19 had ++ or +++ of ketone body in urine. The blood uric acid of pregnant patients was 334 μmol/L (IQR, 269–452). D-dimer and FDP in pregnant patients were 3.32 mg/L (IQR, 2.18–4.21) and 9.6 mg/L (IQR, 5.9–12.4). Results of blood samples collected at birth showed that 16 neonates had leukocytes (15.7 × 109/L (IQR, 13.7–17.2)), neutrophils (11.1 × 109/L (IQR, 9.2–13.2)), CK (401 U/L (IQR, 382–647)), and LDH (445 U/L (IQR, 417–559)). Twenty-four hours after birth, a neonate from COVID-19 woman had fever and positive of SARS-CoV-2 gene. Another woman had strongly positive for SARS-CoV-2 gene (+++) for 4 weeks, and delivered one neonate who had SARS-CoV-2 IgM (46 AU/mL) and IgG (140 AU/mL) on day 1 after birth. In the third trimester, COVID-19 infection in pregnant patients raised high risks of ketonuria, hypercoagulable state, and hyperfibrinolysis, which may lead to severe complications. COVID-19 increased the inflammatory responses of placenta, and fetuses and neonates had potential organ dysregulation and coagulation disorders. There was a potential intrauterine transmission while pregnant women had high titer of SARS-CoV-2, but it is necessary to detect SARS-CoV-2 in the blood cord, placenta, and amniotic fluid to further confirm intrauterine infection of fetuses.

VP51.02: Application value of fetal lung maturity ultrasound evaluation in predicting neonatal dyspnea

In the 2016 guidelines, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM) pointed out that the changes in amniotic fluid surfactants are slight, the sensitivity of fetal lung maturity detected by amniotic fluid is low and the role is limited. Therefore, a reliable non-invasive fetal lung maturity assessment technology is urgently needed to help obstetricians assess fetal lung maturity (FLM) and choose the right time to apply glucocorticoids to improve neonatal outcomes. In this study, an automatic quantitative ultrasound analysis of fetal lung texture (quantusFLM) was used to predict neonatal dyspnea. A total of 70 woman at 29.2–38.5 weeks of gestation were enrolled. They were classified as three groups: 24 cases at 24–33+6 weeks, 16 at 34–36+6 weeks and 30 at 37–39 weeks. The quantitative ultrasound fetal lung maturity analysis (quantusFLMTM) was performed. There were significant differences in the lung maturity results among groups (p <0.05). These differences were established between the 24–33+6 weeks group and both the 34–36+6 weeks (p = 0.006) and 37–39 weeks (p = 0.006) groups. There were no statistically significant differences between 34–36+6 weeks and 37–39 weeks group test results. Early-term preterm infants are more at risk of dyspnea than late-term preterm infants and early-term newborns. QuantusFLM evaluates fetal lung maturity predicted neonatal dyspnea with a sensitivity, specificity and accurace value of 83.1%, 81.8% and 82.9%. In low-risk results of the test, the infant at 24–33+6 weeks group should be alert to the existence of fetal inflammatory response syndrome. Because fetal inflammatory response syndrome promotes fetal lung maturity and fetal lung maturity is relatively high. quantusFLM is a new fetal lung maturity predict neonatal dyspnea. It has the advantages of non-invasive, feasibility, repeatability and good accuracy. It is expected to help clinicians perform fetal lung maturity.

Antenatal thymus volumes in fetuses that delivered

Infection and inflammation have been implicated in the etiology and subsequent morbidity associated with preterm birth. At present, there are no tests to assess for fetal compartment infection. The thymus, a gland integral in the fetal immune system, has been shown to involute in animal models of antenatal infection, but its response in human fetuses has not been studied. This study aims: (a) to generate magnetic resonance imaging (MRI) -derived fetal thymus volumes standardized for fetal weight; (b) to compare standardized thymus volumes from fetuses that delivered before 32weeks of gestation with fetuses that subsequently deliver at term; (c) to assess thymus size as a predictor of preterm birth; and (d) to correlate the presence of chorioamnionitis and funisitis at delivery with thymic volumes in utero in fetuses that subsequently deliver preterm. Women at high-risk of preterm birth at 20-32weeks of gestation were recruited. A control group was obtained from existing data sets acquired as part of three research studies. A fetal MRI was performed on a 1.5T or 3T MRI scanner: T2 weighted images were obtained of the entire uterine content and specifically the fetal thorax. A slice-to-volume registration method was used for reconstruction of three-dimensional images of the thorax. Thymus segmentations were performed manually. Body volumes were calculated by manual segmentation and thymus:body volume ratios were generated. Comparison of groups was performed using multiple regression analysis. Normal ranges were created for thymus volume and thymus:body volume ratios using the control data. Receiver operating curves (ROC) curves were generated for thymus:body volume ratio and gestation-adjusted thymus volume centiles as predictors of preterm birth. Placental histology was analyzed where available from pregnancies that delivered very preterm and the presence of chorioamnionitis/funisitis was noted. Normative ranges were created for thymus volume, and thymus volume was standardized for fetal size from fetuses that subsequently delivered at term, but were imaged at 20-32weeks of gestation. Image data sets from 16 women that delivered <32weeks of gestation (ten with ruptured membranes and six with intact membranes) and 80 control women that delivered >37weeks were included. Mean gestation at MRI of the study group was 28+4 weeks (SD 3.2) and for the control group was 25+5 weeks (SD 2.4). Both absolute fetal thymus volumes and thymus:body volume ratios were smaller in fetuses that delivered preterm (P<.001). Of the 16 fetuses that delivered preterm, 13 had placental histology, 11 had chorioamnionitis, and 9 had funisitis. The strongest predictors of prematurity were the thymus volume Z-score and thymus:body volume ratio Z-score (ROC areas 0.915 and 0.870, respectively). We have produced MRI-derived normal ranges for fetal thymus and thymus:body volume ratios between 20 and 32weeks of gestation. Fetuses that deliver very preterm had reduced thymus volumes when standardized for fetal size. A reduced thymus volume was also a predictor of spontaneous preterm delivery. Thymus volume may be a suitable marker of the fetal inflammatory response, although further work is needed to assess this, increasing the sample size to correlate the extent of chorioamnionitis with thymus size.

Fetal Hemodynamic Response to Maternal Oxygenation in Normal and Complicated Pregnancies.

Maternal oxygenation (MO) is widely applied in obstetrics. Scholars have conducted numerous studies on maternal hyperoxygenation and have reported many theoretical and applied achievements and a number of different points of view. The main purpose of this article is to discuss the effect of maternal oxygenation on fetal circulation during normal and complicated pregnancies and to ascertain its potential side effects and research gaps in this field. In complicated pregnancies, the fetus may benefit from oxygen therapy. However, large randomized controlled trials and longitudinal studies are necessary to support the widespread application of maternal oxygenation in this context.

Autoimmune Hepatitis: Tolerogenic Immunological State During Pregnancy and Immune Escape in Post-partum

The maternal immune system engages in a fine balancing act during pregnancy by simultaneously maintaining immune tolerance to the fetus and immune responses to protect against invading organisms. Pregnancy is an intricately orchestrated process where effector immune cells with fetal specificity are selectively silenced. This requires a sustained immune suppressive state not only by expansion of maternal Foxp3+ regulatory T cells (Tregs) but also by leaning the immune clock toward a Th2 dominant arm. The fetus, known as a semi-allograft or temporary-self, leads to remission of autoimmune hepatitis during pregnancy. However, this tolerogenic immune state reverts back to a Th1 dominant arm, resulting in post-partum flare of AIH. Various hormones play a significant role in endocrine-immune axis during pregnancy. The placenta functions as a barrier between the maternal immune system and the fetus also plays a pivotal role in creating a tolerogenic environment during pregnancy. We review the evidence of immune tolerance during pregnancy and immune escape at post-partum period, focusing on patients with autoimmune hepatitis.

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort

Most persons with fetal alcohol spectrum disorders (FASDs) remain undiagnosed or are diagnosed in later life. To address the need for earlier diagnosis, we previously assessed miRNAs in the blood plasma of pregnant women who were classified as unexposed to alcohol (UE), heavily exposed with affected infants (HEa), or heavily exposed with apparently unaffected infants (HEua). We reported that maternal miRNAs predicted FASD-related growth and psychomotor deficits in infants. Here, we assessed whether fetal sex influenced alterations in maternal circulating miRNAs following prenatal alcohol exposure (PAE). To overcome the loss of statistical power due to disaggregating maternal samples by fetal sex, we adapted a strategy of iterative bootstrap resampling with replacement to assess the stability of statistical parameter estimates. Bootstrap estimates of parametric and effect size tests identified male and female fetal sex-associated maternal miRNA responses to PAE that were not observed in the aggregated sample. Additionally, we observed, in HEa mothers of female, but not male fetuses, a network of co-secreted miRNAs whose expression was linked to miRNAs encoded on the X-chromosome. Interestingly, the number of significant miRNA correlations for the HEua group mothers with female fetuses was intermediate between HEa and UE mothers at mid-pregnancy, but more similar to UE mothers by the end of pregnancy. Collectively, these data show that fetal sex predicts maternal circulating miRNA adaptations, a critical consideration when adopting maternal miRNAs as diagnostic biomarkers. Moreover, a maternal co-secretion network, predominantly in pregnancies with female fetuses, emerged as an index of risk for adverse birth outcomes due to PAE.

Foetal haemodynamic response to anaemia.

This study aims to update new knowledge regarding foetal cardiovascular response to anaemia, using foetal haemoglobin Bart's disease as a study model. Original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The main foetal cardiovascular changes in response to anaemia are consequences of hypervolaemia and increased cardiac output to meet tissue oxygen requirement. New challenging insights are as follows: (i) the earliest morphological change is an increase in cardiac size and remodelling of the sphericity (an increase in diameter more pronounced than that in long axis) followed by several markers, such as placentomegaly and hepatosplenomegaly. (ii) The earliest functional change is increased peak systolic velocity of the red blood cells because of low viscosity, especially in the middle cerebral artery. (iii) The foetal heart has very high reserve potentials to cope with anaemia: increasing workload without increased central venous pressure and increased myocardial performance without compromising shortening fraction. This hard‐working period with good performance lasts long, including most part of the second and third trimester. (iv) At the time cardiomegaly myocardial cellular damage has already occurred, in spite of good cardiac function. (v) Anaemic hydrops foetalis is mainly due to hypervolaemia, hypoalbuminaemia, and high vascular permeability, not heart failure. (vi) Foetal heart failure occurs only when the adaptive mechanism becomes exhausted or long after the development of anaemic hydrops foetalis. Heart failure is a very late result of a longstanding overworked heart. (vii) Ultrasound is highly effective in the detection of foetal response to anaemia. An increase in cardiac size and middle cerebral artery is very helpful in predicting the affected foetuses in pre‐hydropic phase. (viii) Theoretically, intrauterine treatment of anaemic hydrops results in satisfactory outcomes as long as cardiac function is normal, but intrauterine intervention should be strongly considered in pre‐hydropic phase because myocardial cell damage could have already occurred in this phase or early hydropic phase. Anaemic hydrops foetalis is not primarily caused by heart failure as commonly advocated, but it is rather a consequence of hypervolaemia, hypoalbuminaemia, and high vascular permeability while heart failure is a very late consequence of a longstanding overworked heart. New insights gained from this review may be useful to base clinical practice on which sonographic markers imply significant pathological changes, how ultrasound can be helpful in early detection of anaemic response, when intrauterine transfusion for anaemia due to non‐lethal causes should be administered, etc.