Pronostic des nouveau-nés de mère prééclamptique

Preeclampsia (PE) is associated with 3 main risks for the fetus: perinatal death, intrauterine growth restriction (IUGR), preterm birth. Perinatal mortality is increased in infants with IUGR or asphyxia. Conversely, mortality and morbidity associated with preterm birth are not altered by PE without IUGR or asphyxia. Very preterm infant with IUGR are exposed to high risk of prolonged respiratory insufficiency. Neurological complications of prematurity are not more frequent in infants born to mothers with PE. Nevertheless birth asphyxia, (i.e. placental abruption) is associated with impaired neurological out-come especially in infants with neonatal encephalopathy. Long term outcome of infants born to mothers with PE is strongly correlated to gestational age. IUGR increases the risk of hypertension and metabolic syndrome in adulthood. Acute fatty liver of pregnancy can by caused by a fetal fatty-acid oxidation disorder.     

Transamniotic fetal feeding. III. The effect of nutrient infusion on fetal growth retardation

The small-for-gestational age (SGA) infant resulting from intrauterine growth retardation (IUGR) is at high risk for perinatal complications and chronic morbidity. Most IUGR is the result of inadequate transfer of nutrients and/or oxygen from mother to fetus. Transamniotic fetal feeding (TAFF) has been proposed as a method of treating IUGR in which nutrients infused into the amniotic fluid would be swallowed, absorbed, and used by the growth retarded fetus. To study the efficacy of TAFF in the treatment of IUGR, we have previously described a rabbit model for TAFF that takes advantage of the relationship between "natural runting" (IUGR) and position on the uterine horn. We report on a controlled study of the effects of specific nutrient infusion on fetal growth retardation in this model. The infusion of dextrose, a dextrose-amino acid mixture, or lipid did not reverse or ameliorate fetal IUGR compared with controls. In addition, the infusion of lipid emulsion resulted in chronic lipid aspiration and further growth retardation. This work does not support the use of TAFF as a prenatal treatment for IUGR and suggests that oxygen may be the growth-limiting factor in most substrate deficiency IUGR. In addition, the infusion of solutions containing lipid may be harmful to the developing fetus.     

Transamniotic fetal feeding. II. A model of intrauterine growth retardation using the relationship of "natural runting" to uterine position

Intrauterine growth retardation (IUGR) is a leading cause of perinatal morbidity and mortality. Most IUGR is the result of inadequate transfer of nutrients from mother to fetus. Transamniotic fetal feeding (TAFF) has been proposed as a method of treating IUGR in which nutrients, infused into the amniotic fluid, would be swallowed, absorbed, and utilized by the growth retarded fetus. To study this hypothesis, we have developed a rabbit model for IUGR and TAFF. We studied the effects of maternal nutritional deprivation, uterine artery ligation, and fetal position in the uterine horn on fetal body and organ growth in 96 rabbit litters. Nutritional deprivation (n = 28) and vascular interruption (n = 34) yielded inconsistent results with high fetal mortality. We were surprised to find that fetal growth was directly and consistently related to position in the uterine horn. There is a highly significant difference (P less than .0001) in weight between siblings in the no. 1 and no. 3 positions in the rabbit uterine horn at 30 days gestation that is not present at 23 days. This "natural" runting resembles human IUGR, which occurs during the last trimester of pregnancy and shows relative brain sparing. This model, in combination with our previously reported technique for TAFF, will make possible a controlled study of the efficacy of TAFF in the treatment of IUGR.     

Current strategies for immunosuppression following liver transplantation

Background

New strategies for immunosuppression (IS) after liver transplantation (LTx) are in part responsible for the increased patient and graft survival seen over time. With a few basic exceptions—notably the continued use of steroids and calcineurin inhibitors (CNIs)—IS drugs and regimens being used today are different from those used 30 years ago. While graft loss due to acute or chronic rejection has become rare, the side effect burden of IS drugs exerts a significant toll on patients.

Concepts/trends

CNIs continue to form the backbone of IS regimens, although their use is hampered by nephrotoxicity and other adverse effects. Consequently, a variety of CNI reduction or withdrawal strategies have formed the basis of clinical trials or entered into clinical practice. These trials have included the use of everolimus, an mTOR inhibitor, and anti-interleukin-2 receptor antibodies. Basiliximab, as well as other lymphocyte nondepleting and depleting agents, have shown benefit in induction regimens.

Summary

Along with steroid reduction or elimination, current strategies for IS after LTx continue to explore novel combinations of agents, with an aim toward striking a balance between diminution of rejection and the need for avoiding adverse effects of the IS drugs. Long-term maintenance strategies are also discussed in this review, as is development of tolerance and antibody-mediated rejection.     

Effect of umbilical perfusate pH and controlled maternal hypotension on placental drug transfer in the rabbit

The purpose of this study was to explore the effect that fetal acidosis and poor maternal placental blood flow may have on the rate of passage across the placenta of drugs commonly used in labor: bupivacaine and meperidine. The rabbit placenta perfused in situ on the fetal side was used, and antipyrine (phenazone) was included as an index of placental exchange and of maternal placental flow. Bupivacaine and meperidine (both 1.25 mg/mL) and antipyrine (4 mg/mL) were infused into a maternal external jugular vein, at 3 mL/h, after loading, in seven anesthetized does. A single placenta in each doe was perfused via the umbilical arteries with Krebs' bicarbonate buffer at pH 7.5 (phase 1), 7.0 (phase 2), and 7.5 (phases 3-5). During phase 4 maternal blood was withdrawn so as to reduce maternal arterial pressure by 35%, and in phase 5 it was reinfused. Concentrations of drugs were measured during each of the five phases in maternal arterial plasma (Cma) and in the effluent perfusate collected from the umbilical vein (Cuv). From these data, placental clearance rates (Cuv x umbilical flow/Cma) were calculated for each drug at each phase. Clearance of bupivacaine and meperidine increased (P less than 0.03) during phase 2, whereas that of antipyrine did not. Clearance of meperidine and antipyrine, but not of bupivacaine, decreased during phase 4. If these results can be extrapolated to the clinical situation, they suggest that the adverse effects of drugs may well be exacerbated in the presence of fetal compromise.     

Fetal therapy with rhIGF-1 in a rabbit model of intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) may, in part, be due to a deficiency of insulin-like growth factor-1 (IGF-1). The objectives of this study were to determine the relationship between fetal serum IGF-1 levels and fetal and placental size in a rabbit model of IUGR and to compare two techniques of selective, exogenous IGF-1 administration (transamniotic and branch uterine arterial catheter infusion) to growth-retarded fetuses in utero. MATERIALS AND METHODS: Pregnant rabbits (n = 6) had their fetuses harvested near term (31 days) for fetal and placental weighing and serum collection. Growth-retarded fetuses were selectively infused for 7 days with recombinant human IGF-1 (rhIGF-1; 1,440 ng/day) either through a transamniotic catheter (n = 8) or via an adjacent uterine arterial branch catheter (n = 6). Opposite horn runts were sham catheterized, but not infused. At term, the fetal runt pairs and their placentas were harvested and weighed, and their serum was collected. The correlation between fetal and placental weight and endogenous serum IGF-1 was calculated (Pearson coefficient, r), while paired t-tests were used to compare the means between the IGF-1-infused and control groups. RESULTS: There was a significant correlation between fetal (r = 0.4230; P = 0.022) and placental weight (r = 0.4166; P = 0.025) and endogenous serum levels of IGF-1. Transamniotic infusion of rhIGF-1 was associated with an increase in serum IGF-1 level (254 +/- 79 vs 351 +/- 101 ng/ml, P = 0.04) and placental weight (5.4 +/- 2.3 vs 7.1 +/- 3.2 g, P = 0.005), and with a trend toward increased fetal weight between matched fetal runt pairs. Fetal mortality in the uterine arterial catheterized group was 76%, and there was no significant difference in fetal or placental weight or IGF-1 levels between infused and noninfused survivors. CONCLUSIONS: Endogenous fetal serum levels correlate with fetal and placental size in the rabbit IUGR model. Transamniotic administration of rhIGF-1 significantly increases serum IGF-1 levels and placental weight of fetal runts, while uterine vessel catheterization results in prohibitive fetal mortality and does not increase fetal or placental growth or IGF-1 levels.     

Perinatal bone turnover in term pregnancies: the influence of intrauterine growth restriction

Intrauterine growth restriction (IUGR) has been associated with low bone mass in infancy and increased risk for osteoporosis development in adult life. We aimed to investigate the effect of IUGR on bone metabolism in mother/infant pairs, by determining circulating biochemical markers of bone turnover in IUGR and appropriate for gestational age (AGA) pregnancies. Circulating markers of bone formation [bone specific alkaline phosphatase (BALP), total alkaline phosphatase (ALP), osteocalcin (OC)] and bone resorption [cross-linked N-telopeptide of type I collagen (NTx)], as well as intact parathormone (PTH), calcium and phosphorus levels were measured in 40 mothers and their 20 IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal days 1 (N1) and 4 (N4). No significant differences in BALP, ALP, OC, NTx, PTH, calcium or phosphorus levels were observed between the AGA and the IUGR groups. In both groups, maternal BALP levels were lower compared to fetal, N1 and N4 levels (p< or =0.005 in all cases). In the AGA group, maternal NTx and OC levels were lower compared to fetal, N1 and N4 levels (p<0.001 in all cases), and fetal NTx levels were lower compared to N1 and N4 ones (p<0.001 and p=0.002, respectively). In the IUGR group, maternal OC levels were lower compared to fetal, N1 and N4 ones (p<0.001 in each case) and fetal OC levels were elevated compared to N1 and N4 ones (p<0.001 and p=0.003, respectively). N4 NTx levels were elevated compared to maternal, fetal and N1 levels (p=0.009, p<0.001 and p=0.002, respectively) and fetal NTx levels were lower compared to N1 and N4 ones (p=0.001 and p<0.001, respectively). Finally, positive correlations were found between maternal NTx and BALP (r=0.332, p=0.037), as well as ALP (r=0.329, p=0.038) levels, and between maternal, fetal, N1, N4 BALP and respective ALP levels (r=0.432, p=0.005, r=0.534, p=0.001, r=0.778, p<0.001, r=0.694, p<0.001, respectively). In conclusion, maternal, fetal and neonatal bone turnover in IUGR cases may not differ from respective bone metabolism in AGA controls. In addition, fetal and neonatal bone remodeling is markedly enhanced and independent of maternal bone turnover in late pregnancy.     

Indoxyl sulphate and kidney disease: Causes,consequences and interventions

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m²) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest‐growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein‐bound, tryptophan‐derived metabolite that is generated by intestinal micro‐organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.     

Maternal and infant outcomes after injury during pregnancy in Washington State from 1989 to 1997

BACKGROUND: Few population-based studies have assessed maternal and infant outcomes after nonfatal injuries occurring during pregnancy. METHODS: We performed a retrospective cohort study to assess outcomes of pregnant women hospitalized for injury in Washington State from 1989 to 1997. We used the Injury Severity Score (ISS) to classify 266 nonseverely injured (ISS of 1-8) and 28 severely injured (ISS > 9) pregnant women who delivered at their injury hospitalization. We compared these women to 12,578 pregnant women randomly selected from Washington State birth and fetal death certificates who had no injury hospitalization during pregnancy. RESULTS: Nonseverely injured pregnant women were at increased risk of placental abruption and their infants were at increased risk of hypoxia and fetal death. Severely injured pregnant women were at a 17-fold (95% confidence interval, 6.2-46.8) increased risk of placental abruption and their infants were at increased risk of prematurity, low birth weight, and fetal distress, and a 30-fold (95% confidence interval, 9.4-97.1) increased risk of fetal death. CONCLUSION: Nonsevere as well as severe injuries resulting in hospitalization during pregnancy can result in adverse maternal and infant outcomes.     

The significance of intrauterine growth restriction is different from prematurity for the outcome of infants with gastroschisis

Background/purpose

Recent reviews of gastroschisis identify prematurity and low birth weight as predictors of morbidity and mortality. The authors compared the outcomes of intrauterine growth-restricted infants (IUGR) with gastroschisis to those without growth restriction because IUGR is different from prematurity.

Methods

A retrospective analysis was performed for infants born with gastroschisis between 1990 and 2000 at 2 pediatric hospitals. Patients were segregated into 3 groups based on birth weight corrected for gestational age: group 1 (IUGR, <fifth percentile), group 2 (fifth to 25th percentile), and group 3 (>25th percentile). Patient demographics, method of closure, number of surgeries, presence of atresia, and time to full enteral feedings (FPO days) were assessed. Mortality rate, length of stay (LOS), and readmission rates were also compared. Analysis of variance (ANOVA)/Student’s t test and Fisher’s. Exact tests were used for statistical analysis (P < .05 significant). Regression analysis was also performed.

