Arterial health during early childhood following abnormal fetal growth

Background Abnormal fetal growth is associated with increased cardiovascular risk in adulthood. We investigated the effect of fetal programming on arterial health and morphology during early childhood. Methods We examined 90 children (median age 5.81 years, interquartile range: 5.67; 5.95), born small for gestational age with fetal growth restriction, large or appropriate for gestational age (SGA, N = 23, LGA, N = 19, AGA N = 48). We measured body composition, anthropometrics, blood pressure, pulse wave velocity (PWV), lipids, glucose and inflammatory markers, and assessed carotid, brachial, radial and femoral arterial morphology and stiffness using very-high resolution ultrasound (46–71 MHz). Results LGA showed increased anthropometry, lean body mass and body mass index. SGA displayed decreased anthropometry and lean body mass. Blood pressure, PWV, carotid artery stiffness and blood work did not differ groupwise. Differences in lumen diameters, intima-media thicknesses (IMT) and adventitia thicknesses disappeared when adjusted for lean body mass and sex. In multiple regression models arterial dimensions were mainly predicted by lean body mass, with birth weight remaining associated only with carotid and brachial lumen dimensions, and not with IMTs. Carotid-femoral PWV was predicted by height and blood pressure only. No independent effect of adiposity was observed. Conclusions Arterial dimensions in childhood associate with current anthropometrics, especially lean body mass, and sex, explaining differences in arterial layer thickness. We found no signs of fetal programming of cardiovascular risk or arterial health in early childhood.

Antiphospholipid antibodies, genetic thrombophilia and fetal growth retardation

Aim: to study the role of antiphospholipid antibodies (AРA) and genetic thrombophilia as a potential cause of the development or a component in the pathogenesis of early and late fetal growth retardation (FGR).Materials and Methods. There was conducted a prospective randomized controlled trial with 118 women enrolled. The main group consisted of 83 patients, whose pregnancy was complicated by FGR degrees II and III, stratified into two groups: group 1 – 36 pregnant women with early FGR, group 2 – 47 pregnant women with late FGR. Women were subdivided into subgroups according to the FGR severity. The control group consisted of 35 pregnant women with a physiological course of pregnancy. АРА were determined according to the Sydney antiphospholipid syndrome criteria by enzyme immunoassay (ELISA): against cardiolipin, β2 -glycoprotein 1, annexin V, prothrombin, etc. (IgG/IgM isotypes); lupus anticoagulant – by the three-stage method with Russell's viper venom; antithrombin III and protein C levels – by chromogenic method; prothrombin gene polymorphisms G20210A and factor V Leiden – by polymerase chain reaction; homocysteine level – by ELISA.Results. AРA circulation (medium and high titers), genetic thrombophilic defects and/or hyperhomocysteinemia were detected in 40 (48.2 %) patients with FGR, which was significantly higher than that in the control group (p < 0.05): in group 1 (41.7 % of women) AРA (30.6 %) and AРA with genetic thrombophilia or hyperhomocysteinemia (11.1 %) were revealed; in group 2 (51.1 % of women) AРA (21.3 %), AРA with hyperhomocysteinemia (4.3 %), genetic thrombophilia (25.5 %), and due to hyperhomocysteinemia (2.1 %) were found. No differences in prevalence of thrombophilia rate in patients were observed related to FGR severity, but a correlation between the FGR severity and AРA titers was found.Conclusion. Testing for the presence of AРA, genetic thrombophilia and hyperhomocysteinemia should be recommended for patients with FGR (including those with FGR in medical history), especially in the case of its early onset. It is recommended to determine the full AРA spectrum.

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a “rebound” vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. What is New:• The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension.• The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Maternal polymorphic loci of rs1979277 serine hydroxymethyl transferase and rs1805087 5-methylenetetrahydrofolate are correlated with the development of fetal growth restriction: A case-control study

Background: Key reactions in folate-mediated single-carbon metabolism are regulated by folate cycle enzymes. Violations of the folate cycle may be associated with the occurrence of fetal growth restriction (FGR) in pregnant women. Objective: To study the relationship between polymorphisms of folate cycle genes in the mother with the development of FGR. Materials and Methods: In this case-control study, 122 pregnant women with FGR and 243 pregnant women with normal newborn weight were enrolled. The polymorphic loci of folate cycle genes including rs1805087 5-methylenetetrahydrofolate (MTR) and rs1979277 serine hydroxymethyl transferase (SHMT1) were examined. The study of polymorphisms was carried out through the TaqMan probe detection method using polymerase chain reaction. Logistic regression was used to analyze the associations of the polymorphisms. Results: It was established that the T allele rs1979277 of the SHMT1 gene was correlated with the development of FGR within the framework of the allelic (OR = 1.67, 95% CI 1.20-2.33, pperm < 0.01), additive (OR = 1.69, 95% CI 1.20-2.37, pperm < 0.01), dominant (OR = 1.81, 95% CI 1.15-2.87, pperm = 0.01) and recessive (OR = 2.34, 95% CI 1.15-4.73, pperm = 0.01) models. The association of the G rs1805087 allele of the MTR gene with the occurrence of FGR was also identified following the recessive model (OR = 3.01, 95% CI 1.05-8.68, pperm = 0.04). Conclusion: Our results indicated that maternal polymorphic loci rs1979277 SHMT1 and rs1805087 MTR may be associated with the development of FGR. Key words: Polymorphism, Associations, Fetal growth restriction, Folic acid.

Prenatal diagnosis of fetal growth restriction with polyhydramnios, etiology and impact on postnatal outcome

To assess the spectrum of different etiologies, the intrauterine course, outcome and possible prognostic markers in prenatally detected fetal growth restriction (FGR) combined with polyhydramnios. Retrospective study of 153 cases with FGR combined with Polyhydramnios diagnosed by prenatal ultrasound over a period of 17 years. Charts were reviewed for ultrasound findings, prenatal and postnatal outcome. All cases were categorized into etiological groups and examined for differences. Five etiological groups were identified: chromosomal anomalies (n = 64, 41.8%), complex malformation syndromes (n = 37, 24.1%), isolated malformations (n = 24, 15.7%), musculoskeletal disorders (n = 14, 9.2%) and prenatal non-anomalous fetuses (n = 14, 9.2%). Subgroups showed significant disparities in initial diagnosis of combination of both pathologies, Ratio AFI/ gestational weeks and Doppler ultrasound examinations. Overall mortality rate was 64.7%. Fetuses prenatally assigned to be non-anomalous, showed further complications in 42.9% (n = 6). Fetuses prenatally diagnosed with FGR combined with polyhydramnios are affected by a high morbidity and mortality. Five etiologic groups can be differentiated, showing significant disparities in prenatal and postnatal outcome. Even without recognizable patterns prenatally, long-term-follow up is necessary, as neurodevelopmental or growth delay may occur.

Which chart and which cut-point: deciding on the INTERGROWTH, World Health Organization, or Hadlock fetal growth chart

Objective To determine how various centile cut points on the INTERGROWTH-21st (INTERGROWTH), World Health Organization (WHO), and Hadlock fetal growth charts predict perinatal morbidity/mortality, and how this relates to choosing a fetal growth chart for clinical use. Methods We linked antenatal ultrasound measurements for fetuses > 28 weeks’ gestation from the British Columbia Women’s hospital ultrasound unit with the provincial perinatal database. We estimated the risk of perinatal morbidity/mortality (decreased cord pH, neonatal seizures, hypoglycemia, and perinatal death) associated with select centiles on each fetal growth chart (the 3rd, 10th, the centile identifying 10% of the population, and the optimal cut-point by Youden’s Index), and determined how well each centile predicted perinatal morbidity/mortality. Results Among 10,366 pregnancies, the 10th centile cut-point had a sensitivity of 11% (95% CI 8, 14), 13% (95% CI 10, 16), and 12% (95% CI 10, 16), to detect fetuses with perinatal morbidity/mortality on the INTERGROWTH, WHO, and Hadlock charts, respectively. All charts performed similarly in predicting perinatal morbidity/mortality (area under the curve [AUC] =0.54 for all three charts). The statistically optimal cut-points were the 39th, 31st, and 32nd centiles on the INTERGROWTH, WHO, and Hadlock charts respectively. Conclusion The INTERGROWTH, WHO, and Hadlock fetal growth charts performed similarly in predicting perinatal morbidity/mortality, even when evaluating multiple cut points. Deciding which cut-point and chart to use may be guided by other considerations such as impact on workflow and how the chart was derived.

The Gestational Effects of Maternal Appetite Axis Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review

Increased maternal food intake is considered a normal pregnancy adjustment. However, the overavailability of nutrients may lead to dysregulated fetal development and increased adiposity, with long-lasting effects on offspring in later life. Several gut-hormone molecules regulate maternal appetite, with both their orexigenic and anorectic effects being in a state of sensitive equilibrium. The aim of this manuscript is to systematically review literature on the effects of maternal gut-hormone molecules on fetal growth and metabolism, birth weight and the later metabolic health of offspring. Maternal serum ghrelin, leptin, IGF-1 and GLP-1 appear to influence fetal growth; however, a lack of consistent and strong correlations of maternal appetite axis hormones with birth weight and the concomitant correlation with fetal and birth waist circumference may suggest that these molecules primarily mediate fetal energy deposition mechanisms, preparing the fetus for survival after birth. Dysregulated intrauterine environments seem to have detrimental, sex-dependent effects on fetal energy stores, affecting not only fetal growth, fat mass deposition and birth weight, but also future metabolic and endocrine wellbeing of offspring.

Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography–tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman’s correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (>30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value < 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes.