Stavros Sifakis

Intrauterine inflammation and preterm delivery

Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Specifically, chronic amniotic fluid inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, viral infections also appear to be involved. Recently, molecular genetic techniques have helped us better understand the underlying pathophysiologic processes. This is especially important because epidemiological and experimental studies indicate that intrauterine infection and inflammation constitute a risk factor for adverse neurological outcome in preterm infants. Chronic subclinical chorioamnionitis associated with preterm birth can also modify lung development. Although no current clinical strategy is aimed at adapting the maternofetal inflammatory response, immunomodulators may serve as a future intervention in preterm embryos.

DNA methylation in the human placenta and fetal growth (Review)

Throughout in utero development, the placenta plays a key role in controlling growth and development. The placenta acts not only as a gatekeeper of nutrient and waste exchange between mother and developing fetus, but also as a regulator of the intrauterine environment. Its functions can be influenced by the environment encountered throughout pregnancy, thereby altering the appropriate genetic programming needed to allow for appropriate fetal growth. Epigenetic alterations related to environmental exposures have been linked to aberrant fetal growth. DNA methylation, which is the best known DNA epigenetic modification, may provide an attractive mechanism linking environmental cues to placental pathology, with consequences for fetal growth and adult life. Alteration of the methylation patterns of genes expressed in the placenta has recently been found to modify gene expression and subsequently impair function of the placenta. Although there is strong evidence to demonstrate that the environment can affect the pattern of DNA methylation of the placenta during fetal development, a direct association between environmental conditions, methylation alterations and gene expression is difficult to confirm. DNA methylation in the placenta has mainly been investigated in the context of imprinted and non-imprinted genes transcription. Several environmental factors have also been assessed in regard to their association with changes to the epigenetic motives of embryonic and extraembryonic tissues and their impact on pregnancy outcome. In this review, we briefly present the available evidence regarding the role of DNA methylation patterns of the placenta on aberrant fetal growth.

First-trimester maternal plasma cell-free fetal DNA and preeclampsia

OBJECTIVE The purpose of this study was to determine whether, in pregnancies that experience preeclampsia, plasma cell-free fetal DNA (cffDNA) at 11-13 weeks of gestation is increased and whether this increase is related to the uterine artery pulsatility index (PI). STUDY DESIGN Plasma cffDNA and uterine artery PI were measured in 44 cases with preeclampsia, which included 11 cases that required delivery at <34 weeks of gestation and 176 normal control subjects. All fetuses were male, and cffDNA was assessed by amplification of the DYS14 gene. The association between cffDNA and uterine artery PI was assessed by regression analysis. RESULTS Median cffDNA was higher in early preeclampsia (median, 95.5 genome equivalents/mL; interquartile range, 72.7-140.9 genome equivalents/mL), but not late preeclampsia (median, 50.8 genome equivalents/mL; interquartile range, 25.0-103.8 genome equivalents/mL), than control subjects (median, 51.5 genome equivalents/mL; interquartile range, 31.1-84.9 genome equivalents/mL). There was a significant association between cffDNA and uterine artery PI (P = .038) but not in the control subjects (P = .174). CONCLUSION The increase in plasma cffDNA in pregnancies that experience preeclampsia is associated with the degree of impairment in placental perfusion.

The impact of fetal echocardiography on the prevalence of liveborn congenital heart disease

Fetal echocardiography allows for early detection of congenital heart disease, and pregnancy termination may be an option in cases of complex defects. In the current study, the most important factors contributing to the diagnosis and termination of affected pregnancies are reviewed and their combined effect on the future prevalence of liveborn congenital heart disease is evaluated. The relative reduction of the prevalence of the most severe forms of congenital heart disease is estimated as the product of the probability that (1) a fetal cardiac screening is performed (pevaluation), (2) an affected pregnancy is detected (Pdetection), (3) pregnancy termination is decided following antenatal diagnosis (Pdecision). In areas where termination of pregnancy is a realistic and supported option, a universal sonographic screening of all pregnancies (Pevaluation = 1), with an average reported sensitivity of 35% and a termination rate of 43% following antenatal diagnosis, would result in a 15% overall reduction of the prevalence of the most severe forms of congenital heart disease. However, wide variability exists regarding the defect-specific estimates (2–50% prevalence relative reduction) due to considerable differences in the reported diagnostic sensitivity and termination rates associated with each heart defect. If an earlier diagnosis could be achieved, which is reported to be associated with an average 1.4-fold increased probability of termination, the overall reduction of the prevalence of congenital heart disease could approach 21%. As the skills of obstetric and pediatric cardiology sonographers improve, fetal echocardiography is expected to have a substantial impact on the future epidemiology of liveborn congenital heart disease.

Angiogenic factors in placentas from pregnancies complicated by fetal growth restriction (Review)

The placenta is the organ that is responsible for providing the developing fetus with all the nutrients necessary for its growth and is also responsible for removing fetal waste. Placentation is a crucial process that includes angiogenesis. Angiogenesis involves not only the fetal circulation, but also placental and endometrial vascular changes. In this study, we review the literature regarding any impairment in the angiogenic process in placentas from pregnancies complicated by fetal growth restriction (FGR). Angiogenesis is regulated by a list of factors, also known as growth factors, such as the vascular endothelial growth factor (VEGF), the placental growth factor (PlGF) and the basic fibroblastic growth factor (bFGF), as well as the partial pressure of oxygen in the fetoplacental vessels. Other factors, such as transcriptional factors, also play a pivotal role, controlling the above-mentioned growth factors. Alterations in these pathways have been described in cases of growth-restricted fetuses. In this review, we provide an insight into these processes and identify the most crucial factors involved.

Previous Gestational Diabetes Mellitus and Markers of Cardiovascular Risk

The prevalence of gestational diabetes mellitus (GDM) in the developed world has increased at an alarming rate over the last few decades. GDM has been shown to be associated with postpartum diabetes, insulin resistance, hypertension, and dyslipidemia. A history of previous GDM (pGDM), associated or not with any of these metabolic abnormalities, can increase the risk of developing not only type 2 diabetes mellitus but also cardiovascular disease (CVD) independent of a diagnosis of type 2 diabetes later in life. In this paper we discuss the relationship among inflammatory markers, metabolic abnormalities, and vascular dysfunction in women with pGDM. We also review the current knowledge on metabolic modifications occurring in normal pregnancy and the link between alterations of a normal metabolic state with the long-term maternal complications that may result in increased CVD risk. Our review of studies on pGDM prompts us to recommend that these women be considered a population at risk for later CVD events, which however could be avoided via the use of specially designed follow-up programs in the future.

Detection of interleukin-6, interleukin-8, and interleukin-11 in plasma from women with spontaneous abortion

OBJECTIVE To investigate the role of IL-6, IL-8, and IL-11 in the immune-regulatory mechanisms involved in the spontaneous abortion of the first trimester of pregnancy. STUDY DESIGN Plasma levels of IL-6, IL-8, and IL-11 were determined in 68 women who had a spontaneous abortion of unknown aetiology during the first trimester of pregnancy. They were compared with the corresponding levels of 73 age-matched pregnant women who had an uneventful pregnancy, and 52 age-matched non-pregnant women. All enrolled women presented without any severe disease, syndrome or recent infection. Cytokine levels were measured by a sensitive sandwich enzyme-linked immunoassay. RESULTS The women with spontaneous abortion had significantly decreased plasma levels of IL-6, IL-8 and IL-11 compared to those with normal pregnancies (P<0.05). The non-pregnant women had no detectable cytokine levels. CONCLUSIONS The reduced plasma levels of IL-6, IL-8 and IL-11 in women with spontaneous abortion may be related to the underlying aetiopathogenetic mechanisms, however, there is no sufficient evidence for their use as predictive markers of pregnancy outcome.

Placental growth factor (PlGF): a key to optimizing fetal growth

Abstract The needs of the uterus and the fetus for the provision of nutrients and oxygen, supplied by the blood flow, are understandably extremely high, with the circulatory system playing the most important role in this action. Abnormal vascular growth and transformation that create a high vessel resistance network have been associated with various pregnancy pathologies, including miscarriage, small for gestational age (SGA) fetuses with or without preeclampsia and intrauterine growth restriction (IUGR). Placental growth factor (PlGF) has a major role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF and high concentrations of its inhibitor-soluble Fms-like tyrosine kinase-1 (sFlt-1) are linked with impaired angiogenesis and placental development, leading to the above pregnancy complications. The activity of vascular endothelial growth factor (VEGF), which is the most potent of all angiogenic mediators, is partly modulated by PlGF. Although the mechanisms via which PlGF exerts its various effects are still under investigation, we herein discuss the known actions exerted by this major mediator together with its results on fetal growth.

Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

The objective of this study was to investigate the hypothesis that the altered epigenetic mechanisms that regulate IGF2 imprinting in placentas from fetal growth restricted (FGR) pregnancies affect IGF2 expression leading to impaired fetal growth. We investigated gene transcription, genotyping and the methylation patterns of IGF2 from 31 and 17 placentas from FGR-complicated and normal pregnancies, respectively. A statistically significant decrease in IGF2 mRNA levels was observed in the placentas from the FGR pregnancies. Loss of imprinting (LOI) was only detected in the abnormal placentas. The evaluation of the percentage of the methylated reference (PMR) of two different potentially differentially methylated regions (DMR) demonstrated significant PMR values in both sites for the normal and FGR pregnancies with no significant differences. Our results suggest the involvement of the IGF2 imprinted gene in placental function and fetal growth and the possible association of epigenetic alterations with the pathophysiology of fetal growth restriction.

Decreased placental expression of hPGH, IGF-I and IGFBP-1 in pregnancies complicated by fetal growth restriction

OBJECTIVE The human Placental Growth Hormone (hPGH) and the Insulin-like Growth Factor (IGF) system are implicated in fetal development. This study aimed to evaluate the expression of hPGH, IGF-I, IGFBP-1 and IGFBP-3 genes in placentas from pregnancies complicated by fetal growth restriction (FGR). DESIGN The study group was comprised of term placentas from 47 FGR-complicated pregnancies of no recognizable cause. Thirty-seven placentas from normal pregnancies with appropriate for gestational age birth weight were used as controls. The expression status of the genes was evaluated by quantitative real-time PCR. RESULTS hPGH, IGF-I and IGFBP-1 exhibited significantly lower expression compared to the controls (p=0.003, p=0.049 and p=0.001, respectively). Numerically, lower IGFBP-3 expression was also demonstrated in the FGR-affected group, without however reaching statistical significance (p=0.129). Significant co-expression patterns were detected among the study genes in both the FGR and normal pregnancies. CONCLUSION Decreased placental expression levels of hPGH, IGF-I and IGFBP-1 were demonstrated in pregnancies with FGR. Whether these alterations are a causative factor of FGR or accompany other pathogenetic mechanisms requires further investigation.