Results

One hundred thirteen patients were included (group 1 = 17; group 2 = 43; group 3 = 53). Overall, infants with IUGR had similar outcomes to non-IUGR infants, including FPO and total parenteral nutrition (TPN) days, LOS, readmission, and mortality rates. The method of closure did not affect outcome. Infants with atresia had significantly increased times to full feeding (95 v 34 days; P = .034), more surgeries (2.7 v 1.4; P = .002), and longer LOS (106 v 48 days; P = .011). Infants born at less than 37 weeks’ gestation had significantly increased fasting (NPO) days (28 v 18 days; P = .005) and longer LOS (65 v 37 days; P = .006) when compared with infants born at greater than 37 weeks. Logistic regression analysis identified the presence of atresia as an independent risk factor for gastrointestinal dysfunction and the need for prolonged TPN. Prematurity also adversely affected these same parameters, although it did not reach statistical significance.

Conclusions

Although infants with gastroschisis are generally small for gestational age, the outcomes of growth-restricted infants are similar to those of other infants. The type of closure does not affect outcome, regardless of birth weight. The presence of atresia or prematurity does lead to longer times for full feeding and LOS. Therefore, routine premature delivery of infants with gastroschisis should not be advocated, even in the context of IUGR.     

Glomerular number and function are influenced by spontaneous and induced low birth weight in rats

A link exists between low birth weight and diseases in adulthood, such as hypertension, cardiovascular disease, and insulin resistance. Intrauterine growth restriction (IUGR) has been used to explain this association and has been shown to lead to a nephron endowment in humans. A reduction in glomerular number has been described in animal models with induced low birth weight as well but not in animals with spontaneous low birth weight. It therefore is debatable whether the models are suitable. The effect on glomerular number and size was studied in rats with naturally occurring IUGR and experimental IUGR, induced by bilateral uterine artery ligation. Design-based stereologic methods were used. Urinary protein excretion was determined as a measure of renal damage. Results showed a decrease of approximately 20% in glomerular number in both groups of IUGR (control 35,400, naturally occurring IUGR 30,900, and experimental IUGR 28,000 glomeruli per kidney). Mean glomerular volume was increased in both IUGR groups, which was associated with an increased proteinuria. It is concluded that IUGR leads to a nephron endowment with a compensatory glomerular enlargement. This compensation is associated with more proteinuria in the long run. Uterine artery ligation in the pregnant rat is a suitable model to study the effects of IUGR on the kidney.     

Effects of alendronate and pamidronate on cultured rat metatarsal bones: failure to prevent dexamethasone-induced growth retardation

Bisphosphonates are widely used anti-resorptive drugs in the adult population. In children, their use has mainly been limited to patients with osteogenesis imperfecta. However, the powerful effects of bisphosphonates on bone turnover have raised concern about their long-term effects on the growing skeleton. We aimed to study the effects of two commonly used bisphosphonates, alendronate (Aln) and pamidronate (Pam) on normal bone growth as well as their potential to prevent glucocorticoid-induced growth retardation. Effects on bone growth were studied in fetal rat metatarsal bones (day E20) that were cultured for 5-47 days and measured every 2-7 days. Cellular mechanisms were investigated in metatarsal bones and also in the human chondrocytic cell line HCS-2/8. Chondrocyte viability (WST-1), proliferation (BrdU incorporation), differentiation (collagen type X immunohistochemistry) and apoptosis (TUNEL and Cell Death ELISA) were determined. At a clinically relevant concentration of bisphosphonates (1 microM), metatarsal bone growth was stimulated by both Aln (p<0.001 for length and p<0.05 for width) and Pam (p<0.05 for both length and width) from day 19 of culture. The growth-stimulatory effect was associated with increased chondrocyte proliferation (+21% with Aln and +24% with Pam), while cell differentiation and apoptosis were not affected. Despite the finding that both Aln and Pam (1 muM) rescued HCS-2/8 cells from undergoing dexamethasone-induced apoptosis, neither of them was able to prevent dexamethasone-induced growth retardation of fetal rat metatarsal bones. Aln and Pam have the capacity to stimulate the growth of cultured fetal rat metatarsal bones; an effect associated with increased proliferation of growth plate chondrocytes. Our experimental data suggest that bisphosphonates are ineffective in preventing glucocorticoid-induced growth retardation. Nevertheless, based on our in vitro data, both Aln and Pam appear safe to use in growing children, at least with regard to their effects on linear bone growth.     

Extracorporeal photopheresis in the treatment of cardiac allograft rejection: A single-centre experience

Despite novel immunosuppressive (IS) protocols, adverse effects of IS drugs continue to have notable negative impact on patient and cardiac allograft survival after heart transplantation (HTx). Therefore, IS regimens with less toxic side effects are sorely needed. We aimed to evaluate the efficacy of extracorporeal photopheresis (ECP) in combination with tacrolimus-based maintenance IS therapy in the treatment of allograft rejection in adult HTx recipients. Indications for ECP included acute moderate-to-severe or persistent mild cellular rejection, or mixed rejection. Twenty-two patients underwent a median of 22(2–44) ECP treatments after HTx. Median duration of ECP course was 173.5(2–466) days. No relevant adverse effects of ECP were noted. Reduction of methylprednisolone doses was safe throughout the ECP course. ECP, used in conjunction with pharmacological anti-rejection therapy, had a successful reversal of cardiac allograft rejection, decreased the rates of subsequential rejection episodes and normalized the allograft function in patients completing the ECP course. Short- and long-term survivals were excellent (91% at 1 and 5 years post-ECP) and comparable to International Society for Heart and Lung Transplantation registry data on HTx recipient overall survival. In conclusion, ECP can be safely used for the treatment and prevention of cardiac allograft rejection in conjunction with traditional IS regimen.     

Placental,Lipid, and Glucidic Effects of Mammalian Target of Rapamycin Inhibitors: Impact on Fetal Growth and Metabolic Disorders During Pregnancy After Solid Organ Transplantation

Background

Mammalian target of rapamycin inhibitors (mTORi) are a promising new family of immunosuppressive drugs. No teratogenic effects have been reported to date. Their lipid and glucidic effects should not be underestimated, however, especially during pregnancy. Moreover, mTORi may affect fetal growth by mTOR placental activity.

Objective

Our purpose was to highlight mTORi placental impact and metabolic implications to detect possible maternal or fetal effects and define management guidelines in pregnant women after solid organ transplantation.

Methods

A literature search was performed for articles from the Medline and Pubmed databases with the use of the following keywords: mTOR inhibitors, pregnancy, placental transport, lipid metabolism, glucose metabolism.

Results

mTOR works as a positive regulator of system A, system L, and taurine placental amino acid transporter activity, which are critical for the transport of amino acids to the fetus. Exposing trophoblast cells to rapamycin reduces system L activity; therefore, treatment with rapamycin in human pregnancies could alter fetal growth with intrauterine growth restriction (IUGR). Regarding the metabolic effects mTORi increase lipolysis, impair insulin's antilipolytic effect and reduce lipid storage, which may potentially contribute to dyslipidemia. Chronic rapamycin treatment reduces adipose tissue size and β-cell mass/function, causes hyperlipidemia, severe insulin resistance, and glucose intolerance, and promotes hepatic gluconeogenesis.

Conclusions

The studies on mTORi treatment in transplanted pregnant women have not focused to date on the potential metabolic and placental effects. Selection of women at high risk for metabolic disorders could be needed and consideration of switching to another immunosuppressive drug required if diabetes and abnormal blood lipids have been diagnosed in prepregnancy counseling. It seems to be mandatory to encourage prompt reporting of any additional cases of pregnancy during mTORi exposure to provide a better understanding of the placental effects and safety profile of these immunosuppressive drugs.     

What is biparietal diameter/kidney length ratio in cases with renal hyperechogenicity?

The object of this study was to investigate the fetal biparietal diameter/kidney length ratio in normal and hyperechogenic kidneys during the 3rd trimester of gestation. Screened pregnancies were chronically hypoxic [i.e. intrauterine growth retardation (IUGR)]. Depending on the renal manifestation of the intrauterine chronic hypoxia, the cases were divided into two study groups. Group I was composed of 28 fetuses with IUGR and hyperechogenic renal medullae. Group II consisted of 62 fetuses with IUGR and normal echoic kidney. Both study groups included pregnant women from the 3rd trimester. Fetal renal hyperechogenicity is an indicator of depression of fetal renal perfusion, correlated with pathological growth in the fetal kidney development. The fetal biparietal diameter/kidney length ratio was significantly higher in hyperechogenic cases. This may also be an in utero indicator of subsequent intrauterine and neonatal complications. Detailed ultrasound examinations of renal parenchyma and length appear to be useful in the prenatal diagnosis of reduced renal perfusion and of intrauterine hypoxia, allowing detection of possible pathological fetal conditions in utero.