Umberto Simeoni

Offspring of diabetic pregnancy: Short-term outcomes

Diabetes in pregnancy has been shown to induce long-term effects in offspring. While considerable attention is focused on the increased incidence of type 2 diabetes mellitus (T2DM) in adult offspring from diabetic mothers, cardiovascular alterations, including hypertension, are also part of lifelong consequences of in-utero exposure to increased glucose concentrations. This review examines the epidemiologic and mechanistic issues involved in the developmental programming of long-term consequences in offspring of diabetic mothers, with a particular emphasis on the renal and vascular mechanisms of hypertension. The factors of increased incidence of T2DM and of obesity in adults born after exposure to diabetes during pregnancy are also discussed, as evidence is accumulating that a vicious circle involving lifelong consequences of diabetes in pregnancy in offspring contributes to the current worldwide epidemic of T2DM.

Iatrogenic events in admitted neonates: a prospective cohort study

BACKGROUND Iatrogenic events are increasingly recognised as an important problem in all people admitted to hospital. However, few epidemiological data are available for iatrogenic events in neonatal high-risk units. We aimed to assess the incidence, nature, preventability, and severity of iatrogenic events in a neonatal centre and to establish the association of patient characteristics with the occurrence of iatrogenic events in neonates. METHODS We undertook an observational, prospective study from Jan 1, 2005, to Sept 1, 2005, including all neonates admitted in the Division of Neonatology of an academic, tertiary neonatal centre in southern France. Iatrogenic events were defined as any event that compromised the safety margin for the patient, in the presence or absence of harm. The report of an iatrogenic event was voluntary, anonymous, and non-punitive. The primary outcome was the rate of iatrogenic events per 1000 patient days. FINDINGS A total of 388 patients were studied during 10 436 patient days. We recorded 267 iatrogenic events in 116 patients. The incidence of iatrogenic events was 25.6 per 1000 patient days. 92 (34%) were preventable and 78 (29%) were severe. Two iatrogenic events (1%) were fatal, but neither was preventable. The most severe iatrogenic events were nosocomial infections (49/62 [79%]) and respiratory events (nine of 26 [35%]). Cutaneous injuries were frequent (n=94) but generally minor (89 [95%]), as were medication errors (15/19 [76%]). Most medication errors occurred during administration stage (12/19 [63%]) and were ten-fold errors (nine of 19 [47%]). The major risk factors were low birthweight and gestational age (both p<0.0001), length of stay (p<0.0001), a central venous line (p<0.0001), mechanical ventilation (p=0.0021), and support with continuous positive airwary pressure (p=0.0076). INTERPRETATION Iatrogenic events occur frequently and are often serious in neonates, especially in infants of low birthweight. Improved knowledge of the incidence and characteristics of iatrogenic events, and continuous monitoring could help to improve quality of health care for this vulnerable population.

A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants.

Low birth weight (LBW) is associated with increased risk of cardiovascular diseases at adulthood. Nevertheless, the impact of LBW on the endothelium is not clearly established. We investigate whether LBW alters the angiogenic properties of cord blood endothelial colony forming cells (LBW-ECFCs) in 25 preterm neonates compared with 25 term neonates (CT-ECFCs). We observed that LBW decreased the number of colonies formed by ECFCs and delayed the time of appearance of their clonal progeny. LBW dramatically reduced LBW-ECFC capacity to form sprouts and tubes, to migrate and to proliferate in vitro. The angiogenic defect of LBW-ECFCs was confirmed in vivo by their inability to form robust capillary networks in Matrigel plugs injected in nu/nu mice. Gene profile analysis of LBW-ECFCs demonstrated an increased expression of antiangiogenic genes. Among them, thrombospondin 1 (THBS1) was highly expressed at RNA and protein levels in LBW-ECFCs. Silencing THBS1 restored the angiogenic properties of LBW-ECFCs by increasing AKT phosphorylation. The imbalance toward an angiostatic state provide a mechanistic link between LBW and the impaired angiogenic properties of ECFCs and allows the identification of THBS1 as a novel player in LBW-ECFC defect, opening new perspectives for novel deprogramming agents.

Preeclampsia-Like Symptoms Induced in Mice by Fetoplacental Expression of STOX1 Are Reversed by Aspirin Treatment

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.

Apparent Life-Threatening Events in Presumably Healthy Newborns During Early Skin-to-Skin Contact

The death or near death of a presumably healthy newborn in the delivery room is uncommon. We report here 6 cases of apparent life-threatening events (ALTEs) in the delivery room during the first 2 hours of life. In each case, the incident occurred in a healthy infant who was in a prone position on his or her mothers abdomen during early skin-to-skin contact. In most cases, the mother was primiparous, and in all cases the mother and infant were not observed during the initiation of skin-to-skin contact and breastfeeding. There are many benefits of early skin-to-skin contact and breastfeeding in the delivery room. However, in view of the risk of a rare but significant ALTE, we suggest that surveillance of newborns is needed. Although many ALTEs are apparently caused by obstruction, we suggest that a standardized investigational workup be performed after an ALTE.

