Amniotic fluid levels of dimeric inhibins, pro-αC inhibin, activin A and follistatin in Down''s syndrome

OBJECTIVE: In the second trimester of pregnancy, inhibin A is significantly increased in maternal serum and decreased in amniotic fluid in Down's syndrome pregnancies compared to normal. We wished to further evaluate the levels of inhibin A, inhibin B, pro-alpha C inhibin, activin A and the binding protein follistatin in amniotic fluid in Down's syndrome and control pregnancies. DESIGN: Case-matched control study. PATIENTS: 29 Down's syndrome and 290 chromosomally normal control pregnancies were identified from records and amniotic fluid, collected at second trimester amniocentesis, retrieved from routine storage for analysis. MEASUREMENTS: Inhibin A, inhibin B, pro-alpha C inhibin, total activin A and follistatin were measured using sensitive and specific enzyme linked immunosorbent assays. RESULTS: The median (10th-90th percentiles) amniotic fluid inhibin A level in the control pregnancies increased from 334 (122-553) ng/l at 14 weeks' to 695 (316-1475) ng/l at 19 weeks' gestation. The corresponding figures for inhibin B and the alpha-subunit precursor inhibin pro-alpha C were 632 (185-1354) and 2062 (1237-3381) ng/l, respectively at 14 weeks' and 2439 (748-5307) and 3115 (2021-6567) ng/l, respectively at 19 weeks' gestation. Total activin A increased from 3795 (1554-5296) at 14 weeks' to 5086 (3059-8224) at 18 weeks' gestation. Expressed as multiples of the median (MoM) the median (95% CI) amniotic fluid levels of inhibin A, inhibin B, pro-alpha C inhibin and acitivin A in the Down's syndrome samples were 0.77 (0.59-0.85), 0.94 (0.63-1.23), 0.77 (0.49-0.84) and 0.77 (0.53-0.87), respectively. Compared to controls the levels of inhibin A, pro-alpha C inhibin and activin A were significantly lower in Down's syndrome pregnancies (P < 0.01, Mann-Whitney U test). Follistatin levels in the controls declined slightly from 2106 (1421-3538) ng/l at 14 weeks' to 1600 (1281-2543) ng/l at 18 weeks' gestation. Levels in the Downs' syndrome pregnancies were similar to controls. CONCLUSIONS: The data suggest that the production, secretion or metabolism of the inhibin alpha- and beta A-subunits is altered in Down's syndrome pregnancies in the second trimester.     

Increased levels of human placental growth hormone in the amniotic fluid of pregnancies affected by Down syndrome

ObjectiveTo evaluate the concentrations of human placental growth hormone (hPGH) in amniotic fluid (AF) at gestational mid-trimester in normal pregnancies and in pregnancies complicated by Down’s syndrome.DesignAF samples from 21 women with Down’s syndrome pregnancies were analyzed retrospectively. About 47 AF samples from women with singleton, uncomplicated pregnancies, who gave birth to healthy neonates with birth weight appropriate for gestational age were used as controls. All AF samples were obtained during amniocentesis for fetal karyotyping at 16–23 weeks’ gestation. hPGH levels were measured by a solid phase immunoradiometric assay using two different epitopes.ResultsThe mean hPGH values in the AF of the Down’s syndrome-affected pregnancies were significantly higher (P < 0.05) compared to those of normal pregnancies, at 16–23 weeks’ gestation: mean-value ± SD in the AF was 1.96 ± 1.35 μg/l vs. 0.82 ± 0.67 μg/l.ConclusionsHigher hPGH levels in AF were found in pregnancies affected by Down’s syndrome as compared to normal pregnancies at gestational mid-trimester. hPGH was detected in all AF samples, and it provides evidence that this pregnancy-specific hormone enters the fetal compartment and is not limited to the maternal circulation. The physiological role and effect of hPGH on fetal growth in normal and pathological pregnancies needs further investigation.     

Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation

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.     

