Nebojsa Radunovic

Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy.

There is little information available concerning the ontologic development of the human hypothalamic-pituitary-adrenal (HPA) axis nor of the potential interactions among fetal, maternal and placental-derived HPA axis hormones. This study evaluated levels of these hormones in matched maternal and fetal pairs during the second half of uncomplicated pregnancies. Immunoassays were used to measure serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH) and cortisol in 104 matched fetal and maternal blood samples. Fetal specimens were obtained by percutaneous umbilical blood sampling (PUBS) between 18 and 40 weeks in patients whose pregnancies resulted in healthy, term infants. Correlations among these hormones, and the effect of gestational age were assessed. Maternal CRH concentrations [median (range)] [1.10 ng/ml (0.15 to 23.69)] were significantly greater than fetal values [0.35 ng/ml (0.07 to 1.0)]. Levels of maternal CRH (r = 0.73; p < 0.001) but not fetal CRH (r = 0.01; p = 0.98) correlated with gestational age. Maternal ACTH decreased (r = -0.21; p = 0.04) while fetal ACTH increased (r = 0.35; p < 0.003) with gestational age. Both maternal (r = 0.45; p < 0.001) and fetal (r = 0.57; p < 0.001) cortisol levels increased with gestational age. Maternal serum CRH values correlated best with fetal cortisol (r = 0.40; p = 0.0002) and correlated modestly with maternal cortisol (r = 0.28; p = 0.01), fetal ACTH (r = 0.24; p = 0.03) and fetal CRH (r = 0.23; p = 0.04); but not with maternal ACTH (r = -0.12; p = 0.3). Maternal CRH concentrations increase in the third trimester and correlate with rising fetal cortisol levels.

The severely anemic and hydropic isoimmune fetus: changes in fetal hematocrit associated with intrauterine death.

Hydrops caused by isoimmune hemolytic anemia is frequently associated with fetal death following intrauterine intravascular transfusion. To identify possible predictors of procedure-related fetal death, we examined changes in fetal blood volume and hematocrit resulting from the initial transfusion performed on 19 severely anemic, hydropic fetuses. Seven fetuses (36.8%) died at 24-72 hours after transfusion, but in no case was the procedure associated with fetal distress. There were no significant differences between fetuses who died and those who survived in terms of total volume of blood transfused, volume transfused as a percentage of total fetoplacental blood volume, hematocrit of transfused blood, post-transfusion hematocrit, umbilical vein pH, or gestational age at transfusion. Significant differences were noted between hydropic fetuses who died compared with those who survived in the mean pretransfusion hematocrit, 6.7% (+/- 2.0) versus 8.7% (+/- 1.6) (P = .03), and the relative increase in post- over pre-transfusion hematocrit, 5.5-fold (+/- 1.4) versus 3.5-fold (+/- 0.8) (P = .001). Stepwise logistic regression analysis confirmed that only the relative increase in hematocrit was predictive of fetal loss. Moreover, six of seven fetal deaths occurred when the relative increase in hematocrit was greater than fourfold, whereas ten of 12 surviving fetuses had relative increases of less than fourfold. We conclude that large, acute increases in fetal hematocrit following intrauterine transfusion are associated with substantial mortality in hydropic fetuses.

The role of antioxidant vitamins in hypertensive disorders of pregnancy.

Abstract Preeclampsia (PE) is an important and a leading cause of both maternal morbidity and adverse perinatal outcomes. Despite progress in perinatal medicine for patients with an established diagnosis of PE, a therapeutic approach other than termination of pregnancy was unsuccessful. Women predisposed to PE begin pregnancy with a certain degree of endothelial dysfunction, a lesion that precedes shallow placentation. The proposed sequence of events comprises endothelial dysfunction, defective trophoblast invasion, and consequential impaired placental perfusion, immune maladaptation and inflammation. The possible link between these could be oxidative stress by excessive production of reactive oxygen species coupled with inadequate or overwhelmed antioxidant defense mechanisms. These defense mechanisms, involving antioxidant vitamins and enzyme systems, may restrain the extent of damage caused by oxidative stress. Markers of oxidative stress in women with established PE were confirmed. Accordingly, these findings support an expected beneficial effect of antioxidant therapy in the prevention of PE and other pregnancy-related disorders. Numerous studies have been carried out in order to investigate this possible and simple prophylactic and/or therapeutic approach in prevention of oxidative stress and eventual reduction of PE and its perinatal complications. In this review the role of vitamin antioxidants in prevention and treatment of PE is discussed. Despite the logic behind using antioxidant vitamins, the data, thus far, are at best conflicting.

Fetal and maternal plasma endothelin levels during the second half of pregnancy

OBJECTIVE Our objective was to evaluate maternal and fetal endothelin concentrations in uncomplicated pregnancies across the second half of pregnancy. STUDY DESIGN Paired (n = 64) maternal venous and fetal umbilical venous or arterial samples were obtained during cordocentesis. In addition, eight neonatal umbilical vein samples were obtained immediately after delivery. Samples were assessed for hematocrit and pH, and concentrations of endothelin were measured by sensitive enzyme immunoassay. RESULTS No significant correlation was found between either fetal or maternal endothelin levels and gestational age (r = 0.01, p = 0.91 and r = 0.07, p = 0.5, respectively). Fetal plasma endothelin concentrations were significantly lower than neonatal umbilical vein endothelin levels [median 2.5 pg/ml (range 0.9 to 5.73) vs 15.77 pg/ml (8.12 to 19.58), respectively; p < 0.0001] but significantly higher than maternal levels [1.3 pg/ml (0.8 to 3.25); p < 0.0001]. In addition, endothelin values were higher in the umbilical artery than in the umbilical vein, but this difference failed to achieve statistical significance [2.89 pg/ml (1.61 to 5.73) vs 2.29 pg/ml (0.9 to 5.70), respectively; p = 0.06]. No correlation was noted between fetal and maternal endothelin levels (r = 0.12, p = 0.36). CONCLUSION Fetal endothelin levels were significantly higher than maternal levels, but neither correlated with gestational age across the second half of pregnancy.

Fetal Free Thyroxine Concentrations in Pregnant Women with Autoimmune Thyroid Disease

CONTEXT Fetuses from mothers with autoimmune thyroid disease (AITD) may be affected by antithyroid antibodies, antithyroid drugs, and iodine. OBJECTIVE The study correlated fetal free T(4) (fT4) with fetal ultrasound parameters and maternal thyroid function, thyroid antibodies, and medication dose from mothers with AITD. DESIGN AND SETTING The study was designed as a prospective cohort study and conducted in an academic referral center. PATIENTS Eighty-three of 85 women with AITD completed the study; 38 were treated for hyperthyroidism and 25 for hypothyroidism, and 20 were euthyroid. MAIN OUTCOME MEASURES Outcomes were as follows: 1) fetal-fT4, TSH, ultrasound parameters (morphology, biometrics, heart rate); and 2) maternal-fT4, TSH, antithyroid drug dose, and antithyroid antibodies, thyroid peroxidase and TSH receptor (TRAK). Parameters were determined at the same time, between the 22nd and 33rd wk gestation. RESULTS A total of 48.3% of fetuses from hyperthyroid mothers, 60% of fetuses from hypothyroid mothers, and 10% of fetuses from euthyroid mothers had elevated fT4 levels (P = 0.006). In hypothyroid mothers, the presence of both thyroid antibodies was related to fetal hyperthyroidism, whereas absence was related to fetal euthyroidism (P = 0.019). Hyperthyroid mothers (TRAK-positive, thyroid peroxidase-negative) with hyperthyroid fetuses had significantly higher mean TRAK than hyperthyroid mothers with euthyroid fetuses (13.7 vs. 3.7 IU/liter; P = 0.02). Fetal fT4 correlated weakly negatively with maternal TSH within the normal range, but not with ultrasound parameters or with antithyroid drug dose. CONCLUSION High fetal fT4 levels were unexpectedly frequent in women with AITD, including maternal autoimmune hypo- and hyperthyroidism. Further studies are needed, as well as noninvasive methods to assess fetal thyroid function.

Fetal and maternal plasma leptin levels during the second half of normal pregnancies and those with Down syndrome

Objective: To assess the correlation of fetal and maternal plasma leptin concentrations during the second half of uncomplicated, euploid pregnancies and to compare these values with those obtained from pregnancies with Down syndrome. Methods: Paired maternal venous and fetal umbilical blood samples were obtained during cordocentesis in 36 uncomplicated, euploid pregnancies and nine pregnancies with Down syndrome fetuses. Concentrations of leptin were measured by sensitive radioimmunoassay. Results: Among pregnancies with euploid fetuses, there was significant correlation between both fetal and maternal leptin levels and gestational age (r = 0.464, p = 0.005 and r = 0.629, p < 0.001, respectively). Fetal plasma leptin concentrations also correlated with maternal levels (r = 0.485, p = 0.003), but fetal levels were significantly lower than maternal values (mean 2.12 ± 0.44 ng/ml vs. 17.79 ± 5.48 ng/ml, respectively; p < 0.001). Down syndrome fetuses had significantly lower fetal plasma leptin levels than gestational age-matched control euploid fetuses (0.72 + 0.54 ng/ml vs. 2.12 + 0.44 ng/ml; p < 0.002). However, there was no difference in maternal leptin concentrations between euploid and Down syndrome pregnancies. Conclusion: In euploid pregnancies, fetal leptin levels were significantly lower than the corresponding maternal values but increased across gestation. Down syndrome was associated with significantly lower fetal leptin levels.

β-Endorphin concentrations in fetal blood during the second half of pregnancy

OBJECTIVE: Endogenous opiates may play a role in both fetal physiologic functions and the adaptation to intrauterine stress. However, our understanding of this role is hampered by an absence of data on circulating levels of these substances during fetal life. STUDY DESIGN: We measured serum \gB-endorphin values with a radioimmunoassay in 81 paired fetal and maternal blood samples and 24 neonatal cord specimens. The former samples were uneventfully obtained from uncomplicated pregnancies between 18 and 39 weeks of gestation at the time of cordocentesis for prenatal diagnosis. RESULTS: Mean fetal β-endorphin concentrations were significantly lower than β-endorphin values from neonates (90.5 pg/ml [±59.4] vs 228.4 pg/ml [±166.2]; p p r = −0.193; p = 0.07). However, fetal β-endorphin concentrations were significantly correlated with maternal values (Spearmans rank r = 0.47; p CONCLUSION: These findings suggest that delivery or fetal adaptation to an extrauterine environment is associated with significant increases in β-endorphin release. Moreover, although the fetal pituitary may be the primary source of circulating fetal β-endorphin, a maternal or placental contribution cannot be excluded. Our data identify a physiologic range for fetal β-endorphin concentrations.

Altered response of human umbilical artery to 5-HT in gestational diabetic pregnancy

The aim of this investigation was to evaluate serotonin (5-HT) action on isolated human umbilical arteries (HUA) from normal and gestational diabetes mellitus (GDM) pregnancies. 5-HT caused HUA contraction in a concentration-dependent manner in both investigated groups but with lower efficacy in GDM. After endothelial denudation or in the presence of indomethacin (cyclooxygenase inhibitor), the 5-HT-evoked response was comparably augmented, but only in arteries from uncomplicated pregnancies. 5-HT contractions were unchanged by L-NOARG (NO-synthase inhibitor) or glibenclamide (K(ATP) channel blocker) in both investigated groups. Whereas nifedipine (Ca(2+) channel blocker) reduced the contractile effect of 5-HT and was more potent in GDM, ouabain (Na(+)/K(+)-ATPase inhibitor) caused the contraction of HUA prior to 5-HT addition in both groups, but with a significantly reduced effect in GDM. In vascular rings from GDM, methiothepin (a 5-HT(1)/5-HT(2) receptor antagonist) significantly reduced 5-HT-induced contraction to a similar extent as compared to uncomplicated pregnancies. Ketanserin (a 5-HT(2A) receptor antagonist) produced a concentration-dependent inhibition of the 5-HT effect in GDM. In conclusion, in normal pregnancies, 5-HT produced a concentration- and endothelium-dependent contraction of HUA, most probably via endothelial prostacyclin. In contrast, the contractile effect of 5-HT in GDM was reduced with apparent endothelial dysfunction. In both normal and diabetic pregnancies, voltage-gated Ca(2+) channels and Na(+)/K(+)-ATPase contribute to the 5-HT-evoked contraction, as well to the regulation of basal vascular tone, but those actions were notably impaired in GDM. In uncomplicated and diabetic pregnancies, the transduction mechanism of 5-HT involves activation of mixed population of 5-HT(1) and 5-HT(2A) receptors in the HUA.

The Different Effects of Resveratrol and Naringenin on Isolated Human Umbilical Vein: The Role of ATP‐Sensitive K+ Channels

The blood flow from the placenta to the fetus depends on human umbilical vein (HUV) vascular tone. ATP‐sensitive K+ (KATP) channels link the metabolic state of the cell to membrane potential, and their activation in the HUV represents protection against hypoxia. The aims of our study were to assess the effects of resveratrol and naringenin on the HUV and to define the roles of KATP channels in their effects. Serotonin or 100 mM K+ were used for precontraction of the HUV without endothelium. The cumulative concentration–response curves were obtained by adding increasing concentrations of resveratrol or naringenin. Glibenclamide was used, in order to test the role of KATP channels in its effect. Resveratrol induced more potent vasodilatation of serotonin‐ and 100 mM K+‐precontracted HUV than naringenin. Glibenclamide induced significant shift to the right of the concentration–response curves of resveratrol and P1075 (a specific opener of KATP channels). Western blotting showed that HUV expressed protein Kir6.1. Thus, resveratrol and naringenin produce dilatation of HUV. It seems that KATP channels are involved in the relaxation of HUV induced by resveratrol, while naringenin seems to interact with other ion channels. The K+ channel‐independent mechanism(s) of these polyphenols could not be excluded. Copyright

Fetal and maternal plasma homocysteine levels during the second half of uncomplicated pregnancy.

Abstract Objective: To measure fetal and maternal plasma homocysteine (Hcy) concentrations in uncomplicated pregnancies. Methods: Paired maternal venous and fetal umbilical cord blood (n = 81) samples were evaluated for plasma Hcy and vitamin B12 levels, in addition to eight neonatal umbilical cord blood samples obtained immediately following delivery. Results: Both fetal and maternal Hcy concentrations were positively correlated with advancing gestational age (ρ = 0.44, p < 0.0001; and ρ = 0.27, p < 0.05, respectively). Fetal plasma Hcy concentrations [2.2 µmol/l (IQR: 2.0–3.2)] were significantly lower than both neonatal umbilical vein [5.0 µmol/l (IQR: 4.4–6.5); p < 0.001] and maternal plasma Hcy levels [4.4 μmo/l (IQR: 3.4–5.4); p < 0.001]. In addition, Hcy values at term were higher in the umbilical vein compared with the umbilical artery [5.0 μmol/l (IQR: 3.4–5.4) versus 4.2 μmol/l (IQR: 3.7–5.5), respectively; p = 0.016]. Significant correlation was noted and between fetal and maternal Hcy levels (ρ = 0.50, p < 0.0001), while fetal Hcy was negatively correlated with maternal B12 concentrations (ρ = −0.32, p < 0.001). Conclusions: Fetal Hcy levels were significantly lower than maternal and neonatal levels and correlated with gestational age across the second half of pregnancy.