Effects Of Maternally Administered Drugs On The Fetal And Neonatal Kidney

The number of pregnant women and women of childbearing age who are receiving drugs is increasing. A variety of drugs are prescribed for either complications of pregnancy or maternal diseases that existed prior to the pregnancy. Such drugs cross the placental barrier, enter the fetal circulation and potentially alter fetal development, particularly the development of the kidneys. Increased incidences of intrauterine growth retardation and adverse renal effects have been reported. The fetus and the newborn infant may thus experience renal failure, varying from transient oligohydramnios to severe neonatal renal insufficiency leading to death. Such adverse effects may particularly occur when fetuses are exposed to NSAIDs, ACE inhibitors and specific angiotensin II receptor type 1 antagonists. In addition to functional adverse effects, in utero exposure to drugs may affect renal structure itself and produce renal congenital abnormalities, including cystic dysplasia, tubular dysgenesis, ischaemic damage and a reduced nephron number. Experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood. Although neonatal data for many drugs are reassuring, such findings stress the importance of long-term follow-up of infants exposed in utero to certain drugs that have been administered to the mother.

[Breast feeding: health benefits for child and mother].

The prevalence of breastfeeding in France is one of the lowest in Europe: 65% of infants born in France in 2010 were breastfed when leaving the maternity ward. Exclusive breastfeeding allows normal growth until at least 6 months of age, and can be prolonged until the age of 2 years or more, provided that complementary feeding is started after 6 months. Breast milk contains hormones, growth factors, cytokines, immunocompetent cells, etc., and has many biological properties. The composition of breast milk is influenced by gestational and postnatal age, as well as by the moment of the feed. Breastfeeding is associated with slightly enhanced performance on tests of cognitive development. Exclusive breastfeeding for at least 3 months is associated with a lower incidence and severity of diarrhoea, otitis media and respiratory infection. Exclusive breastfeeding for at least 4 months is associated with a lower incidence of allergic disease (asthma, atopic dermatitis) during the first 2 to 3 years of life in at-risk infants (infants with at least one first-degree relative presenting with allergy). Breastfeeding is also associated with a lower incidence of obesity during childhood and adolescence, as well as with a lower blood pressure and cholesterolemia in adulthood. However, no beneficial effect of breastfeeding on cardiovascular morbidity and mortality has been shown. Maternal infection with hepatitis B and C virus is not a contraindication to breastfeeding, as opposed to HIV infection and galactosemia. A supplementation with vitamin D and K is necessary in the breastfed infant. Very few medications contraindicate breastfeeding. Premature babies can be breastfed and/or receive mothers milk and/or bank milk, provided they receive energy, protein and mineral supplements. Return to prepregnancy weight is earlier in breastfeeding mothers during the 6 months following delivery. Breastfeeding is also associated with a decreased risk of breast and ovarian cancer in the premenopausal period, and of osteoporosis in the postmenopausal period.

Adverse consequences of accelerated neonatal growth: cardiovascular and renal issues

Epidemiological and experimental studies show that the risk of cardiovascular and metabolic diseases at adulthood is inversely related to the weight at birth. Although with less evidence, low birth weight has been suggested to increase the risk of chronic kidney disease (CKD). It is well established that the developmental programming of arterial hypertension and of renal disease involves in particular renal factors, especially nephron endowment, which is reduced in low birth weight and maternal diabetes situations. Experimental studies, especially in rodents, have demonstrated the long-term influence of postnatal nutrition and/or postnatal growth on cardiovascular, metabolic and renal functions, while human data are scarce on this issue. Vascular and renal diseases appear to have a “multihits” origin, with reduced nephron number the initial hit and rapid postnatal growth the second hit. This review addresses the current understanding of the role of the kidney, both as a mechanism and as a target, in the developmental origins of adult disease theory, with a particular focus on the long-term effects of postnatal growth and nutrition.

Cullins in human intra-uterine growth restriction: expressional and epigenetic alterations.

Intra-uterine growth restriction (IUGR) is defined by a restriction of fetal growth during gestation. It is a prevalent significant public health problem that jeopardizes neonatal health but also that can have deleterious consequences later in adult life. Cullins constitute a family of seven proteins involved in cell scaffold and in selective proteolysis via the ubiquitin-proteasome system. Most Cullins are critical for early embryonic development and mutations in some Cullin genes have been identified in human syndromes including growth retardation. Our work hypothesis is that Cullins, particularly CUL4B and CUL7, are involved in placental diseases and especially in IUGR. Thus, expression of Cullins and their cofactors was analyzed in normal and pathological placentas. We show that they present a constant significant over-expression in IUGR placentas, whose extent is dependent on the position of the interrogated fragment along the cDNAs, suggesting the existence of different isoforms of the genes. Particularly, the CUL7 gene is up-regulated up to 10 times in IUGR and 15 times in preeclampsia associated with IUGR. The expression of cofactors of Cullins participating to functional complexes has also been evaluated and showed a similar significant increase in IUGR. Promoters of Cullin genes appeared to be under the control of the SP1 transcription factor. Finally, methylation levels of the CUL7 promoter in placental tissues are modulated according to the pathological conditions, with a significant hypomethylation in IUGR. These results concur to pinpoint the Cullin family as a new set of markers of IUGR.

The Intensity of IUGR-Induced Transcriptome Deregulations Is Inversely Correlated with the Onset of Organ Function in a Rat Model

A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised.