Anesthesia for fetal procedures and surgery.

Many of the anesthetic considerations for fetal procedures and surgery are identical to those for nonobstetric surgery during pregnancy, including concern for maternal safety, avoidance of both teratogenic drugs and fetal asphyxia, and the prevention of preterm labor and delivery. Anesthesia is required for the mother and quite often the fetus to perform many fetal procedures. Fetal procedures and surgery can be divided into subgroups according to their anesthetic requirements. For example: procedures that only require a needle insertion into the uterus but not into the fetus, such as intrauterine infusions; laser surgical photocoagulation of the communicating placental circulation for twin-twin transfusion syndrome (TTTS) and radio-frequency umbilical cord ablation for managing twin reversed arterial perfusion (TRAP), which are not really fetal procedures, rather they are placental or cord procedures; surgical procedures performed directly on the fetus; and the EX-utero Intrapartum Treatment (EXIT) procedure. Anesthetic considerations also depend on other factors, such as the location of the placenta. Unlike maternal surgery, for fetal procedures, the fetus is not an innocent bystander for whom the least anesthetic interference is used. Instead, the fetus can be the primary patient and may benefit from anesthesia, with close monitoring of the anesthetic effects to ensure well-being. Fetal asphyxia, hypoxia, or distress can be most effectively recognized, predicted, and avoided by fetal monitoring. Monitoring is also crucial for assessing the fetal response to corrective maneuvers.     

Development of cardiovascular function in the horse fetus

In mammals, the mechanisms regulating an increase in fetal arterial blood pressure with advancing gestational age remain unidentified. In all species studied to date, the prepartum increase in fetal plasma cortisol has an important role in the maturation of physiological systems essential for neonatal survival. In the horse, the prepartum elevation in fetal cortisol and arterial blood pressure are delayed relative to other species. Hence, the mechanisms governing the ontogenic increase in arterial blood pressure in the horse fetus may mature much closer to term than in other fetal animals. In the chronically instrumented pony mare and fetus, this study investigated how changes in fetal peripheral vascular resistance, in plasma concentrations of noradrenaline, adrenaline and vasopressin, and in the maternal-to-fetal plasma concentration gradient of oxygen and glucose relate to the ontogenic changes in fetal arterial blood pressure and fetal plasma cortisol concentration as term approaches. The data show that, towards term in the horse fetus, the increase in arterial blood pressure occurs together with reductions in metatarsal vascular resistance, elevations in plasma concentrations of cortisol, vasopressin, adrenaline and noradrenaline, and falls in the fetal : maternal ratio of blood   P _a,O2  and glucose concentration. Correlation analysis revealed that arterial blood pressure was positively related with plasma concentrations of vasopressin and noradrenaline, but not adrenaline in the fetus, and inversely related to the fetal : maternal ratio of blood   P _a,O2  , but not glucose, concentration. This suggests that increasing vasopressinergic and noradrenergic influences as well as changes in oxygen availability to the fetus and uteroplacental tissues may contribute to the ontogenic increase in fetal arterial blood pressure towards term in the horse.     

Characteristic patterns of maternal and fetal arterial construction in the rabbit placenta

We studied vascular structure of the rabbit placenta, especially on three-dimensional morphological patterns and developmental process. Basic structure of maternal arterial system was re-constructed during day 13–18 of pregnancy, forming main routes for blood supply through the arterial sinuses and radial arteries. Intra-villous spaces were drastically developed showing as branches from the terminal radial arteries. Fetal arterial system was generated accompanied with maternal vascular development, showing characteristic features such as the perforating linear artery, hairpin flexion, and circular anastomoses in the capillaries. From the correlation of maternal and fetal blood currents, gas-exchange style in the rabbit placenta was considered as counter-current and pool mixed patterns. These data demonstrated an original feature for the placental arterial systems in rabbits, which differed from other animals having a property for discoid placenta.     

Pathogenesis of bovine neosporosis

The protozoan parasite Neospora caninum is a major pathogen of cattle and dogs, being a significant cause of abortion in cattle in many countries. It is one of the most efficiently transmitted parasites, with up to 90% of cattle infected in some herds. The pathogenesis of abortion due to Neospora is complex and only partially understood. Losses occur after a primary infection during pregnancy but more commonly as the result of recrudescence of a persistent infection during pregnancy. Parasitaemia is followed by invasion of the placenta and fetus. It is suggested that abortion occurs when primary parasite-induced placental damage jeopardises fetal survival directly or causes release of maternal prostaglandins that in turn cause luteolysis and abortion. Fetal damage may also occur due to primary tissue damage caused by the multiplication of N. caninum in the fetus or due to insufficient oxygen/nutrition, secondary to placental damage. In addition, maternal immune expulsion of the fetus may occur associated with maternal placental inflammation and the release of maternal pro-inflammatory cytokines in the placenta. Thus N. caninum is a primary pathogen capable of causing abortion either through maternal placental inflammation, maternal and fetal placental necrosis, fetal damage, or a combination of all three. The question of how N. caninum kills the fetus exposes the complex and finely balanced biological processes that have evolved to permit bovine and other mammalian pregnancies to occur. Defining these immunological mechanisms will shed light on potential methods of control of bovine neosporosis and enrich our understanding of the continuity of mammalian and protozoal survival.     

Fetal magnesium homeostasis in the sheep.

The fetal plasma magnesium concentration exceeds that of the mother but the difference is small compared to that of ionized calcium concentration. Although not fully independent of changes in maternal magnesaemia, fetal magnesaemia showed a high degree of autonomy during both hypermagnesaemic and hypomagnesaemic changes induced in the ewe. As with calcium, the placental gradient is reversed after fetal thyroparathyroidectomy (TXPTX) with thyroxine replacement. During perfusion in situ of the placenta from such TXPTX fetuses isolated from the fetus itself, a stable positive placental gradient of magnesium concentration could be re-established between the perfusing blood and the maternal circulation. As with calcium, this gradient could be increased by fetal calf parathyroid extract, parathyroid hormone-related protein (PTHrP 1-141), PTHrP (1-84) but not by PTHrP (1-34). It was concluded that a mid-molecule portion of PTHrP can stimulate a putative placental pump which is responsible for the gradients of both calcium ions and magnesium across the ovine placenta.     

Transport of Proteins Across the Human Placenta

PROBLEM: The transport of various proteins across the human placenta was investigated by comparing maternal and fetal concentrations of tetanus antigen (TT-AG), anti-tetanus (TT)-immunoglobulin G (IgG) (following maternal vaccination), IgA, human chorionic gonadotropin (hCG), human placental lactogen (hPL), and alpha-fetoprotein (AFP) at term. METHOD OF STUDY: The concentrations of the six proteins were determined using enzyme-linked immunosorbent assay in serum of maternal venous and umbilical (fetal) vein samples obtained at delivery from uncomplicated term pregnancies (n = 16). RESULTS: The ratios (mean ± standard deviation) of fetal (umbilical) to maternal level were 1.41 ± 0.33 (anti-TT-IgG), 0.91 ± 0.37 (TT-AG), 0.002 ± 0.001 (IgA), 0.003 ± 0.001 (hCG), and 0.008 ± 0.004 (hPL), while the maternal:fetal concentration ratio of AFP was 0.002 ± 0.002. IgA, hCG, hPL, and AFP showed a close correlation between maternal and fetal levels varying between r² = 0.47 to 0.73 (P < 0.004–0.0001). Because AFP is produced by the fetus while IgA originates in the mother, the appearance of small amounts of these two proteins in the maternal or fetal compartment, respectively, suggests a slow rate of diffusion following a high concentration gradient. The detection of hCG and hPL in fetal serum is also interpreted as diffusion from the maternal into the fetal blood. Anti-TT-IgG has a significantly higher concentration in the fetal as compared with the maternal serum, which is in line with the well-documented active transfer of IgG. Fetal TT-antigen levels were similar to maternal concentrations, showing a close correlation (r² = 0.74, P < 0.0001) between the two proteins. CONCLUSIONS: The correlation between maternal and fetal concentrations of various proteins like IgA (150,000 Da), hCG (42,000 Da), and hPL (21,000 Da) suggests passive diffusion of these macromolecules across the placenta from the maternal to the fetal side, albeit at a slow rate. A similar process is postulated for AFP (70,000 Da) diffusing in the opposite direction from the fetus to the mother. There was no significant difference between the transplacental fetomaternal gradient of IgA and hCG and the maternal-fetal gradient of AFP. In view of the substantially larger volume of circulating maternal as compared with fetal blood, a significantly higher rate of crossing of AFP as compared with the other proteins must be assumed. It is uncertain whether a difference in the rate of transplacental transfer in the two directions or an additional source of AFP production in the maternal compartment explains the high maternal level. Anti-TT-IgG concentration is significantly higher in fetal than in maternal serum suggesting active transfer from the mother to the fetus. Furthermore, there is considerable transfer of TT-AG and a close correlation of fetal:maternal ratios of anti-TT-IgG (150,000 Da) and TT-AG (150,000 Da) could be an indication for a specific transfer of the antigen antibody complex.     

Transport and accumulation of α-aminoisobutyric acid (A.I.B.) in the guinea pig placenta

Active transport of A.I.B. from mother to fetus was studied. This was done in the intact animal and using the isolated placenta, artificially perfused at both sides. It was shown that A.I.B. is actively accumulated in the placental cells. An estimate of the kinetic constants is given. It is shown that this accumulation takes place predominantly from the maternal side of the placenta.A.I.B. that has been accumulated is cleared to the maternal and fetal circulation in equal amounts. So the netto active transport from mother to fetus is brought about by an unequal distribution of carriers, the maternal side being most active.     

The role of blood flow distribution in the regulation of cerebral oxygen availability in fetal growth restriction

Fetal growth restriction (FGR) elicits hemodynamic compensatory mechanisms in the fetal circulation. These mechanisms are complex and their effect on the cerebral oxygen availability is not fully understood. To quantify the contribution of each compensatory mechanism to the fetal cerebral oxygen availability, a mathematical model of the fetal circulation was developed. The model was based on cardiac-output distribution in the fetal circulation. The compensatory mechanisms of FGR were simulated and their effects on cerebral oxygen availability were analyzed. The mathematical analysis included the effects of cerebral vasodilation, placental resistance to blood flow, degree of blood shunting by the ductus venosus and the effect of maternal-originated placental insufficiency. The model indicated a unimodal dependency between placental blood flow and cerebral oxygen availability. Optimal cerebral oxygen availability was achieved when the placental blood flow was mildly reduced compared to the normal flow. This optimal ratio was found to increase as the hypoxic state of FGR worsens. The model indicated that cerebral oxygen availability is increasingly dependent on the cardiac output distribution as the fetus gains weight.     

Oxygenation of the placental-fetal unit in humans

This review focuses on the role of oxygen and the changes in oxygen levels in the different trimesters of pregnancy in the human placenta. In the first trimester, the physiological conversion of the spiral arteries restricts maternal blood flow into the intervillous space creating a low oxygen environment for the trophoblast and the embryo. In the second trimester, progressive conversion of the spiral arteries allows unhindered entrance of maternal blood into the intervillous space. In early pregnancy, pathology of spiral artery conversion may promote premature flow of maternal blood resulting in miscarriage. In more advanced pregnancy, incomplete conversion of spiral arteries impairs maternal blood flow to the placenta, causing chronic hypoxia and growth restriction of the fetus. Chronically reduced maternal supply of oxygen to the placental-fetal unit may be partially balanced by metabolic reprogramming of the placenta. Acute impairment of oxygenation in the perinatal period and its effect on the placental-fetal unit will also be discussed.     

Haem oxygenase-1 dictates intrauterine fetal survival in mice via carbon monoxide

Pregnancy establishment implies the existence of a highly vascularized and transient organ, the placenta, which ensures oxygen supply to the fetus via haemoproteins. Haem metabolism, including its catabolism by haem oxygenase-1 (HO-1), should be of importance in maintaining the homeostasis of haemoproteins and controlling the deleterious effects associated with haem release from maternal or fetal haemoglobins, thus ensuring placental function and fetal development. We demonstrate that HO-1 expression is essential to promote placental function and fetal development, thus determining the success of pregnancy. Hmox1 deletion in mice has pathological consequences for pregnancy, namely suboptimal placentation followed by intrauterine fetal growth restriction (IUGR) and fetal lethality. These pathological effects can be mimicked by administration of exogenous haem in wild-type mice. Fetal and maternal HO-1 is required to prevent post-implantation fetal loss through a mechanism that acts independently of maternal adaptive immunity and hormones. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of haem catabolism by HO-1 that restores placentation and fetal growth. In a clinical relevant model of IUGR, CO reduces the levels of free haem in circulation and prevents fetal death. We unravel a novel physiological role for HO-1/CO in sustaining pregnancy which aids in understanding the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy pathologies.     

Placental pathology in fetal thrombophilia

The aim of this study was to test the hypothesis that placental vascular lesions of the fetal circulation are caused by fetal thrombophilic mutations. The study included 64 newborns of women with one or more of the following pregnancy complications: preeclampsia, placental abruption, and intrauterine growth restriction. The most prevalent inherited thrombophilias--factor V Leiden, factor II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase C677T--were examined in maternal blood and fetal umbilical cord blood. One pathologist reviewed all of the slides for fetal vascular lesions. Associations between fetal thrombotic vasculopathy and fetal thrombophilia were tested for using Fisher's exact test; Z scores and gestational age were compared using the Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64 newborns, 15 of whom had coexistent maternal thrombophilia. There was no statistical difference in the prevalence of thrombotic lesions of the fetal circulation between newborns with and without thrombophilia. The combination of maternal and fetal thrombophilia was also not associated with increased fetal vascular lesions. The results indicate that fetal thrombophilia alone, even in the context of maternal underperfusion, is not associated with fetal vascular lesions of the placenta, although it may represent an underlying risk factor for lesions triggered by other process(es).     

Extrauterine incubation of fetal goats applying the extracorporeal membrane oxygenation via umbilical artery and vein

The fetus is an unstable subject for an isolated physiological and biochemical study. To study the fetus in a controlled and stable environment, a trial was done using 12 goat fetuses. Extrauterine incubation system was devised using an extracorporeal membrane oxygenation system. The system consisted of a venous reservoir with a servo-controlled roller pump and a membrane oxygenator. The extra-corporeal circuit and membrane oxygenator were primed with the maternal whole blood of 200 mL. Fetal umbilical cords was exposed by Cesarean section. Fetal umbilical arterial blood was drained via the drainage cannula. The drained blood was perfused to the oxygenator by the roller pump. The highly oxygenated and decarboxylated blood was returned to an umbilical vein via the perfusion catheter. The blood flow rate was controlled manually using a roller pump. Fetal heart rate, blood pressure, and electrocardiogram were continuously recorded. Gas analysis of drained and perfused blood was performed hourly. With this system, the fetuses were able to survive under fairly stable physiological condition for periods of up to 34 hr. The extrauterine incubation system used in this study could therefore be a encouraging future experimental model in researching the artificial placenta for premature fetuses.     

Nonlinear analysis of heart rate variability to assess the reaction of ewe fetuses undergoing fetal cardiac surgery

Fetal cardiac surgery (FCS) represents a challenging issue for the in utero treatment of congenital heart defects. However, FCS has still not gained the sufficient reliability for clinical practice due to an incompletely elucidated fetal stress response. For example, blood sampling can contribute to its onset, leading to fetoplacental unit dysfunction, one of the main causes of failure of the surgical procedure. In order to address this issue, the role of the autonomic control system during an experimental procedure of cardiac bypass on ewe fetuses was investigated by means of recurrence quantification analysis (RQA), a well-recognized method for the analysis of nonlinear systems. RQA was applied to time series extracted from fetal arterial pressure recordings before and after the cardiac bypass established by means of an extracorporeal circuit, including an axial blood pump, and taking advantage of the capability of the placenta to work as a natural oxygenator. Statistically significant correlations were found among RQA-based metrics and fetal blood gas data, suggesting the possibility to infer the clinical status of the fetus starting from its hemodynamic signals.This study shows the relevance of RQA as a complementary tool for the monitoring of the fetal status during cardiac bypass.     

Feto-maternal cell trafficking

The embryonic and fetal development in the maternal uterine environment implies that different population of fetal progenitors must be in close contact to the maternal tissues. Accordingly, fetal mesenchymal and hematopoietic stem and progenitor cells have been described in the placenta and the fetal blood. Seeding in the materinal circulation, fetal progenitor cells can be detected in the circulation of pregnant women during most pregnancies. Decades after delivery, fetal CD34⁺ or mesenchymal stem cells are still detectable in maternal circulation or bone marrow. Recent studies point to the possibility for fetal progenitor cells persisting after pregnancy to home to maternal injured tissue and to adopt various phenotypes. Fetal cells in various maternal tissues can express epithelial, hepatocytic, hematopoietic, renal, cardiomyocytic, glial, or neuronal markers in human as well as mouse models. This apparent multipotency has been attributed to a fetal population of stem/progenitor cells acquired by the mother during pregnancy, named the pregnancy-associated progenitor cells. We will discuss the possible origins of this cell population and review the most recent data suggesting that these fetal microchimeric cells may participate in maternal tissue regeneration processes. An erratum to this article is available at .     

Passage of inert substances and oxygen in the human placenta

1. The vascular arrangement and the perfusion pattern of the human placenta is discussed from the point of view of the transfer of substances from the maternal blood through the placental membrane into the fetal blood. The functional unit of the human placenta is a stream of maternal blood in the intervillous space opposed to a large series of fetal capillaries (the multivillous stream bed system).2. The transfer of each inert substance in the human placenta is dependent upon the concentration difference of the substance in the maternal and fetal blood entering the placenta, the rates of blood flow and the permeability coefficient of the placental membrane. These relationships are graphically presented.3. The placental transfer of oxygen during maternal hypoxia in the human depends upon the difference in O₂ partial pressure in the entering blood streams, the rates of blood flow, the oxygen affinity and the capacity of maternal and fetal blood and the diffusion capacity of the placental membrane. These relationships are graphically presented.4. The transfer of oxygen under normal conditions in the human placenta depends upon the rates of blood flow and the diffusion capacity. These relationship are graphically presented for conditions of special composition of maternal and fetal blood entering the placenta.5. The transfer characteristics of the human placenta are compared with those in placentas with other vascular arrangements and perfusion patterns. The system of the human placenta is more efficient than a concurrent system and a pool system, but less efficient than a countercurrent system if the diffusion capacity of the placental membrane is high in relation to the fetal transport capacity. If the diffusion capacity is low in relation to the fetal transport capacity, all systems have about the same efficiency.With 4 Figures in the Text     

Electronic model as an aid in teaching fetal heart rate monitoring

A model of the uterus-placenta-fetus system was designed using an electronic device which proportions at its outputs the representative signals of the fetal heart rate (FHR) and uterine contractions (UC). The uterus subsystem provides a voltage variable in time similar to the pressure of the UC. The placenta subsystem is controlled by the difference between the UC and the maternal arterial pressure as well as by the time in which the blood flow to the fetus is reduced. The fetus subsystem provides a voltage representative of the FHR.     

Uptake of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the N-methyl-4-phenylpyridinium ion (MPP+) into fetal mouse brain through the placenta

The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to be taken up into fetal mice through the placenta from a maternal mouse. C57 black mice were mated and MPTP (30 mg/kg) was given intramuscularly at the 18th day of gestation. Definite amounts of MPTP were detected in fetal brains by assay using high-performance liquid chromatography (HPLC) at 1 h after MPTP injection, and much higher contents of MPTP were found in maternal brains, too. An oxidative product of MPTP, the N-methyl-4-phenylpyridinium ion (MPP+), was also detected in brains of both mother and fetus and its concentrations in their brains were followed at 1, 3, 6, 12, 24 h after MPTP injection. The time to reach the maximal MPP+ concentration in brains was different between mother and fetus; 1 h and 3 h respectively. In addition to brain, considerable amounts of MPP+ were found in fetal liver, maternal liver and kidney, and in the placenta.     

Plasma renin activity during ovine pregnancy.

Chronic intravascular catheterization in maternal, fetal, and neonatal sheep was utilized to assess basal plasma renin activity (PRA) and changes in PRA in response to furosemide. Maternal PRA increased from base-line levels during the last trimester of pregnancy and remained elevated for 12 wk postpartum. Fetal basal levels of PRA were variable but usually greater than maternal levels. Intravenous administration of furosemide to pregnant ewes resulted in a prompt and significant increase in maternal PRA with inconsistent changes in fetal PRA. Fetal and neonatal animals with low basal levels showed a significant increase in PRA; maternal PRA did not change. Animals with higher basal levels did not respond to the stimulus, perhaps reflecting a maximum renin secretory rate. These data are consistent with the conclusions that fetal renin originated predominantly from the fetal kidney, that fetal PRA receives no significant contribution from the maternal circulation, and that renin does not cross the ovine placenta.     

The role of the insulin-like growth factor system in prenatal growth

Fetal growth is a complex process involving multiple environmental and genetic factors. Fetal growth restriction is associated with morbidity among small for gestational age (SGA) neonates as well as in children and adults who are former SGA infants. Over the last decade it has been recognized that the insulin-like growth factor axis has a critical role in mediating fetal and postnatal growth. However, how these hormones are involved in common pathological processes, leading to fetal growth restriction (FGR), remains unknown. In humans and mice, mutations or targeted deletions of the IGF ligands IGF1 and IGF2, as well as the IGF type-I receptor and its main signaling molecule IRS1 lead to FGR. IGFs are low in human SGA newborns; however, only a small minority of these infants have mutations of IGF-related molecules, rather, idiopathic or maternal factors are thought to induce FGR in most of these cases. Fetal growth is complex process governed by multiple genetic factors, but ultimately influenced by environmental processes, chief among them being nutrient supply from the mother to the placenta and from the placenta to the fetus. Understanding the molecular processes by which maternal factors contribute to fetal growth is an important step in developing strategies for diagnosing and treating different variants of fetal growth retardation. As our knowledge of these mechanisms become more sophisticated, we may find that many "idiopathic" cases of IUGR are also caused by subtle alterations in the IGF axis including heterozygotic mutations, polymorphisms, and epigenetic regulation.     

Pregnancy immunology and maternal alloimmune responses

Pregnancy is an “immunological Paradox”. This is because pregnant women are tolerant of their semi-allogeneic fetus but are not immunosuppressed and indeed make strong antibody responses. The immunological changes required are driven mainly by the placenta, an organ derived from cells of the blastocyst surrounding the embryo. Trophoblast cells on the surface of the placenta form the interface between the fetus and maternal tissues and blood. They differentiate into (a) villous syncytiotrophoblast (ST) that are in contact with maternal blood and transfer gases and nutrients between maternal and fetal blood and (b) extravillous trophoblast cells that invade into the maternal decidua lining the uterus. Trophoblast cells escape allorecognition because they lack classical HLA class I and II molecules. Local immunoregulation, or tolerance, in the decidua is mediated mainly by HLA-G+ extravillous trophoblasts that prevent killing of fetal and placental cells by maternal natural killer cells, cytotoxic T cells and macrophages, thus ensuring the fetus is not rejected. Placental hormones orchestrate the composition and regulatory function of maternal immune cells in the decidua. ST at the surface of chorionic villi, together with ST debris that is shed into maternal blood, maintain a state of mild maternal systemic inflammation by enhancing innate immunity and skewing the immune response towards humoral (antibody) immunity. This enables a healthy immune system to be maintained in pregnant women, with robust protective antibody responses to pathogens whilst enabling survival of the fetus. However, this immunological skewing ensures that pregnant women readily form alloantibodies to incompatible fetal alloantigens. If fetomaternal haemorrhage (FMH) occurs, they can make antibodies to fetal red cells, platelets and leucocytes that are in her blood. The alloantibodies are initially of low affinity but after re-immunisation of the woman with further FMH (most commonly at delivery), they become functionally effective, high titre IgG. Maternal IgG is transferred by the ST to the fetus, to give the baby protective immunity to survive infancy. This has the unfortunate consequence that alloantibodies to blood cells are also transported, leading to haemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT). Both HDFN and FNAIT may result in death or serious neurological damage to the baby. HDFN due to anti-D can be prevented by administration of prophylactic anti-D to the mother, destroying or clearing D-positive fetal red cells in FMH from her circulation before they can become immunogenic.