| The extravillous circulations. The yolk sac is the first of the extraembryonic membranes to be vascularized, and likely plays a key role in maternal-fetal transport during the period of organogenesis before the chorionic circulation is fully established at ∼12 weeks. Changes in the resistance offered by each circulation may affect gene expression and differentiation of the fetal cardiomyocytes. From Burton et al. (2016) with permission. 

| The extravillous circulations. The yolk sac is the first of the extraembryonic membranes to be vascularized, and likely plays a key role in maternal-fetal transport during the period of organogenesis before the chorionic circulation is fully established at ∼12 weeks. Changes in the resistance offered by each circulation may affect gene expression and differentiation of the fetal cardiomyocytes. From Burton et al. (2016) with permission. 

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The placenta is the largest fetal organ, and toward the end of pregnancy the umbilical circulation receives at least 40% of the biventricular cardiac output. It is not surprising, therefore, that there are likely to be close haemodynamic links between the development of the placenta and the fetal heart. Development of the placenta is precocious, an...

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... embryonic heart starts as a primitive tube and the first contractions are seen at ∼22 days (beginning of the 5th week after the last menstrual period). The heart starts to beat before the development of the conduction system, and before a competent valvular mechanism has formed (Collins, 2016). The primitive bilateral aortae, each consisting of ventral and dorsal parts, fuse during the 4th embryonic week (6 weeks LMP) to form a single definitive descending aorta. The umbilical arteries connect to the primitive dorsal aorta (Figure 1). Cardiac output and heart rate increase in proportion with the developing embryonic body. By 10 weeks the fetal heart rate reaches its peak at around 170 beats/min (bpm) and then slows down to 120-160 bpm for the rest of pregnancy (van Heeswijk et al., 1990). Abnormally slow (Doubilet and Benson, 2005) and fast ( Doubilet et al., 2000) heart rates during the second month of pregnancy have been associated with a high risk of embryonic demise. It is hypothesized that subsequent hypoperfusion of the secondary yolk sac, causing a progressive loss of structure and necrosis or oedema can explain why in a pregnancy destined to miscarry, changes in the diameter of the sac may precede arrest of the embryonic heart by a few days ( Datta and Raut, ...
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... capillary network can be identified within the mesenchymal layer of the human yolk sac from ∼5 weeks gestational age (Pereda and Niimi, 2008), and venous drainage is through the region of the developing liver into the sinus venosus (Figure 1). The size of these capillaries remains below the resolution of standard ultrasound imaging during the biological life of the secondary yolk sac, and only the larger vessels on the vitelline duct have been studied in utero with color Doppler imaging toward the end of the first-trimester when it is no longer functional ( Mäkikallio et al., 2004). The yolk sac shows degenerative changes from 10 weeks of gestation suggesting that its involution in normal pregnancies is a spontaneous event rather than the result of mechanical compression by the expanding amniotic cavity ( Jauniaux et al., 1991d). In early fetal demise, the yolk sac increases in size and becomes less dense due to oedema just before or immediately after activity of the fetal heart has stopped. These variations in size and appearance of the yolk sac are the consequence of abnormal fetal development or death rather than being the primary cause of the early pregnancy failure ( Jauniaux et al., ...

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... An article published in 2019 confirmed that ambient black carbon particles reached the fetal side of the human placenta (Bové et al., 2019), and there were thousands of carbon pollution particles in the placenta near the fetal side (Hove et al., 2003), which meant the fetus that we thought was safe has been exposed to all kinds of air pollutants. The development of the placenta is premature and earlier than the fetus, and the development of the heart and placenta may be closely linked (Burton et al., 2018). Since cardiac gene expression is highly sensitive to biomechanical cues, and the placenta is the largest fetal organ (Burton, 2018), some effects on the placenta may affect the differentiation of cardiomyocytes and the morphology of the heart (Hove, 2003, Kowalski et al., 2014. ...
