Maternal Obesity Modulates Cord Blood Concentrations of Proprotein Convertase Subtilisin/Kexin-type 9 Levels.

Context: In utero exposure to maternal obesity or diabetes is considered a pro-inflammatory state. Objective: To evaluate whether cord blood proprotein convertase subtilisin/kexin-type 9 (PCSK9), which is regulated by inflammation and metabolic derangements, is elevated in neonates born to overweight, obese, or diabetic mothers. Methods: A retrospective study in full-term neonates born between 2010 and 2023, at Brigham and Women's Hospital. There were 116 neonates included in our study, of which 74 (64%) were born to overweight/obese mothers and 42 (36%) were born to nonoverweight/nonobese mothers. Results: Neonates born to overweight/obese mothers had significantly higher cord blood concentrations of PCSK9 compared with neonates born to nonoverweight/nonobese group (323 [253-442] ng/mL compared with 270 [244-382] ng/mL, P = .041). We found no significant difference in cord blood concentrations of PCSK9 between neonates of diabetic mothers compared with neonates of nondiabetic mothers. In multivariate linear regression analysis, higher cord plasma PCSK9 concentration was significantly associated with maternal overweight/obesity status (b = 50.12; 95% CI, 4.02-96.22; P = .033), after adjusting for gestational age, birth weight, male sex, and intrauterine growth restriction. Conclusion: Neonates born to mothers with overweight/obesity have higher cord blood PCSK9 concentrations compared with the nonoverweight/nonobese group, and higher cord blood PCSK9 concentrations were significantly associated with maternal overweight/obesity status, after adjusting for perinatal factors. Larger longitudinal studies are needed to examine the role of PCSK9 in the development of metabolic syndrome in high-risk neonates born to overweight, obese, or diabetic mothers.

Pneumoprotein CC16 in the Umbilical Cord Blood of Preterm Neonates.

OBJECTIVE: We examined the impact of perinatal factors on cord serum club cell protein (CC16) and the association of CC16 with mechanical ventilation and bronchopulmonary dysplasia (BPD) in preterm neonates. STUDY DESIGN: A retrospective cohort study including 60 neonates born with gestational age (GA) < 34 weeks. The impact of categorical perinatal factors on cord blood levels of CC16 was examined with univariate and multivariate regression analyses. RESULTS: In neonates with GA < 32 weeks, cord blood CC16 concentrations were significantly lower compared to neonates with GA between 320/7 and 336/7 weeks (5.4 ± 2.5 compared to 7.6 ± 2.9 ng/mL, p = 0.039). Neonates with prolonged rupture of membranes had significantly lower CC16 compared to those without prolonged rupture of membranes (4.0 ± 1.9 compared to 7.2 ± 2.2, p < 0.001). Finally, neonates with BPD had significantly lower CC16, compared to neonates without BPD (4.2 ± 2.1 compared to 7.0 ± 2.2 ng/mL, p = 0.004).Prolonged rupture of membranes was significantly negatively associated with CC16 (b = -2.67, 95% confidence interval [CI] -0.49 to -4.85, p = 0.017), after adjusting for GA (b = 0.23, 95% CI 0.03-0.42, p = 0.022), mode of conception, and mode of delivery. Finally, higher CC16 levels were significantly inversely associated with BPD (odds ratio = 0.33, 95% CI 0.12-0.88, p = 0.028), after adjusting for GA (b = 0.27, 95% CI 0.09-0.78, p = 0.015), and birth weight. CONCLUSION: Prolonged rupture of membranes was significantly negatively associated with cord serum CC16, after adjusting for GA, conception, and delivery mode, and CC16 was significantly inversely associated with BPD, after adjusting for GA and birth weight. KEY POINTS: · Neonates with prolonged rupture of membranes had lower CC16 levels.. · CC16 was significantly negatively associated with BPD.. · CC16 could be a biomarker of lung injury and BPD..

Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen/hypoxia (SU/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle). In addition, soleus atrophy may contribute to impaired exercise endurance. Studies in L6 rat myoblasts have showed that myotube differentiation is associated with increased FoxO1 levels and type II fiber markers, while the inhibition of FoxO1 leads to increased type I fiber markers. We conclude that the formation of aggregates and a FoxO1-mediated shift in the skeletal muscle fiber-type specification may underlie skeletal muscle dysfunction in an experimental study of PH.

Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension.

Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding protein 4 (FABP-4), fibroblast growth factor -21 (FGF-21), adiponectin, and the mRNA levels of FABP-4, FGF-21, and peroxisome proliferator-activated receptor γ (PPARγ) in lung tissue of patients with idiopathic PH and healthy controls. We also evaluated lung and adipose tissue expression of these mediators in the three most commonly used experimental rodent models of pulmonary hypertension. Circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in PH patients compared to controls and the mRNA levels of these regulators and PPARγ were also significantly increased in human PH lungs and in the lungs of rats with experimental PH compared to controls. These findings were coupled with increased levels of adipose tissue mRNA of genes related to glucose uptake, glycolysis, tricarboxylic acid cycle, and fatty acid oxidation in experimental PH. Our results support that metabolic alterations in human PH are recapitulated in rodent models of the disease and suggest that adipose tissue may contribute to PH pathogenesis.

GLYCOSYLATED FIBRONECTIN AND INHIBIN ARE LOWER AND ANTI-MÜLLERIAN HORMONE IS HIGHER IN UMBILICAL CORD BLOOD WHEN MOTHERS HAVE PREECLAMPSIA.

Objective: Preeclampsia is a common disorder of pregnancy, causing significant morbidity and mortality for mothers and infants. Several molecules, including glycosylated fibronectin (GlyFn), the inhibin-related proteins, anti-müllerian hormone (AMH), and the insulin-like growth factor axis, are altered in maternal plasma in the setting of preeclampsia; however, these molecules have not been previously measured in cord blood of infants born to mothers with preeclampsia, which may represent changes in fetal physiology. We evaluated potential biomarkers of preeclampsia in umbilical cord blood to fill the gap in knowledge. Methods: This is a case-control study of 196 neonates born at a tertiary teaching hospital in Boston from 2010-2017. Forty-nine neonates born to mothers with preeclampsia were matched 1:3 by gestational age, sex, and birth weight z-score with 147 controls. Eleven analytes were measured in cord blood by enzyme-linked immunosorbent assay. Binary logistic regression analyses were performed to evaluate associations between preeclampsia and analytes. Results: Mean cord blood levels of GlyFn and total inhibin were significantly lower in neonates born to mothers with preeclampsia compared to controls, and AMH levels were significantly higher in males born to mothers with preeclampsia than male controls. Associations remained significant after controlling for maternal and neonatal characteristics. Conclusion: Cord blood levels of GlyFn and inhibin are decreased and AMH (male) levels are increased in infants of preeclamptic mothers, which is opposite the pattern these biomarkers show in serum of mothers with preeclampsia. These molecules may be important in the pathophysiology and long-term effects of preeclampsia on the developing fetus. Abbreviations: AMH = anti-müllerian hormone; ELISA = enzyme-linked immunosorbent assay; GlyFn = glycosylated fibronectin; IGF = insulin-like growth factor; IGFBP5 = insulin-like growth factor binding protein 5; LOD = limit of detection; PAPP-A = pregnancy-associated plasma protein A; PAPP-A2 = pregnancy-associated plasma protein A2.

Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length.

BACKGROUND: A newborn's birth weight for gestational age provides important insights into his or her fetal growth and well-being. While the underlying mechanisms regulating fetal growth remain to be fully elucidated, the IGF axis plays an important role. Some components of this axis have been well-characterized in umbilical cord blood, but others have not yet been studied. We measured the proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and the established molecules IGF-I and -II in umbilical cord blood to better characterize the IGF axis in relation to birth weight and length. METHODS: We performed a case-control study of 180 neonates born at a tertiary teaching hospital in Boston. To maximize power, infants were recruited in a 1:3:1 ratio with 37 SGA, 111 AGA, and 37 LGA infants matched by gestational age, sex, and delivery mode. IGF-I, IGF-II, IGFBP-4, IGFBP-5, PAPP-A, and PAPP-A2 were measured in umbilical cord blood by ELISA. Associations between birth weight and birth length Z-scores and the Z-scores of the above molecules were analyzed using linear regression models and analysis of covariance. RESULTS: Birth weight and length Z-scores were positively associated with Z-scores of IGF-I, IGF-II, total IGFBP-4, and IGFBP-5, with IGF-I having the strongest association. Birth weight and length Z-scores were negatively associated with Z-scores of intact IGFBP-4, PAPP-A, and PAPP-A2 levels. CONCLUSIONS: We confirm previous findings of significant associations between the IGFs in cord blood and newborn size and for the first time show positive associations between cord blood total IGFBP-4 and -5 and birth weight and a negative association between intact IGFBP-4 and birth weight. We also show for the first time a reciprocal relationship between cord blood levels of PAPP-A and PAPP-A2 and newborn size. The implications of these findings need to be further examined in large longitudinal studies and likely have diagnostic and therapeutic potential.

Cord blood fatty acid-binding protein-4 levels are upregulated at both ends of the birthweight spectrum.

AIM: Fatty acid-binding protein-4 (FABP4) is an adipokine associated with obesity and signs of the metabolic syndrome. We aimed to investigate at birth in term neonates with normal and abnormal intrauterine growth concentrations of FABP4 and associate them with various perinatal parameters. METHODS: Serum cord blood FABP4 levels were prospectively determined by ELISA in 80 singleton term appropriate-for-gestational-age (AGA), intrauterine growth-restricted (IUGR) and large-for-gestational-age (LGA) neonates. RESULTS: Compared to the AGA group, cord blood FABP4 levels were increased in the IUGR and LGA groups. Additionally, they were higher in early-term than full-term neonates. A significant U-shaped correlation was recorded between serum FABP4 levels and birthweight. A significant negative correlation between cord blood FABP4 and gestational age in the whole study population was noted. CONCLUSION: Cord blood FABP4 levels were significantly higher at the extremes of foetal growth at term and negatively correlated with gestational age, being increased in early-term versus full-term neonates. Further longitudinal studies with larger sample sizes are required to elucidate FABP4 implication in foetal growth and its association with future adverse cardiometabolic outcomes in the offspring.

Effectiveness and Safety of 4-factor Prothrombin Complex Concentrate (4PCC) in Neonates With Intractable Bleeding or Severe Coagulation Disturbances: A Retrospective Study of 37 Cases.

BACKGROUND: To date, clinical experience with prothrombin complex concentrate (PCC) in the neonatal population has been limited. AIM: The objective of this study was to describe our experience regarding the effectiveness and safety of PCC administration in newborns with severe bleeding or coagulopathy resistant to conventional therapy. METHODOLOGY: We retrospectively analyzed data from 37 neonates with intractable bleeding or severe coagulation disturbances. All patients received intravenous bolus administration of 20 or 30 u/kg of PCC per dose, as a rescue procedure. RESULTS: Hemostasis was achieved in the majority of neonates and we observed statistically significant improvement in prothrombin time, international normalized ratio, and activated partial thromboplastin time (P<0.001, P=0.044, P<0.001, respectively). Thirteen neonates survived, whereas 24 did not survive. In those who survived, PCC had been administered earlier (<24 h) in the disease process compared with those who died (P=0.043). Neither acute adverse events nor thromboembolic complications were observed in all neonates. CONCLUSIONS: In our study, PCC seemed to be a safe and effective intervention for hemostasis and early intervention was more effective as a rescue therapy, without any adverse event. Further prospective controlled trials are required to determine optimal dose and timing of PCC administration in neonates.

GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans.

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

Pharmacotherapy of obesity: Available medications and drugs under investigation.

Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5-10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented.

Preadipocyte factor-1 in maternal, umbilical cord serum and breast milk: The impact of fetal growth.

BACKGROUND/OBJECTIVE: To study the concentrations of preadipocyte factor-1 (Pref-1) -an inhibitor of adipocyte differentiation, implicated in adipose tissue metabolism, late metabolic disorders and fetal growth- in maternal and umbilical cord serum, as well as maternal milk and correlate above concentrations with intrauterine growth and other perinatal parameters. MATERIAL AND METHODS: Pref-1 concentrations were determined by ELISA in antepartum maternal and umbilical cord serum, as well as day 3 to 4 postpartum breast milk, deriving from 80 women, who delivered 40 appropriate (AGA), 20 large for gestational age (LGA) and 20 intrauterine growth restricted (IUGR) neonates, classified by the use of customized birth-weight standards adjusted for significant determinants of fetal growth. RESULTS: Umbilical cord serum Pref-1 concentrations were significantly higher than antepartum maternal ones (p < 0.001), while breast milk concentrations were the lowest (p < 0.001 concerning umbilical serum, p < 0.001 concerning maternal serum). Umbilical cord serum Pref-1 concentrations were significantly lower in the LGA group than in the AGA one (p = 0.044). Breast milk and maternal serum Pref-1 concentrations did not differ between the three intrauterine growth groups. Maternal serum and breast milk Pref-1 concentrations did not correlate with maternal age, body mass index before and after gestation, birth weight, body length, and customized centile. A positive weak correlation was recorded between maternal serum and milk Pref-1 concentrations (r = 0.238, p = 0.034). CONCLUSIONS: Pref-1 concentrations in umbilical cord serum are higher than in antepartum maternal serum, probably pointing to its fetal origin and role in intrauterine growth. Breast milk concentrations, being extremely low, and possibly implying infant protection from metabolic disorders, positively correlate with maternal serum ones, conceivably suggesting a transfer of the substance from the circulation to the breast. Umbilical cord serum Pref-1 concentrations were lower in LGA fetuses/neonates, as compared to respective AGA ones.

Late preterm infants: Week by week outcomes of morbidity and mortality.

The aim of this study was to determine the clinical outcome of late preterm infants (LPI) week by week. Our patients were divided into three groups according to gestational age (GA); group A: 34 - 34+6/7 weeks, group B: 35 - 35+6/7 weeks and group C: 36 - 36+6/7 weeks. Out of 10650 deliveries, 1280 (12%) were late preterm, 1004 (78.5%) of which were carried out by caesarean section. A total of 1527 infants were studied with 565 (37%) requiring admission to NICU while 5 deaths were recorded (neonatal mortality rate was estimated at 3.2 ‰). Our study demonstrates that the rate of respiratory disorders, sepsis, feeding disorders and abnormal neurological examination in LPIs was inversely proportional to their GA. Furthermore, infants of 34+0/7 - 34+6/7 weeks of GA required a longer hospitalization in the NICU than their more mature peers.