Silvia Visentin

Aortic intima media thickness in fetuses and children with intrauterine growth restriction.

OBJECTIVE: To measure aortic intima media thickness and diameter by ultrasonography in fetuses with intrauterine growth restriction (IUGR) and in appropriate for gestational age (AGA) fetuses and in the same children after a mean follow-up of 18 months. METHODS: This was a prospective study performed between January 2006 and August 2008. Fetuses were classified as having IUGR if the estimated fetal weight was below the 10th percentile and umbilical artery pulsatility index was greater than 2 standard deviations; they were classified as AGA if the estimated fetal weight was between the 10th and 90th percentiles. Abdominal aortic intima media thickness and diameter were measured in each fetus with IUGR and in each AGA fetus at a mean gestational age of 32 weeks. The same measurements were taken in the children after a mean follow-up of 18 months. RESULTS: Thirty-eight fetuses with IUGR and 32 AGA fetuses were enrolled in the study. Aortic intima media thickness median values were significantly higher in IUGR than in AGA both in utero (1.9 mm compared with 1.15 mm; P<.001) and after birth (2.4 mm compared with 1.03 mm; P<.001) and were significantly correlated (P=.018, r=0.48). At 32 weeks of gestation, aortic intima media thickness in fetuses with IUGR was inversely correlated with estimated fetal weight (P<.003; r=−0.58). Median diameter of the abdominal aorta and blood-flow velocity at 32 weeks of gestation were significantly higher in fetuses with IUGR compared with AGA fetuses (median diameter 4.5 mm compared with 3.6 mm, P<.001, blood-flow velocity 42.5 cm/s compared with 23.3 cm/s, P<.001). At follow-up, in 25 children who had had IUGR and 25 children who had been AGA, there was no significant difference in median diameter of the abdominal aorta (6.8 mm compared with 7.5 mm, P=.21). CONCLUSION: Aortic wall thickening in fetuses and children with IUGR shows differences with respect to those who were AGA. This may reflect a correlation between impaired growth in utero, Doppler abnormalities, low birth weight, and early signs of vascular dysfunction. LEVEL OF EVIDENCE: II

Early Primary Cytomegalovirus Infection in Pregnancy: Maternal Hyperimmunoglobulin Therapy Improves Outcomes Among Infants at 1 Year of Age

BACKGROUND Primary cytomegalovirus (CMV) infection during pregnancy is the leading infectious cause of congenital neurological disabilities. Early CMV infection carries a higher risk of adverse neonatal outcome (sensorineural hearing loss or neurological deficits). Intravenous hyperimmunoglobulin (HIG) therapy seems to be promising, but its efficacy needs further investigation. METHODS Since 2002, we have enrolled consecutively all pregnant women with early (ie, before gestational week 17) CMV infection. Beginning in 2007, all women were offered treatment with HIG (200 UI per kilogram of maternal weight, in a single intravenous administration). Outcome of infants was evaluated at the age of 1 year. RESULTS Of the 592 women with early primary CMV infection, amniocentesis for CMV DNA detection was performed for 446. Of the 92 CMV-positive fetuses, pregnancy was terminated for 24, HIG was administered to mothers of 31, and no treatment was received by mothers of 37. Fetuses of treated mothers did not differ from fetuses of nontreated mothers according to mothers age, gestational week of infection, CMV load, or detection of abnormal ultrasonography findings. At the 1-year evaluation, 4 of 31 infants with treated mothers (13%; 95% confidence interval [CI], 1%-25%) and 16 of 37 infants with nontreated mothers (43%; 95% CI, 27%-59%) presented with poor outcomes (P < .01, by the 2-tailed Fisher exact test). CONCLUSIONS HIG treatment improved the outcome of fetuses from women who had primary CMV infection before gestational week 17.

Cord blood metabolomic profiling in intrauterine growth restriction

A number of metabolic abnormalities have been observed in pregnancies complicated by intrauterine growth restriction (IUGR). Metabolic fingerprinting and clinical metabolomics have recently been proposed as tools to investigate individual phenotypes beyond genomes and proteomes and to advance hypotheses on the genesis of diseases. Non-targeted metabolomic profiling was employed to study fetal and/or placental metabolism alterations in IUGR fetuses by liquid chromatography high-resolution mass spectrometry (LC-HRMS) analysis of cord blood collected soon after birth. Samples were collected from 22 IUGR and 21 appropriate for gestational age (AGA) fetuses. Birth weight differed significantly between IUGR and AGA fetuses (p < 0.001). Serum samples were immediately obtained and deproteinized by mixing with methanol at room temperature and centrifugation; supernatants were lyophilized and reconstituted in water for analysis. LC-HRMS analyses were performed on an Orbitrap mass spectrometer linked to a Surveyor Plus LC. Samples were injected into a 1.0 × 150-mm Luna C18 column. Spectra were collected in full-scan mode at a resolution of approximately 30,000. Data were acquired over the m/z range of 50–1,000, with measurements performed in duplicate. To observe metabolic variations between the two sets of samples, LC-HRMS data were analyzed by a principal component analysis model. Many features (e.g., ionic species with specific retention times) differed between the two classes of samples: among these, the essential amino acids phenylalanine, tryptophan, and methionine were identified by comparison with available databases. Logistic regression coupled to a receiver-operating characteristic curve identified a cut-off value for phenylalanine and tryptophan, which gave excellent discrimination between IUGR and AGA fetuses. Non-targeted LC-HRMS analysis of cord blood collected at birth allowed the identification of significant differences in relative abundances of essential amino acids between IUGR and AGA fetuses, emerging as a promising tool for studying metabolic alterations.

Early origins of adult disease: Low birth weight and vascular remodeling

Cardiovascular diseases (CVD) and diabetes still represent the main cause of mortality and morbidity in the industrialized world. Low birth weight (LBW), caused by intrauterine growth restriction (IUGR), was recently known to be associated with increased rates of CVD and non-insulin dependent diabetes in adult life (Barkers hypothesis). Well-established animal models have shown that environmentally induced IUGR (diet, diabetes, hormone exposure, hypoxia) increases the risk of a variety of diseases later in life with similar phenotypic outcomes in target organs. This suggests that a range of disruptions in fetal and postnatal growth may act through common pathways to regulate the developmental programming and produce a similar adult phenotype. The identification of all involved signaling cascades, underlying the physiopathology of these damages in IUGR fetuses, with their influence on adult health, is still far from satisfactory. The endothelium may be important for long-term remodeling and in the control of elastic properties of the arterial wall. Several clinical and experimental studies showed that IUGR fetuses, neonates, children and adolescents present signs of endothelial dysfunction, valuated by aorta intima media thickness, carotid intima media thickness and stiffness, central pulse wave velocity, brachial artery flow-mediated dilation, laser Doppler skin perfusion and by the measure of arterial blood pressure. In utero identification of high risk fetuses and long-term follow-up are necessary to assess the effects of interventions aimed at preventing pregnancy-induced hypertension, reducing maternal obesity, encouraging a healthy life style and preventing childhood obesity on adult blood pressure and cardiovascular disease in later life.

Intrauterine growth restriction is associated with persistent aortic wall thickening and glomerular proteinuria during infancy

Low birth weight, caused either by preterm birth or by intrauterine growth restriction, has recently been associated with increased rates of adult renal and cardiovascular disease. Since aortic intima–media thickening is a noninvasive marker of preclinical vascular disease, we compared abdominal aortic intima–media thickness among intrauterine growth restricted and equivalent gestational age fetuses in utero and at 18 months of age. The relationship between intrauterine growth restriction, fetal aortic thickening, and glomerular function during infancy was measured by enrolling 44 mothers with single-fetus pregnancies at 32 weeks gestation: 23 growth restricted and 21 of appropriate gestational age as controls. Abdominal aortic intima–media thickness was measured by ultrasound at enrollment and again at 18 months of age. Fetuses with intrauterine growth restriction had significantly higher abdominal aortic intima–media thickness compared with age controls when measured both in utero and at 18 months. At 18 months, the median urinary microalbumin and median albumin–creatinine ratio were significantly higher in those infants who experienced intrauterine growth restriction compared to the controls. Our results show that intrauterine growth restriction is associated with persistent aortic wall thickening and significantly higher microalbuminuria during infancy.

Consequences in Infants That Were Intrauterine Growth Restricted

Intrauterine growth restriction is a condition fetus does not reach its growth potential and associated with perinatal mobility and mortality. Intrauterine growth restriction is caused by placental insufficiency, which determines cardiovascular abnormalities in the fetus. This condition, moreover, should prompt intensive antenatal surveillance of the fetus as well as follow-up of infants that had intrauterine growth restriction as short and long-term sequele should be considered.

Changes in amniotic fluid and umbilical cord serum proteomic profiles of foetuses with intrauterine growth retardation

Foetal growth is a result of a complex net of processes, requiring coordination within the maternal, placental, and foetal compartments, the imbalance or lack of which may lead to intrauterine growth restriction (IUGR). IUGR is the major cause of perinatal morbidity and mortality, and is also related to enhanced morbidity and metabolic abnormalities later in life. In the present study, the protein profiles of umbilical cord serum (UCS) and amniotic fluid (AF) of ten IUGR and ten appropriate for gestational age newborns have been analysed by 2‐DE, and nanoHPLC‐Chip/MS technology. A total of 18 and 13 spots were found to be differentially expressed (p<0.01) in UCS and AF respectively. The unique differentially expressed proteins identified by MS/MS analysis were 14 in UCS, and 11 in AF samples. Protein gene ontology classification indicate that 21% of proteins are involved in inflammatory response, 20% in immune response, while a smaller proportion are related to transport, blood pressure, and coagulation. These results support the conclusion that the IUGR condition alters the expression of proteins involved in the coagulation process, immune mechanisms, blood pressure and iron and copper homeostasis control, offering a new insight into IUGR pathogenesis.

Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: The PREGNANTS study

BACKGROUND: Antiphospholipid syndrome is an autoimmune, hypercoagulable state that is caused by antiphospholipid antibodies. Anticardiolipin antibodies, anti‐&bgr;2 glycoprotein‐I, and lupus anticoagulant are the main autoantibodies found in antiphospholipid syndrome. Despite the amassed body of clinical knowledge, the risk of obstetric complications that are associated with specific antibody profile has not been well‐established. OBJECTIVE: The purpose of this study was to assess the risk of obstetric complications in women with primary antiphospholipid syndrome that is associated with specific antibody profile. STUDY DESIGN: The Pregnancy In Women With Antiphospholipid Syndrome study is a multicenter, retrospective, cohort study. Diagnosis and classification of antiphospholipid syndrome were based on the 2006 International revised criteria. All women included in the study had at least 1 clinical criteria for antiphospholipid syndrome, were positive for at least 1 antiphospholipid antibody (anticardiolipin antibodies, anti‐&bgr;2 glycoprotein‐I, and/or lupus anticoagulant), and were treated with low‐dose aspirin and prophylactic low molecular weight heparin from the first trimester. Only singleton pregnancies with primary antiphospholipid syndrome were included. The primary outcome was live birth, defined as any delivery of a live infant after 22 weeks gestation. The secondary outcomes were preeclampsia with and without severe features, intrauterine growth restriction, and stillbirth. We planned to assess the outcomes that are associated with the various antibody profile (test result for lupus anticoagulant, anticardiolipin antibodies, and anti‐&bgr;2 glycoprotein‐I). RESULTS: There were 750 singleton pregnancies with primary antiphospholipid syndrome in the study cohort: 54 (7.2%) were positive for lupus anticoagulant only; 458 (61.0%) were positive for anticardiolipin antibodies only; 128 (17.1%) were positive for anti‐&bgr;2 glycoprotein‐I only; 90 (12.0%) were double positive and lupus anticoagulant negative, and 20 (2.7%) were triple positive. The incidence of live birth in each of these categories was 79.6%, 56.3%, 47.7%, 43.3%, and 30.0%, respectively. Compared with women with only 1 antibody positive test results, women with multiple antibody positive results had a significantly lower live birth rate (40.9% vs 56.6%; adjusted odds ratio, 0.71; 95% confidence interval, 0.51–0.90). Also, they were at increased risk of preeclampsia without (54.5% vs 34.8%; adjusted odds ratio, 1.56; 95% confidence interval, 1.22–1.95) and with severe features (22.7% vs 13.8%, adjusted odds ratio, 1.66; 95% confidence interval, 1.19–2.49), of intrauterine growth restriction (53.6% vs 40.8%; adjusted odds ratio, 2.31; 95% confidence interval, 1.17–2.61) and of stillbirth (36.4% vs 21.7%; adjusted odds ratio, 2.67; 95% confidence interval, 1.22–2.94). In women with only 1 positive test result, women with anti‐&bgr;2 glycoprotein‐I positivity present alone had a significantly lower live birth rate (47.7% vs 56.3% vs 79.6%; P<.01) and a significantly higher incidence of preeclampsia without (47.7% vs 34.1% vs 11.1%; P<.01) and with severe features (17.2% vs 14.4% vs 0%; P=.02), intrauterine growth restriction (48.4% vs 40.1% vs 25.9%; P<.01), and stillbirth (29.7% vs 21.2% vs 7.4%; P<.01) compared with women with anticardiolipin antibodies and with women with lupus anticoagulant present alone, respectively. In the group of women with >1 antibody positivity, triple‐positive women had a lower live birth rate (30% vs 43.3%; adjusted odds ratio,0.69; 95% confidence interval, 0.22–0.91) and a higher incidence of intrauterine growth restriction (70.0% vs 50.0%; adjusted odds ratio,2.40; 95% confidence interval, 1.15–2.99) compared with double positive and lupus anticoagulant negative women. CONCLUSION: In singleton pregnancies with primary antiphospholipid syndrome, anticardiolipin antibody is the most common sole antiphospholipid antibody present, but anti‐&bgr;2 glycoprotein‐I is the one associated with the lowest live birth rate and highest incidence of preeclampsia, intrauterine growth restriction, and stillbirth, compared with the presence of anticardiolipin antibodies or lupus anticoagulant alone. Women with primary antiphospholipid syndrome have an increased risk of obstetric complications and lower live birth rate when <1 antiphospholipid antibody is present. Despite therapy with low‐dose aspirin and prophylactic low molecular weight heparin, the chance of a liveborn neonate is only 30% for triple‐positive women.

Fetal aorta wall inflammation in ultrasound-detected aortic intima/media thickness and growth retardation

Several studies have reported that fetuses with intrauterine growth restriction (IUGR) and infants with low birth weight present increased intima/media thickness (aIMT) of the abdominal aorta wall compared with fetuses and infants appropriate for gestational age (AGA). Evidence suggested that aIMT might be related to inflammation, probably indicating a very early stage of future adulthood disease, such as atherosclerosis. We aimed to investigate histological findings in the abdominal aorta wall of one IUGR stillbirth in which ultrasound had detected aIMT. Microscopy observations of the abdominal aorta wall confirmed the intima thickening and detected condensation of the elastic fibers forming an evident internal elastic membrane and presence of inflammatory elements, such as macrophages, activated endothelial cells, and fibroblastoid cells. The present study highlights that IUGR associated with aIMT is related to inflammation, which might represent a very early sign of future adult lesions.

Fetal aortic wall thickness: a marker of hypertension in IUGR children?

Fetuses with intrauterine growth restriction (IUGR) have significant aortic intima-media thickening (aIMT), which suggests that preclinical atherosclerosis might predispose the infants to hypertension. However, the natural course of aIMT in babies with IUGR remains an open question.The study enrolled 77 pregnant women between January 2007 and August 2009. The fetuses were classified as AGA (appropriate for gestational age) or IUGR, if the estimated fetal weight was between the 10th and 90th percentile or below the 10th percentile (with umbilical artery pulsatility index (PI) >2s.d.), respectively. Anthropometric parameters and aIMT were detected in each IUGR and AGA fetus at a mean gestational age of 32 weeks. The follow-up was performed in 25 IUGR and 25 AGA infants at a mean postnatal age of 18 months; the previous measurements were repeated, and blood pressure measurements were taken. The maximum aIMT was significantly higher in the IUGR fetuses and infants compared with the AGA infants, both in utero (2.05±0.43 vs. 1.05±0.19 mm, P<0.001) and at the follow-up (2.3±0.8 vs. 1.06±0.18 mm, P<0.0001), the resulting values significantly correlated (P=0.018) with one another. The systolic blood pressure was significantly increased in the IUGR subjects (123±16 vs. 104±8.5 mm Hg, P<0.0004), and it correlated with the prenatal and postnatal aIMT values (P<0.0156 and P<0.0054, respectively). The aortic wall thickening progression in IUGR fetuses and infants differed from AGA, which may predispose the infants to hypertension early in life and cardiovascular risk later in life.