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Context: Vascular endothelial growth factor (VEGF) promotes placental vascularization, which is inadequate in preeclampsia and intrauterine growth retardation (IUGR). The soluble receptor of VEGF (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1, is produced in the placenta and reduces VEGF activity. Therefore, elevated sVEGFR-1 could contribute to the development of preeclampsia and IUGR., Objective: The objective of this study was to study maternal serum sVEGFR-1 concentration in early pregnancy ending in preeclampsia and IUGR., Design: This was a case-control study., Setting: This study was conducted at Helsinki University Central Hospital (Helsinki, Finland), a tertiary referral center., Patients: Patients included 124 pregnant women, of whom 49 developed preeclampsia, 16 gave birth to IUGR infants without preeclampsia, and 59 remained normotensive and gave birth to normal-sized infants. Serum samples were collected at 12-15 and 16-20 gestational weeks., Main Outcome Measures: Serum sVEGFR-1 concentrations were determined by ELISA., Results: Women with subsequent preeclampsia had higher [median; interquartile range (IQR)] concentrations of sVEGFR-1 at 16-20 wk gestation (436 and 282-699 ng/liter; P = 0.005) than the controls (296 and 184-508 ng/liter). The conclusion was the same if women with mild (340 and 285-750 ng/liter; P = 0.043) or severe (497 and 235-699 ng/liter; P = 0.022) preeclampsia were analyzed separately. An elevated sVEGFR-1 concentration at 16-20 wk gestation is associated with an increased risk of preeclampsia but not of isolated IUGR. Soluble VEGFR-1 concentration decreased by 15% from the first to the second sampling in the controls but not in women with preeclampsia or IUGR., Conclusion: Elevated sVEGFR-1 concentrations at 16-20 wk gestation precede the clinical manifestations of preeclampsia. By neutralizing VEGF, sVEGFR-1 may contribute to inadequate placental vascularization.

Background: To study the role of progesterone (P4) in the regulation of circulating leptin in early human pregnancy, we measured the levels of leptin before and after administration of the antiprogestin mifepristone, followed by misoprostol in early pregnancy., Methods: Thirty-four women requesting termination of pregnancy, with < or =63 days of amenorrhea, received 200 mg of mifepristone on day 0, followed by either oral or vaginal administration of 0.8 mg of misoprostol on day 2. Five serial serum samples were assayed for leptin, human chorionic gonadotrophin (hCG), P4, estradiol (E2), cortisol, and mifepristone., Results: Circulating leptin concentrations decreased by 8.7 +/- 29.7% (mean +/- standard deviation) (p < 0.05) following the ingestion of mifepristone. After misoprostol administration on day 2, a decrease of 12.6 +/- 17.0% (p < 0.05) was followed by a rebound on day 3 to 87.6 +/- 25.7% of the pretreatment values. Two weeks after mifepristone, leptin levels had declined by 25.4 +/- 30.4%. In contrast, E2, P4, and hCG concentrations continued to increase following mifepristone, followed by rapid declines from day 2 to day 3. Serum cortisol concentrations increased by 89.7% +/- 82.7% in response to mifepristone, but this increase did not correlate with the decrease in leptin. The decrease in leptin levels on day 2 correlated with the decreases in P4 (r = 0.37, p < 0.05) and in E2 (r = 0.44, p < 0.05) levels., Conclusions: The fall in leptin levels following mifepristone implies a role for P4 in the regulation of leptin in early pregnancy. Moreover, the significant correlation between the changes in leptin and those of P4 and E2 at the time of luteolysis suggests that corpus luteum may also play a role in the regulation of circulating leptin in early pregnancy.

Background: Women suffering from fear of labor have reduced pain tolerance during a cold pressor test (CPT) during and after pregnancy., Methods: We compared levels of norepinephrine, adrenocorticotropin (ACTH), cortisol and beta-endorphin before and during the CPT up to 60 min in 20 normotensive women with and 20 without fear of labor at 37.4 +/- 0.2 (mean +/- SE) gestational weeks and at 41.9 +/- 1.6 weeks after delivery., Results: Baseline levels of norepinephrine in the pregnant fear group (1.63 +/- 0.18 nmol/L) were higher (p = 0.068) than in controls (1.38 +/- 0.14 nmol/L) but after delivery they were lower in the fear group (1.75 +/- 0.31 nmol/L vs. 2.31 +/- 0.26 nmol/L, p = 0.064). ACTH, cortisol and beta-endorphin did not differ between pregnant and nonpregnant groups. The CPT caused a 28.4% smaller response in norepinephrine in the pregnant fearful women than in controls, whereas the responses of ACTH and beta-endorphin were similar between groups during and after pregnancy. The CPT caused no significant response in cortisol. Pregnant fearful women had higher diastolic blood pressure (85.6 +/- 4.5 mmHg, mean +/- SE) than the controls (74.9 +/- 3.4 mmHg, p = 0.065)., Conclusions: Women with fear of labor were characterized by changes in norepinephrine but not in ACTH, cortisol or beta-endorphin before and during the CPT, indicating a normal pituitary-adrenal axis function.

According to experimental studies, 17 beta-estradiol associates with lipoproteins in blood in the form of fatty acid esters. However, concentrations of endogenous estradiol esters in human lipoprotein fractions have not been previously reported. We investigated the distribution of estradiol fatty acid esters between plasma lipoproteins in 10 healthy women during late pregnancy. Following extraction from serum and ultracentrifugally isolated, gel-filtered lipoproteins, estradiol esters were separated from nonesterified estradiol by column chromatography. After saponification and chromatographic purification of the estradiol ester fraction, the concentration of hydrolyzed esters was determined by estradiol time-resolved fluoroimmunoassay. Of total serum estradiol, a mean of 0.7% (549 pmol/liter, n = 10) was in the form of fatty acid esters. Estradiol fatty acid ester concentrations measured in serum and lipoprotein fraction correlated positively (n = 10; r = 0.98; P < 0.001). The majority of lipoprotein estradiol esters, 54%, was recovered in high-density lipoprotein, and 28% in low-density lipoprotein fraction. Most lipoprotein fractions contained undetectable amounts of nonesterified estradiol (< 36 pmol/liter). In conclusion, our results indicate that estradiol fatty acid esters are mostly bound by lipoproteins in blood in vivo.

Objective: Cervical tissue expresses all the isoenzymes of nitric oxide synthase. We studied the concentrations of nitric oxide metabolites in the cervical fluid in nonpregnant (n = 11) and pregnant women (n = 106)., Study Design: Cervical fluid was collected into a Dacron polyester swab, and nitric oxide metabolites were eluted into physiologic saline solution, which was assayed for nitric oxide metabolites with the Griess reaction. The detection limit of the method is 0.2 micromol/L., Results: Cervical fluid nitric oxide metabolite was detectable in 46% of nonpregnant women (median, <0.2 micromol/L; 95% CI, 0-49), in 63% of women in early pregnancy (median, 11 micromol/L; 95% CI, 0-23) and in 82% of women in late pregnancy (median, 128 micromol/L; 95% CI, 21-276). In late pregnancy, the cervical fluid nitric oxide metabolite level was higher in women with Bishop score of > or =6 (median, 163 micromol/L; 95% CI, 105-276) than in women with Bishop score of <6 (median, 86 micromol/L; 95% CI, 21-99). Cervical fluid nitric oxide metabolite concentration before the onset of labor in parous women (median, 97 micromol/L; 95% CI, 78-283) was higher (P =.008) than that in nulliparous women (median, 28 micromol/L; 95% CI, 0-95). Cervical fluid nitric oxide metabolites before the initiation of labor (median, 33 micromol/L; 95% CI, 0-95) rose to 3.5-fold (median, 115 micromol/L; 95% CI, 78-284) after the commencement of uterine contractions and showed a significant relationship to Bishop score (r = 0.39, P =.01). Cervical fluid nitric oxide metabolite concentrations were not relative to simultaneous plasma nitric oxide metabolite levels (n = 41 women, r = 0.14, P =.41). Rupture of fetal membranes tended to decrease cervical fluid nitric oxide metabolite levels, whereas gentle cervical manipulation elevated it 6.6-fold in 1 minute. The administration of glyceryl trinitrate (0.5 mg, nitric oxide donor) intracervically resulted in a significant rise in the cervical fluid nitric oxide metabolite level in 2 minutes., Conclusion: Cervical fluid nitric oxide metabolite level rises after cervical ripening, nitric oxide donor administration, or cervical manipulation, which supports a role for cervical nitric oxide in cervical ripening.

Endometriosis-associated infertility is poorly treatable with various forms of surgery. Therefore, assisted reproduction techniques (ARTs), such as controlled ovarian hyperstimulation, intrauterine insemination, or in vitro fertilization, are commonly used for endometriosis-associated infertility. Endometriosis impairs the efficacy of in vitro fertilization. There is no evidence that ovulation suppression before ART would enhance the efficacy of ART. Resection of minimal/mild endometriosis and/or restoration of the normality of pelvic anatomy may enhance the efficacy of ART, but aggressive ovarian surgery should be avoided, because it reduces the ovarian reserves and the likelihood of pregnancy after ART. The outcome of ART pregnancy is not affected by the history of endometriosis, but the presence of endometrioma may predispose to preterm birth or fetal growth retardation in ART-induced pregnancies. As a whole, infertility due to endometriosis is best treated with various forms of ART, and the earlier clinicians apply these techniques, the more likely pregnancy may ensue. [ABSTRACT FROM AUTHOR]

Objective. Endostatin, an important anti-angiogenic factor produced by endothelial cells, is elevated in established pre-eclampsia. We measured maternal serum endostatin concentrations in early pregnancy associated with later pre-eclampsia and intrauterine growth retardation (IUGR). Design. Retrospective case-control study. Setting. University Central Hospital. Sample. Serum samples were collected at 12-15 and 16-20 gestational weeks from a total of 124 pregnant women of whom 49 developed pre-eclampsia, 16 gave birth to infants with IUGR without pre-eclampsia, and 59 remained normotensive giving birth to healthy, normal-weight infants. Methods. Enzyme-linked immunosorbent assay. Main outcome measures. Endostatin concentrations in serum. Results. At 12-15 gestational weeks, there was no difference in median endostatin concentrations between the groups. At 16-20 gestational weeks, the median endostatin concentration was higher in the women with subsequent pre-eclampsia (p=0.026), especially preceding a later severe form of the disease (p=0.041), than in the controls. The results were further confirmed by receiver operating characteristic (ROC) analysis showing an area under the curve (AUC) of 0.64 (95% confidence interval: 0.50-0.81) for endostatin to identify subsequent pre-eclampsia, and 0.71 (0.53-0.89) in cases of severe pre-eclampsia. Optimal cut-off values were determined and used for calculations of sensitivity and specificity, which were 80 and 52% (cut-off value = 58.0 µg/L) in pre-eclampsia, and 80 and 65% (cut-off value = 65.5 µg/L) in the severe form of the disease. Conclusions. The concentrations of endostatin in maternal serum at 16-20 weeks' of gestation are associated with an increased risk of pre-eclampsia but not IUGR. [ABSTRACT FROM AUTHOR]

Objective: The cells of the human uterine cervix synthesize nitric oxide, which may be a factor in cervical ripening. We studied the effect of misoprostol on cervical nitric oxide release in nonpregnant and pregnant women. Study design: Seventy-two nonpregnant (n = 15) and pregnant (n = 57; 26 in early pregnancy, 31 in late pregnancy) women were treated with either vaginal misoprostol (n = 54) or vaginal placebo (n = 18). The dose of misoprostol was 400 µg in nonpregnant and early pregnancy group, and 25 µg in late pregnancy group. Serial cervical fluid samples, collected before and up to 3 hours after misoprostol/placebo, were assessed for the concentration of nitric oxide metabolites by means of the Griess reaction. Results: Placebo had no effect on cervical fluid nitric oxide metabolite level. In 1 to 3 hours, misoprostol induced 4.3- to 5.2-fold elevations in cervical fluid Nox concentrations in early pregnancy (P < .01), and 4.4- to 18.2-fold elevations in late pregnancy (P < .01), but these responses did not differ significantly from each other. Misoprostol had no effect on cervical fluid nitric oxide metabolites in nonpregnant women. There was a trend towards a relationship between cervical nitric oxide stimulation after misoprostol and cervical ripening. Conclusion: Vaginal misoprostol stimulates cervical nitric oxide release in pregnancy. This suggests a joint action of nitric oxide and prostaglandins in cervical ripening. [ABSTRACT FROM AUTHOR]

BACKGROUND. Fatty acid esters of 17β-estradiol (E2) are estrogen metaboiites associated with lipoproteins in blood. AIM. To study the effects of estrogen therapy on concentrations of serum E2 fatty acid esters in postmenopausal women with a history of an estrogen-related liver disorder, intrahepatic cholestasis of pregnancy (ICP), and in healthy women in a double-blind, crossover fashion. METHOD. ICP (n = 10) and control women (n = 10) received increasing doses of E2 valerate orally 2–4 mg/day, or transdermal E2 50–100 μg/day for 6 weeks. After a 4-week wash-out period, the subjects crossed over to the alternate E2 treatment. Concentrations of serum E2 fatty acid esters were quantified after saponification by fluoroimmunoassay. RESULTS. Oral E2 administration increased median serum E2 fatty acid ester concentrations from 57 to 73 pmol/L in the 1CP and from 56 to 74 pmol/L in the control group, in association with elevations in serum E2, estrone and sex hormone-binding globulin levels. Transdermal E2 treatment did not increase serum E2 ester levels. CONCLUSIONS. The increase in serum E2 fatty acid esters during oral E2 administration may be attributed, at least partly, to the higher estrogen dose during oral compared with transdermal therapy. A history of ICP did not affect esterification of E2 during estrogen therapy. [ABSTRACT FROM AUTHOR]

We investigated the production of prostacyclin and thromboxane in pregnant women with a previous venous thromboembolic event before, during and after the use of unfractionated heparin and low molecular weight heparin (dalteparin). Twenty women were studied before starting heparin prophylaxis (before 20 weeks of gestation), during heparin prophylaxis (at 30 weeks of gestation) and after heparin prophylaxis (16 weeks after delivery). Ten pregnant women with no history of thromboembolism were studied as the control group. Urinary output of the stable metabolite of prostacyclin (2,3-dinor-6-keto-PGF1α) and that of thromboxane A2 (2,3-dinor-TxB2), as well as a number of markers of thrombophilia were measured and expressed as mean (±SEM). Women with a history of thromboembolism were characterized by normal prostacyclin production but elevated thromboxane production (44·0 ± 4·1 versus 19·0 ± 3·6 ng/mmol creatinine, P < 0·001) at 12 weeks of pregnancy. Heparin prophylaxis (regardless of the type) had abolished elevated thromboxane concentrations at 30 weeks of gestation. Four months after delivery, thromboxane dominance had returned (25·2 ± 3·5 versus 13·6 ± 2·1 ng/mmol creatinine, P < 0·01). The presence of hereditary thrombophilia (9/20) was not associated with any changes in prostanoid concentrations. Thus, women with a history of venous thromboembolic events have thromboxane dominance during and after pregnancy, but this dominance can be eliminated through the use of heparins. [ABSTRACT FROM AUTHOR]

