Paternal microbiome perturbations impact offspring fitness.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Maternal COVID-19 causing intrauterine foetal demise with microthrombotic placental insufficiency: a case report.

BACKGROUND: Pregnant women have an increased risk of getting infected with SARS-CoV-2 and are more prone to severe illness. Data on foetal demise in affected pregnancies and its underlying aetiology is scarce and pathomechanisms remain largely unclear. CASE: Herein we present the case of a pregnant woman with COVID-19 and intrauterine foetal demise. She had no previous obstetric or gynaecological history, and presented with mild symptoms at 34 + 3 weeks and no signs of foetal distress. At 35 + 6 weeks intrauterine foetal death was diagnosed. In the placental histopathology evaluation, we found inter- and perivillous fibrin depositions including viral particles in areas of degraded placental anatomy without presence of viral entry receptors and SARS-CoV-2 infection of the placenta. CONCLUSION: This case demonstrates that maternal SARS-CoV-2 infection in the third trimester may lead to an unfavourable outcome for the foetus due to placental fibrin deposition in maternal COVID-19 disease possibly via a thrombogenic microenvironment, even when the foetus itself is not infected.

Effects of Pparγ1 deletion on late-stage murine embryogenesis and cells that undergo endocycle.

Peroxisome proliferator-activated receptor (PPAR) γ1, a nuclear receptor, is abundant in the murine placenta during the late stage of pregnancy (E15-E16), although its functional roles remain unclear. PPARγ1 is encoded by two splicing isoforms, namely Pparγ1canonical and Pparγ1sv, and its embryonic loss leads to early (E10) embryonic lethality. Thus, we generated knockout (KO) mice that carried only one of the isoforms to obtain a milder phenotype. Pparγ1sv-KO mice were viable and fertile, whereas Pparγ1canonical-KO mice failed to recover around the weaning age. Pparγ1canonical-KO embryos developed normally up to 15.5 dpc, followed by growth delays after that. The junctional zone of Pparγ1canonical-KO placentas severely infiltrated the labyrinth, and maternal blood sinuses were dilated. In the wild-type, PPARγ1 was highly expressed in sinusoidal trophoblast giant cells (S-TGCs), peaking at 15.5 dpc. Pparγ1canonical-KO abolished PPARγ1 expression in S-TGCs. Notably, the S-TGCs had unusually enlarged nuclei and often occupied maternal vascular spaces, disturbing the organization of the fine labyrinth structure. Gene expression analyses of Pparγ1canonical-KO placentas indicated enhanced S-phase cell cycle signatures. EdU-positive S-TGCs in Pparγ1canonical-KO placentas were greater in number than those in wild-type placentas, suggesting that the cells continued to endoreplicate in the mutant placentas. These results indicate that PPARγ1, a known cell cycle arrest mediator, is involved in the transition of TGCs undergoing endocycling to the terminal differentiation stage in the placentas. Therefore, PPARγ1 deficiency, induced through genetic manipulation, leads to placental insufficiency.

Residential proximity to roadways and placental-associated stillbirth: a case-control study.

We conducted a retrospective case-control study of 1,097 women in Massachusetts and Rhode Island, USA, to examine the association between stillbirth related to placental abruption or placental insufficiency and maternal exposure to traffic-related air pollution. We utilized distance to nearest roadway proximity metrics as a proxy for traffic-related air pollution exposure. No meaningful increase in the overall odds of placental-associated stillbirths was observed (adjusted OR: 1.1, 95% CI: 0.5-2.8). However, mothers living within 50 m of a roadway had a 60% increased odds of experiencing a stillbirth related to placental abruption compared to mothers living greater than 200 m away. This suggestive finding was imprecise due to the small case number in the highest exposure category (95% CI: 0.6-4.0). Future studies of placental abruption with more precise exposure assessments are warranted.

Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

The hypoxia of high-altitude (HA) residence increases the risk of intrauterine growth restriction (IUGR) and preeclampsia 3-fold, augmenting perinatal morbidity and mortality and the risk for childhood and adult disease. Currently, no effective therapies exist to prevent these vascular disorders of pregnancy. The peroxisome proliferator-activated receptor γ (PPAR-γ) is an important regulator of uteroplacental vascular development and function and has been implicated in the pathogenesis of IUGR and preeclampsia. Here, we used a model of HA pregnancy in mice to determine whether hypoxia-induced fetal growth restriction reduces placental PPAR-γ protein expression and placental vascularization and, if so, to evaluate the effectiveness of the selective PPAR-γ agonist pioglitazone (PIO) for preventing hypoxia-induced IUGR. Hypoxia resulted in asymmetric IUGR, placental insufficiency, and reduced placental PPAR-γ expression; PIO prevented approximately half of the fetal growth restriction and attenuated placental insufficiency. PIO did not affect fetal growth under normoxia. Although PIO was beneficial for fetal growth, PIO treatment reduced placental vascular density of the labrynthine zone in normoxic and hypoxic (Hx) conditions, and mean vascular area was reduced in the Hx group. Our results suggest that pharmacological PPAR-γ activation is a potential strategy for preventing IUGR in pregnancies complicated by hypoxia, although further studies are needed to identify its likely metabolic or vascular mechanisms.-Lane, S. L., Dodson, R. B., Doyle, A. S., Park, H., Rathi, H., Matarrazo, C. J., Moore, L. G., Lorca, R. A., Wolfson, G. H., Julian, C. G. Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

BACKGROUND: Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated. METHOD: The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020. DISCUSSION: During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR. TRIAL REGISTRATION: DRKS00011374 registered at September 29th, 2017 and NCT03669185 , registered September 13th, 2018.

Skeletal muscle protein accretion rates and hindlimb growth are reduced in late gestation intrauterine growth-restricted fetal sheep.

KEY POINTS: Adults who were affected by intrauterine growth restriction (IUGR) suffer from reductions in muscle mass, which may contribute to insulin resistance and the development of diabetes. We demonstrate slower hindlimb linear growth and muscle protein synthesis rates that match the reduced hindlimb blood flow and oxygen consumption rates in IUGR fetal sheep. These adaptations resulted in hindlimb blood flow rates in IUGR that were similar to control fetuses on a weight-specific basis. Net hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was significantly lower in IUGR fetal sheep. Among all fetuses, blood O2 saturation and plasma glucose, insulin and insulin-like growth factor-1 were positively associated and norepinephrine was negatively associated with hindlimb weight. These results further our understanding of the metabolic and hormonal adaptations to reduced oxygen and nutrient supply with placental insufficiency that develop to slow hindlimb growth and muscle protein accretion. ABSTRACT: Reduced skeletal muscle mass in the fetus with intrauterine growth restriction (IUGR) persists into adulthood and may contribute to increased metabolic disease risk. To determine how placental insufficiency with reduced oxygen and nutrient supply to the fetus affects hindlimb blood flow, substrate uptake and protein accretion rates in skeletal muscle, late gestation control (CON) (n = 8) and IUGR (n = 13) fetal sheep were catheterized with aortic and femoral catheters and a flow transducer around the external iliac artery. Muscle protein kinetic rates were measured using isotopic tracers. Hindlimb weight, linear growth rate, muscle protein accretion rate and fractional synthetic rate were lower in IUGR compared to CON (P < 0.05). Absolute hindlimb blood flow was reduced in IUGR (IUGR: 32.9 ± 5.6 ml min-1 ; CON: 60.9 ± 6.5 ml min-1 ; P < 0.005), although flow normalized to hindlimb weight was similar between groups. Hindlimb oxygen consumption rate was lower in IUGR (IUGR: 10.4 ± 1.4 µmol min-1  100 g-1 ; CON: 14.7 ± 1.3 µmol min-1  100 g-1 ; P < 0.05). Hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was lower in IUGR (IUGR: 1.3 ± 0.5 µmol min-1  100 g-1 ; CON: 2.9 ± 0.2 µmol min-1  100 g-1 ; P < 0.05). Blood O2 saturation (r2  = 0.80, P < 0.0001) and plasma glucose (r2  = 0.68, P < 0.0001), insulin (r2  = 0.40, P < 0.005) and insulin-like growth factor (IGF)-1 (r2  = 0.80, P < 0.0001) were positively associated and norepinephrine (r2  = 0.59, P < 0.0001) was negatively associated with hindlimb weight. Slower hindlimb linear growth and muscle protein synthesis rates match reduced hindlimb blood flow and oxygen consumption rates in the IUGR fetus. Metabolic adaptations to slow hindlimb growth are probably hormonally-mediated by mechanisms that include increased fetal norepinephrine and reduced IGF-1 and insulin.

Placental Weight and Risk of Cryptorchidism and Hypospadias in the Collaborative Perinatal Project.

Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.

Intra- versus retroplacental hematomas: a retrospective case-control study on pregnancy outcomes.

BACKGROUND: Intrauterine hematomas are a common pregnancy complication. The literature lacks studies about outcomes based on hematoma localization. Thus, we aimed to compare pregnancies complicated by an intraplacental hematoma to cases with a retroplacental hematoma and to a control group. METHODS: In a retrospective case-control study, 32 women with an intraplacental hematoma, 199 women with a retroplacental hematoma, and a control group consisting of 113 age-matched women with no signs of placental abnormalities were included. Main outcome measures were pregnancy complications. RESULTS: Second-trimester miscarriage was most common in the intraplacental hematoma group (9.4%), followed by women with a retroplacental hematoma (4.2%), and controls (0%; p = 0.007). The intraplacental hematoma group revealed the highest rates for placental insufficiency, intrauterine growth retardation, premature preterm rupture of membranes, preterm labor, preterm delivery <37 weeks, and early preterm delivery <34 weeks (p < 0.05), followed by the retroplacental hematoma group. When tested in multivariate models, intraplacental hematomas were independent predictors for placental insufficiency (ß = 4.19, p < 0.001) and intrauterine growth restriction (ß = 1.44, p = 0.035). Intrauterine fetal deaths occurred only in women with a retroplacental hematoma (p = 0.042). CONCLUSIONS: Intra- and retroplacental hematomas have different risk profiles for the affected pregnancy and act as independent risk factors.

Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model.

Chronic placental hypoxia is one of the root causes of placental insufficiencies that result in pre-eclampsia and maternal hypertension. Chronic hypoxia causes disruption of trophoblast (TB) development, invasion into maternal decidua, and remodeling of maternal spiral arteries. The pregnant guinea pig shares several characteristics with humans such as hemomonochorial placenta, villous subplacenta, deep TB invasion, and remodeling of maternal arteries, and is an ideal animal model to study placental development. We hypothesized that chronic placental hypoxia of the pregnant guinea pig inhibits TB invasion and alters spiral artery remodeling. Time-mated pregnant guinea pigs were exposed to either normoxia (NMX) or three levels of hypoxia (HPX: 16%, 12%, or 10.5% O2) from 20 day gestation until midterm (39-40 days) or term (60-65 days). At term, HPX (10.5% O2) increased maternal arterial blood pressure (HPX 57.9 ± 2.3 vs. NMX 40.4 ± 2.3, P < 0.001), decreased fetal weight by 16.1% (P < 0.05), and increased both absolute and relative placenta weights by 10.1% and 31.8%, respectively (P < 0.05). At midterm, there was a significant increase in TB proliferation in HPX placentas as confirmed by increased PCNA and KRT7 staining and elevated ESX1 (TB marker) gene expression (P < 0.05). Additionally, quantitative image analysis revealed decreased invasion of maternal blood vessels by TB cells. In summary, this animal model of placental HPX identifies several aspects of abnormal placental development, including increased TB proliferation and decreased migration and invasion of TBs into the spiral arteries, the consequences of which are associated with maternal hypertension and fetal growth restriction.

Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results.

OBJECTIVE: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? DESIGN: Secondary outcomes of the FRUIT-RCT. SETTING: Multicentre, international. POPULATION: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. METHODS: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test. MAIN OUTCOME MEASURES: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. RESULTS: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. CONCLUSION: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. TWEETABLE ABSTRACT: LMWH does not influence fetal growth or uterine or umbilical flow velocities.

Fathers that are born small program alterations in the next-generation preimplantation rat embryos.

BACKGROUND: Low birth weight is associated with increased risk of adult cardiovascular and metabolic disease development, with recent studies highlighting transmission to subsequent generations via both maternal and paternal lines. However, the timing of parent-specific programming of disease risk to the next generation remains to be characterized. OBJECTIVE: The aim of this study was to examine how paternal low birth weight affects the cellular and molecular physiology of the next-generation [second-generation (F2)] blastocysts, before uterine implantation. METHODS: Uteroplacental insufficiency was surgically induced in Wistar Kyoto pregnant rats in late gestation, giving rise to first-generation restricted (born small) and sham-operated control (normal birth weight) male offspring, respectively. First-generation restricted and control male rats were naturally mated with normal females. RESULTS: Resultant F2 blastocysts derived from restricted males displayed reduced expression of growth regulatory genes of the mammalian target of rapamycin pathway compared with F2 control blastocysts (9-74%; P < 0.05). No differences were found in F2 restricted blastocyst structural characteristics, cell number, or carbohydrate utilization at the time of blastocyst retrieval or after 24 h of in vitro culture. However, histidine, methionine, pyruvate, serine, and tryosine consumption and aspartate and leucine production were greater in F2 restricted outgrowth than in controls (P < 0.05). CONCLUSIONS: The findings from this study clearly indicate that male rat offspring born small, arising from uteroplacental insufficiency, have physiologic alterations that manifest as modifications in gene expression levels and nutrient metabolism of F2 blastocysts, even in the absence of overt cellular growth differences. These data demonstrate that growth restriction and associated disease risk have the capacity to be transmitted to the next generation of offspring via the male germ line and is manifest as early as the blastocyst stage of development.

A Method for Detection of Cholesterol Synthesis in the Placenta during Exacerbation of Cytomegalovirus Infection.

Histochemical analysis showed that exacerbation of cytomegalovirus infection even at early terms of gestation (weeks 5-6) suppresses synthesis of mevalonic acid, squalene, and 7α-dehydrocholesterol dehydrogenase in the placenta. Inhibition of cholesterol biosynthesis in the placenta at the early stages of gestation decreases production of sex hormones, reduces cholesterol concentration in the maternal peripheral blood, and impairs cholesterol supply to the fetus, which is associated with the risk of placental insufficiency.

Famines in the last 100 years: implications for diabetes.

Overnutrition is a major cause of diabetes. The contrary situation of undernutrition has also been suggested to increase the risk of the disease. Especially undernutrition during prenatal life has been hypothesized to program the structure and physiology of the fetus in such a way that it is more prone to develop diabetes in later life. Famines over the last 100 years have provided historical opportunities to study later-life health consequences of poor nutritional circumstances in early life. The majority of studies based on famine exposure during prenatal life clearly show that diabetes risk is increased. Postnatal famine exposure in childhood, adolescence, or young adulthood also seems to raise risk for diabetes, although prenatal famine effects seem to be more substantial. These study results not only have implications for the consequences of famines still happening but also for pregnancies complicated by factors mimicking poor nutritional situations.

Blood-brain barrier breakdown in reduced uterine perfusion pressure: a possible model of posterior reversible encephalopathy syndrome.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by headaches, altered mental status, seizures, and visual disturbances and is associated with white matter vasogenic edema. There are no experimental models to study PRES brain changes. METHODS: Twenty-eight pregnant Wistar rats were divided into 4 groups of 7: (1) pregnant-control; (2) reduced uterine perfusion pressure (RUPP); (3) invasive blood pressure (IBP); and (4) reduced uterine perfusion pressure plus invasive blood pressure (RUPP-IBP). The RUPP and RUPP-IBP groups were submitted to a reduction of uterine perfusion pressure at pregnancy days 13 to 15. The invasive mean arterial pressure of the IBP and RUPP-IBP groups was measured on day 20. The blood-brain barriers (BBBs) of all groups were analyzed using 2% Evans Blue dye on day 21. RESULTS: RUPP rats had higher blood pressures and increased BBB permeability to Evans Blue dye compared with the control animals. Brain staining occurred in 11 of 14 RUPP rats and in none of the control groups (P < .0001). CONCLUSIONS: The physiopathology of PRES remains unclear. Here, we described the use of RUPP rats as a potential model to better comprehend this syndrome.

[Congenital heart diseases in pregnant women--a risk factor for fetal distress].

The condition of fetoplacental system in pregnant women with congenital heart diseases was studied by means of ultrasound, dopplerometry, cardiotocography, by determination of estradiol, progesterone and placental lactogen in the blood of pregnant women and in the umbilical cord and by means of pathomorphologic study of the placenta. It is shown that congenital heart diseases complicated by heart failure in pregnant women--a important risk factor for fetal distress bouth in the preclinical stage of placental insufficiency (violation of the utero-placental blood flow, changes of fetoplacental hormones levels) and in conjunction with clinical signs of fetal suffering (distress and growth retardation).

Intrauterine fetal demise can be remote from the inciting insult in an animal model of hypoxia-ischemia.

BACKGROUND: Fetal hypoxia-ischemia (H-I) results in significant morbidity and mortality. Little is known about the timing of death in human stillbirths. The vulnerability of the fetus varies with age at the time of insult, but it is unknown what happens to the timing of fetal death in relation to a fetal insult. We asked the question of whether the timing of fetal death was influenced by the age at which the insult occurred. METHODS: Fetal H-I was achieved at three ages by sustained uterine ischemia in rabbits, mimicking the acute placental insufficiency of placental abruption. RESULTS: H-I at 22 d gestation (E22) resulted in fewer perinatal deaths than at E25 and E29. Fetal deaths were grouped into early and late perinatal deaths. Early perinatal death mostly occurred immediately after H-I and these fetuses delivered before term. Late perinatal death occurred between the insult and delivery at term gestation. Early perinatal death occurred more often in the E25 hypoxic-ischemic group as compared with those of the E22 hypoxic-ischemic group. CONCLUSION: There is an increasing vulnerability to hypoxia with increasing gestational age. Perinatal deaths may occur long after the episode of H-I. The timing of an intrauterine hypoxic-ischemic event cannot be inferred from the detection of fetal death.

Quantifying Fetal Reprogramming for Biomarker Development in the Era of High-Throughput Sequencing.

Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.

Case of placental insufficiency and premature delivery in a Fontan pregnancy: physiological insights and considerations on risk stratification.

OBJECTIVES: The coexistence of two complex physiologies such as Fontan and pregnancy is still not fully understood. We aim to add a unique and essential knowledge to help our colleagues in the management of Fontan patients that undergo pregnancy as well as the fetus and the placenta perfusion. METHODS AND RESULTS: We analyse the coexistence of Fontan and pregnancy physiology on a complex case of a woman with hypoplastic left heart syndrome palliated with a univentricular repair who became pregnant, delivered very prematurely and had atypical placental findings. CONCLUSION: Histopathological analysis of the placenta could help us to refine the understanding of Fontan physiology adaptation during pregnancy, predict women and fetal outcomes as well as to plan a better pre-pregnancy status. However, further evidence is needed in order to reach a more solid and unified conclusion.

Dimming the Powerhouse: Mitochondrial Dysfunction in the Liver and Skeletal Muscle of Intrauterine Growth Restricted Fetuses.

Intrauterine growth restriction (IUGR) of the fetus, resulting from placental insufficiency (PI), is characterized by low fetal oxygen and nutrient concentrations that stunt growth rates of metabolic organs. Numerous animal models of IUGR recapitulate pathophysiological conditions found in human fetuses with IUGR. These models provide insight into metabolic dysfunction in skeletal muscle and liver. For example, cellular energy production and metabolic rate are decreased in the skeletal muscle and liver of IUGR fetuses. These metabolic adaptations demonstrate that fundamental processes in mitochondria, such as substrate utilization and oxidative phosphorylation, are tempered in response to low oxygen and nutrient availability. As a central metabolic organelle, mitochondria coordinate cellular metabolism by coupling oxygen consumption to substrate utilization in concert with tissue energy demand and accretion. In IUGR fetuses, reducing mitochondrial metabolic capacity in response to nutrient restriction is advantageous to ensure fetal survival. If permanent, however, these adaptations may predispose IUGR fetuses toward metabolic diseases throughout life. Furthermore, these mitochondrial defects may underscore developmental programming that results in the sequela of metabolic pathologies. In this review, we examine how reduced nutrient availability in IUGR fetuses impacts skeletal muscle and liver substrate catabolism, and discuss how enzymatic processes governing mitochondrial function, such as the tricarboxylic acid cycle and electron transport chain, are regulated. Understanding how deficiencies in oxygen and substrate metabolism in response to placental restriction regulate skeletal muscle and liver metabolism is essential given the importance of these tissues in the development of later lifer metabolic dysfunction.