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Exposure to air pollution during pregnancy has been linked to birth defects. But the directions of studies on the associations between air pollutants exposure and effect on the incidence of congenital heart disease (CHDs) were inconsistent. To date, few studies were concentrated on the effects of both particulate matter and gaseous air pollutant exposure on CHDs across the full gestational week simultaneously. Our study aimed to investigate the critical exposure windows for each air pollutant throughout 40 gestational weeks. Data on CHDs, air pollution, and meteorological factors from 2013 to 2019 were collected in Lanzhou, China. A distributed lag nonlinear model combined with a quasi-Poisson regression model was applied to evaluate the weekly exposure–lag–response association between air pollutants levels and CHDs, and the subgroup analyses were conducted by gender (baby boy and baby girl). The study included 1607 mother–infant pairs. The results demonstrated that exposure of pregnant women to particulate matter ≤ 5 μm (PM2.5) at lag 1–4 weeks was significantly associated with the risk of CHDs, and the strongest effects were observed in the lag 1 week (1.150, 95%CI 1.059–1.248). For exposure to particulate matter ≤ 10 μm (PM10) at lag 1–3 weeks, the strongest effects were observed in the lag 1 week (1.075, 95% CI 1.026–1.128). For exposure to sulfur dioxide (SO2) at lag 1–4 weeks, the strongest effects were observed in the lag 1 week (1.154, 95% CI 1.025–1.299). For exposure to carbon monoxide (CO) at lag 1–3 weeks, the strongest effects were observed in the lag 1 week (1.089, 95% CI 1.002–1.183). For exposure to ozone (O3) concentration at lag 9–15 weeks, the strongest effects were observed in the lag 15 weeks (1.628, 95% CI 1.001–2.649). The cumulative effects of PM2.5, PM10, SO2, and CO along weeks with a maximum of 1.609 (95%CI 1.000–2.589), 1.286 (95%CI 1.007–1.641), 1.648 (95%CI 1.018–2.668), and 1.368 (95%CI 1.003, 1.865), respectively. The effects were obvious in the initial gestational weeks too. Through the gender stratification analysis, the air pollutants with significant effects were PM2.5 for baby boys and PM2.5, PM10, SO2, CO, NO2, and O3 for baby girl. For the relationship between CHDs and air pollution in Lanzhou, PM2.5, PM10, SO2, CO, and O3 played an important role in the initial gestational weeks, especially for baby girl.
... Timing for insulin assessment must also be defined in pregnancy, because insulin secretion and sensitivity progressively change after placental formation near the end of the first trimester, at approximately 10-12 weeks of gestation. 64 Placental-induced hyperinsulinaemia may have been a confounding variable in two women from this case series (Case #2 and Case #4) who underwent OGTT testing at 14 + 5 weeks of gestation due to practical limitations. The key limitation of this case series is that the interpretation of case series data is limited to speculation. ...
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Background: Pathological insulin resistance in pregnancy is associated with an increased risk for complications such as gestational diabetes mellitus and pre-eclampsia. Individuals with pathological insulin resistance also exhibit hyperinsulinaemia. Currently, there are no diagnostic criteria for pathological hyperinsulinaemia in pregnancy that may be used to indicate risk of adverse outcomes. Aim: This case series aimed to explore the relationship between first trimester insulin response patterns and gestational outcomes. Setting: Auckland, New Zealand. Methods: Participants included four pregnant women with prepregnancy body mass index ≥ 25 kg/m2 and aged 25–35 years. Glucose and insulin response patterns were examined following a 120 min oral glucose tolerance test (OGTT) at 12–15 weeks of gestation using a modified Kraft methodology. Outcomes assessed at 25 and 35 weeks of gestation included gestational weight gain (GWG), blood pressure, fasting capillary blood glucose and foetal growth. Lifestyle and medical information were collected at each trimester. After delivery, total GWG, infant size, delivery method and clinical outcomes were recorded. Results: Kraft pattern IIB hyperinsulinaemia was identified in two cases. Amongst them, Case #1 experienced excessive GWG, induction of labour and surgically assisted delivery. Case #4 delivered by emergency caesarean, and the neonate required intensive care admission for 17 h. No cases developed hyperglycaemia or hypertension. Infant weights were between 3.75 kg and 3.86 kg. Conclusion: Dynamic insulin assay provides a promising template to assess metabolic risk in the first trimester of pregnancy. Diagnosing hyperinsulinaemia early in pregnancy means that lifestyle-based initiatives could be introduced earlier to mitigate excess GWG and potential adverse outcomes.
... Hence, early embryonic and placental development occurs jointly in a low oxygen environment. Subsequently, at approximately 10 weeks of gestation, the enmeshed trophoblast cell "plugs" start to dislodge allowing the maternal arterial circulation to flow to the intervillous space, facilitating the full establishment of the uteroplacental circulation, alongside the contemporaneous elaboration of the feto-placental circulation (Burton and Jauniaux, 2018a;Burton and Jauniaux, 2018b), thereby enabling nutrients to be transferred from maternal blood flowing to the intervillous space, to fetal blood in the capillaries within the core of the placental villi via "haemotrophic" nutrition. ...
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Homocysteine is a metabolite generated by methionine cycle metabolism, comprising the demethylated derivative of methionine. Homocysteine can be metabolised by the transsulphuration pathway to cystathionine, which requires vitamin B6, or can undergo remethylation to methionine. Homocysteine remethylation to methionine is catalysed by methionine synthase activity which requires vitamin B12, regenerating methionine to allow synthesis of the universal methyl donor S-adenosylmethionine required for methylation and gene transcription regulation. The methyl-group donated for homocysteine remethylation comes from 5-methyltetrahydrofolate generated by the folate cycle, which allows tetrahydrofolate to be returned to the active folate pool for nucleotide biosynthesis. Therefore the integrated actions of the methionine and folate cycles, required to metabolise homocysteine, also perpetuate methylation and nucleotide synthesis, vitally important to support embryonic growth, proliferation and development. Dysregulated activities of these two interdependent metabolic cycles, arising from maternal suboptimal intake of nutrient co-factors such as folate and vitamin B12 or gene polymorphisms resulting in reduced enzymatic activity, leads to inefficient homocysteine metabolic conversion causing elevated concentrations, known as hyperhomocysteinemia. This condition is associated with multiple adverse pregnancy outcomes including neural tube defects (NTDs). Raised homocysteine is damaging to cellular function, binding to proteins thereby impairing their function, with perturbed homocysteine metabolism impacting negatively on embryonic development. This review discusses the “cross-talk” of maternal-fetal homocysteine interrelationships, describes the placental transport of homocysteine, homocysteine impacts on pregnancy outcomes, homocysteine and methylation effects linking to NTD risk and proposes a putative pathway for embryonic provision of folate and vitamin B12, homocysteine-modulating nutrients that ameliorate NTD risk.
... Later in gestation, the placental blood vessels are also covered by a basement membrane [12,84]. Apart from the barrier function between maternal and fetal blood circulation, the placental villi, in particular the outer syncytiotrophoblast, have a significant role in the fetal-maternal gas and nutrient exchange as well as endocrine and metabolic activity [23,73]. Microvilli at the apical side of the syncytiotrophoblast enlarge the surface area to increase the exchange ability [12,84]. ...
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Human pregnancy depends on the proper development of the embryo prior to implantation and the implantation of the embryo into the uterine wall. During the pre-implantation phase, formation of the morula is followed by internalization of blastomeres that differentiate into the pluripotent inner cell mass lineage, while the cells on the surface undergo polarization and differentiate into the trophectoderm of the blastocyst. The trophectoderm mediates apposition and adhesion of the blastocyst to the uterine epithelium. These processes lead to a stable contact between embryonic and maternal tissues, resulting in the formation of a new organ, the placenta. During implantation, the trophectoderm cells start to differentiate and form the basis for multiple specialized trophoblast subpopulations, all of which fulfilling specific key functions in placentation. They either differentiate into polar cells serving typical epithelial functions, or into apolar invasive cells that adapt the uterine wall to progressing pregnancy. The composition of these trophoblast subpopulations is crucial for human placenta development and alterations are suggested to result in placenta-associated pregnancy pathologies. This review article focuses on what is known about very early processes in human reproduction and emphasizes on morphological and functional aspects of early trophoblast differentiation and subpopulations.
... Фетальная часть плаценты называется хорионом, где артерии хориона берут свое начало из пуповины и кровоснабжают капиллярное ложе плаценты (ворсинки хориона). В течение 5-й недели беременности, когда происходит васкуляризация плаценты, участки кровообращения хориона наблюдаются в мезенхиме ворсинок плаценты [5]. Ремоделирование и изменения в сосудистом сопротивлении плаценты происходят в конце I триместра, когда плацента окончательная сформирована. ...
Article
It has been increasingly recognized that structural abnormalities and functional changes in the placenta can adversely affect developing fetal heart. In this article, we examine a role of the placenta as well as potential impact of placental insufficiency on a fetus with congenital heart disease (CHD). The fetal heart and placenta are directly connected because they develop simultaneously with common regulatory and signaling pathways. Moreover, placenta-associated complications are more common in pregnant women carrying fetus with CHD, and the fetal response to placental insufficiency may lead to postnatal preservation of remodeled heart. The mechanisms underlying this placenta–fetus axis potentially consists of genetic factors, oxidative stress, chronic hypoxia, and/or angiogenic imbalance. Thus, the mother–placenta–fetus circulation is critical in understanding the CHD formation. It is necessary to study the changing factors involved in these processes for early identification, imaging, quantification of placental insufficiency, and development of new prenatal therapies in the CHD patient population.
... During this early stage of gestation, the heart is among the first organs to develop, undergoing proliferation and differentiation through 7 weeks GA with increasing heart rate peaking at 10 weeks GA (170 beats per minute) followed by a gradual decrease (to 120-160 beats per minute) from this peaking age onwards [33,34]. At this early time in life, vagal fibers are arranged, and by 14 weeks GA, the spiral development profile of myelination starts. ...
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To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed “the self-regulation clock” and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the “clock” circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates.
... Recent studies suggest a shared developmental pathway between the placenta and fetal heart. [41][42][43] Placentas from pregnancies carrying fetuses with CHD often have adverse changes, such as vascular malperfusion or low placental/birth weight ratio. 44,45 A recent study by Rychik et al found that placental thrombosis, abnormal chorangiosis, and infarction were common in newborns with CHD. ...
Article
BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal–fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in‐hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4 days (interquartile range [IQR], 3–6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights <2.5 kg (18% versus 4%) than those without impaired MFE. Impaired MFE was associated with a higher risk of death (hazard ratio [HR], 6.05; 95% CI, 3.59–10.21; P <0.001) after adjusting for age at surgery, Hispanic ethnicity, genetic syndrome, cardiac diagnosis, surgeon, and birth era. Children with impaired MFE had almost double the risk of prolonged hospital stay (HR, 1.95; 95% CI, 1.41–2.70; P <0.001). CONCLUSIONS Children exposed to an impaired MFE had a higher risk of death following stage 1 Norwood reconstruction. Prenatal exposures are potentially modifiable factors that can be targeted to improve outcomes after pediatric cardiac surgery.
... Both the heart and placenta are highly vascular organs that develop under the influence of a complex balance of pro-angiogenic and antiangiogenic vascular growth factors. 13 Reports have described an increase in placental abnormalities (both vascular and villous) in pregnancies complicated by CHD, based on pathology 14 and imaging studies. [15][16][17][18] Late gestation fall-off in fetal growth resembling lateonset placental-based fetal growth restriction has been observed in certain (but not all) CHD lesions. ...
... 3 The yolk sac becomes vascularized at 24 days postconception, with vascularization of the chorioallantoic placenta happening shortly thereafter; variations in either of these extraembryonic circulations can impact cardiac development. 71,79 During the early stages of pregnancy, hypoxia prevents the invasion of trophoblasts into the uterus; in later stages, the trophoblast cells migrate and replace the maternal vascular wall within the uterine wall, creating a low-resistance state that encourages oxygen and nutrient exchange. 79 The maintenance of a hypoxic environment and prohibition of premature trophoblast invasion has been shown to be mediated by numerous cytokines, such as tumor necrosis factor a, interleukin 1a, and interleukin 1b. ...
Article
Congenital heart disease (CHD) is the most common congenital abnormality worldwide, affecting 8 to 12 infants per 1000 births globally and causing >40% of prenatal deaths. However, its causes remain mainly unknown, with only up to 15% of CHD cases having a determined genetic cause. Exploring the complex relationship between genetics and environmental exposures is key in understanding the multifactorial nature of the development of CHD. Multiple population-level association studies have been conducted on maternal environmental exposures and their association with CHD, including evaluating the effect of maternal disease, medication exposure, environmental pollution, and tobacco and alcohol use on the incidence of CHD. However, these studies have been done in a siloed manner, with few examining the interplay between multiple environmental exposures. Here, we broadly and qualitatively review the current literature on maternal and paternal prenatal exposures and their association with CHD. We propose using the framework of the emerging field of the exposome, the environmental complement to the genome, to review all internal and external prenatal environmental exposures and identify potentiating or alleviating synergy between exposures. Finally, we propose mechanistic pathways through which susceptibility to development of CHD may be induced via the totality of prenatal environmental exposures, including the interplay between placental and cardiac development and the internal vasculature and placental morphology in early stages of pregnancy.
... Human fetoplacental endothelial cells are an ideal model for studying epigenetic functions because of their indirect contact with fetal circulation [5]. Many articles have reported that the abnormal structure and function of fetoplacental endothelial cells leads to an increased risk of congenital heart disease in offspring [6,7]. Therefore, it is necessary to clarify the role of fetoplacental endothelial cells in fetal cardiovascular development. ...
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Gestational diabetes mellitus (GDM) increases the risk of fetal heart malformations, though little is known about the mechanism of hyperglycemia-induced heart malformations. Thus, we aimed to reveal the global landscape of miRNAs and mRNAs in GDM-exposed fetoplacental arterial endothelial cells (dAECs) and establish regulatory networks for exploring the pathophysiological mechanism of fetal heart malformations in maternal hyperglycemia. Gene Expression Omnibus (GEO) datasets were used, and identification of differentially expressed miRNAs (DEMs) and genes (DEGs) in GDM was based on a previous sequencing analysis of dAECs. A miRNA-mRNA network containing 20 DEMs and 65 DEGs was established using DEMs altered in opposite directions to DEGs. In an in vivo study, we established a streptozotocin-induced pregestational diabetes mellitus (PGDM) mouse model and found the fetal cardiac wall thickness in different regions to be dramatically increased in the PGDM grouValidation of DEMs and DEGs in the fetal heart showed significantly upregulated expression of let-7e-5p, miR-139-5p and miR-195-5p and downregulated expression of SGOL1, RRM2, RGS5, CDK1 and CENPA. In summary, we reveal the miRNA-mRNA regulatory network related to fetal cardiac development disorders in offspring, which may shed light on the potential molecular mechanisms of fetal cardiac development disorders during maternal hyperglycemia.