Objective: We studied whether transdermal nitroglycerin, a donor of nitric oxide, affects uterine, umbilical, and fetal cerebral blood flow in pregnancies complicated by preeclampsia and impaired uteroplacental blood flow.Study Design: Seventeen patients with preeclampsia were treated with a nitroglycerin patch, 10 mg per 24 hours, for three consecutive days between 28 and 36 weeks' gestation. The uterine, umbilical, and fetal middle cerebral artery pulsatility index and resistance index were assessed by color Doppler ultrasonography before the start of treatment, daily during treatment, and on the first 2 days after the removal of the last patch.Results: The nitroglycerin patch caused a significant fall in the mean uterine pulsatility index and resistance index that reached its maximum (18% +/- 4% and 17% +/- 3%, respectively, from baseline) on the last treatment day. After the removal of the last patch, uterine pulsatility index and resistance index rose to the pretreatment value within 12 hours. No significant changes in umbilical or middle cerebral artery pulsatility index and resistance index were observed during treatment. Maternal mean arterial pressure fell from 122 +/- 8 to 117 +/- 7 mm Hg (P = .05).Conclusion: Transdermal administration of nitroglycerin may offer a potential for treatment for patients with preeclampsia who have increased uteroplacental impedance. [ABSTRACT FROM AUTHOR]

Alcohol use exceeding 3 to 5 daily drinks is associated with a 30% to 50% risk of delivering a child with fetal alcohol effects (FAE). FAE could be prevented if women were counseled and if they decreased their drinking. Therefore, we need sensitive and specific markers to detect alcohol abuse during pregnancy. We investigated whether acetaldehyde-hemoglobin adducts (Hb-Ach) could be such a marker. Using an antiserum specific for acetaldehyde-generated epitopes in proteins, we measured the levels of Hb-Ach from the red cells of 19 women visiting the outpatient department of pregnant alcohol abusers and from 14 non pregnant controls. The pregnant women were carefully followed to receive personal antenatal care and intensive counseling on alcohol. Nevertheless, eight of the women delivered infants with FAE. The remaining 11 women had healthy infants, although only four of them stopped drinking totally. The highest concentrations of Hb-Ach were found from women who subsequently delivered children with FAE. When compared with the pregnant women abstaining from ethanol the Hb-Ach values were found to be elevated in five of eight (63%) of the women who gave birth to children with FAE, whereas only in two/seven (28%) of the mothers who despite drinking delivered healthy children. Hb-Ach measurements during pregnancy may prove to be useful to monitor the compliance of women withdrawing from alcohol and to distinguish the mothers at risk of affected offspring. The studies also support a pathophysiological role of acetaldehyde in producing ethanol-associated fetal injury. [ABSTRACT FROM AUTHOR]

The article presents an obituary for professor and scientist Per Bergsjö.

OBJECTIVE: Nitric oxide may be a factor in cervical ripening. We compared the nitric oxide metabolite levels in cervical fluid in women going beyond term and in women delivering spontaneously at term. METHODS: We studied a total of 208 women with singleton pregnancies: 108 women who went beyond term (294 days or longer), and 100 women who went spontaneously into labor at term. Cervical fluid samples, collected well before the initiation of labor, were assessed for nitric oxide metabolites using an assay with a detection limit of 3.8 μmol/L. RESULTS: Women going beyond term had detectable levels of nitric oxide metabolites in their cervical fluid (60%) less often (P = .001) than women delivering at term (87%). The nitric oxide metabolite concentration in cervical fluid in women going beyond term (median 23.5 μmol/L; 95% confidence interval less than 3.8, 31.8) was 4.5 times lower (P < .001) than that in women delivering at term (median 106.0 μmol/L; 95% confidence interval 81.8, 135.0). Such a difference (14.0 versus 106.0 μmol/L) also existed when only the 66 women going into spontaneous postterm labor were included in the comparison. Both nulliparous (median less than 3.8 μmol/L) and parous (median 31.3 μmol/L) women going beyond term had lower (P < .01) cervical fluid nitric oxide metabolite levels than nulliparous and parous women delivering at term (medians 76.1 and 101.3 μmol/L, respectively). In the postterm group, women with cervical fluid nitric oxide metabolite concentrations at or below the median failed more often (P < .001) to progress in labor and had longer (P = .02) duration of labor than those with cervical fluid nitric oxide metabolite concentrations above the median. CONCLUSION: Reduced cervical nitric oxide release may contribute to prolonged pregnancy. [ABSTRACT FROM AUTHOR]