Insulin-like growth factors in amniotic fluid

The concentrations of insulin-like growth factors I and II (IGF-I and IGF-II) in amniotic fluid were determined by specific immunoassays in 58 women. IGF-I concentrations were constant throughout gestation at approximately 20 ng/ml; the mean IGF-II concentration was 114 +/- 13 (+/- SE) ng/ml at the earliest period of gestation studied and remained unchanged at 26 to 33 weeks despite a greater than 50% decrease in amniotic fluid total protein. A precipitous decrease in IGF-II concentration occurred at term which was not explainable by alterations in total amniotic fluid protein concentration. The concentrations of IGF-I and IGF-II in amniotic fluid did not correlate with concentrations of these factors in maternal serum (r = 0.08 and 0.09, respectively). [125I]IGF-I and [125I]IGF-II, after incubation with amniotic fluid, bound to a 40-45 K protein (or proteins). A carrier protein of greater mol wt, as in serum, was not detected. These findings indicate that there is dynamic control of IGF in amniotic fluid during normal pregnancy.     

A longitudinal analysis of maternal serum insulin-like growth factor I (IGF-I) and total and nonphosphorylated IGF-binding protein-1 in human pregnancies complicated by intrauterine growth restriction

In cord blood and late gestation maternal serum, IGF-I is positively correlated with birth weight, whereas IGF-binding protein-1 (IGFBP-1) is inversely correlated with birth weight. Our goal was to determine whether maternal serum or amniotic fluid concentrations of IGF-I, IGFBP-1, or nonphosphorylated IGFBP-1 (npIGFBP-1) in early gestation predict later fetal growth abnormalities. Maternal serum was collected prospectively across gestation (5-40 wk) from 749 pregnant subjects. Amniotic fluid was collected after amniocentesis during wk 15-26 from 207 subjects. We compared median serum concentrations of IGF-I, IGFBP-1, and npIGFBP-1 in 38 subjects who delivered growth-restricted infants with the control group of 236 subjects with normal weight infants for each gestational age grouping, wk 5-12, 13-23, and 24-34. In the control group median IGF-I concentrations were 14.8, 11, and 15.6 nmol/liter for wk 5-12, 13-23, and 24-34, respectively, compared with 13.7, 14.3, and 10.6 nmol/liter in the intrauterine growth restriction (IUGR) group. Median IGFBP-1 concentrations were 8.5, 30.4, and 24.4 nmol/liter, respectively, in controls, compared with 11.4, 28.6, and 25.5 nmol/liter in the IUGR group. Median npIGFBP-1 concentrations were 6.9, 22, and 17.4 nmol/liter, respectively, in controls, compared with 5.0, 32.1, and 24.2 nmol/liter in the IUGR group. In the control group the median amniotic fluid IGFBP-1 level was 13,160 nmol/liter, and the median npIGFBP-1 level was 15,970 nmol/liter; in the IUGR group these levels were 13,440 and 18,440 nmol/liter, respectively. No clinically useful differences were found between the IUGR and control groups. Our results do not support the use of maternal serum IGF-I or IGFBP-1 or amniotic fluid IGFBP-1 or npIGFBP-1 early in gestation to predict later fetal growth restriction.     

Detection of endocrine disrupting chemicals in samples of second trimester human amniotic fluid

Man-made chemicals that have been shown to modulate endocrine function in animal models, so-called "endocrine disrupters", are suspected to play a role in the development of male reproductive tract abnormalities and neurobehaviroal deficits in children. However in utero exposure to environmental contaminants has not been documented previously. The present study was performed to test our hypothesis that man-made chemicals can be quantified in human amniotic fluid during the second trimester. Gas chromatographic/mass spectrometric (GC/MS) analysis was performed on amniotic fluid samples (n=53) from women (n=51) undergoing routine amniocentesis with a mean (+/- SEM) age of 36.5 +/- 0.5 years and between 15 and 23 weeks of gestation. Analytes included common PCB congeners, the DDT metabolites p,p'-DDE, and o,p'-DDE as well as the pesticides: hexachlorobenzene (HCB); and the three isomers of hexachlorocyclohexane (alpha,beta and gamma-HCH). The limit of quantitation (LOQ) for PCBs was 0.01 ng/ml and for the other organochlorines contaminants is was 0.1 ng/ml. The contaminants alpha-HCH with a mean (+/- SD) concentration of 0.15 +/- 0.06 (ng/ml) and p,p'-DDE with a mean (+/- SD) concentration of 0.21 +/- 0.18 ng/ml were detected in the amniotic fluid. PCB specific congeners were detected with a much lower frequency and levels were in the range of the LOQ. Overall one in three amniotic fluid samples tested positive for at least one environmental contaminant. Therefore, we conclude that approximately one in three fetuses in the Los Angeles area are exposed to endocrine modulatory environmental contaminants in utero the consequences of which remain unknown at this time.     

Thrombopoietin levels in cord blood plasma and amniotic fluid in fetuses with alloimmune thrombocytopenia and healthy controls

To extend our knowledge of the kinetics of fetal thrombopoietin (TPO), we studied TPO levels in cord blood plasma and amniotic fluid collected from 15 fetuses considered to be at risk of fetomaternal alloimmune thrombocytopenia and also from 10 healthy controls at caesarean delivery. In the plasma of all 25 fetuses and newborn infants studied, TPO was detected above the lower limit of detection (7 pg/ml) and correlated inversely with platelet counts (r = -0.53, P = 0.006). At term, TPO detected in amniotic fluid was at significantly lower levels (7 pg/ml; range 0-22 pg/ml) than simultaneously obtained cord plasma TPO (114 pg/ml; range 43-201 pg/ml; P < 0.001). There was no correlation between levels of TPO in amniotic fluid and cord plasma or platelet counts. In the serial samples collected from the five fetuses with HPA-1a alloimmunization before 37 weeks' gestation, the TPO levels in amniotic fluid were significantly higher than at term (P = 0.013): from 22 to 28 weeks' gestation, 42 pg/ml (30-78 pg/ml); from 32 weeks', 24 pg/ml (17-33 pg/ml); at term, 8 pg/ml (4-13 pg/ml), correlating inversely with gestational age (r = -0.81, P = 0.003). Thus, TPO is present in amniotic fluid at levels apparently inversely related to gestational age. Whether these high levels seen early in pregnancy are normal or are associated with the HPA-1 alloimmunization remains to be shown.     

Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy

Serum melatonin concentrations were studied in normal pregnant women and in women with several types of pathologic pregnancies, e.g., twins, preeclampsia or intrauterine growth retardation (IUGR). Blood samples were collected from the maternal antecubital vein at 14:00 hr (daytime) and 02:00 hr (nighttime) during pregnancy, and also from the umbilical vein and artery immediately after delivery. Serum melatonin concentrations were measured by radioimmunoassay. Daytime serum melatonin levels in normal (single fetus; singleton) pregnancies were low. While the levels showed an increasing tendency toward the end of pregnancy, no statistically significant changes occurred. On the other hand, the nighttime serum melatonin levels increased after 24 weeks of gestation, with significantly (P < 0.01) high levels after 32 weeks; these values decreased to non-pregnant levels on the 2nd day of puerperium. Nighttime serum melatonin levels were significantly (P < 0.05) higher in twin pregnancies after 28 weeks of gestation than in singleton pregnancies, whereas the patients with severe preeclampsia showed significantly (P < 0.05) lower serum melatonin levels than the mild preeclampsia or the normal pregnant women after 32 weeks of gestation. Melatonin concentrations in umbilical vessels showed a higher tendency in neonates who were born during at night compared with the other neonates; moreover, those in the umbilical artery were generally higher than those in the umbilical vein. The present results indicate that in humans, the maternal serum melatonin levels show a diurnal rhythm, which increases until the end of pregnancy, reflecting some pathologic states of the feto-placental unit. Fetuses may produce melatonin with a circadian rhythm.     

Maternal plasma concentrations of soluble endoglin in pregnancies with intrauterine growth restriction

CONTEXT: Soluble endoglin (sEng), a coreceptor for TGF with antiangiogenic properties, acts synergistically with soluble fms-like tyrosine kinase 1 (sFlt1) to induce symptoms of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in animal models and to promote a preeclamptic phenotype. Pregnant women with preeclampsia show increased sEng concentrations in circulation, whereas the sEng increase is detectable months before the clinical onset of the disease. OBJECTIVE: The aim of the study was to determine whether maternal sEng is altered in pregnancies with normotensive intrauterine growth restriction (IUGR). DESIGN: sEng and sFlt1 were retrospectively determined by a commercial ELISA. PATIENTS: The study included 11 normotensive pregnancies with IUGR, 18 pregnancies with manifest preeclampsia, and 15 gestational-age-matched controls. RESULTS: Patients with preeclampsia showed significantly higher sEng concentrations compared with controls (57.0 ng/ml vs. 5.3 ng/ml; P < 0.001). Also IUGR pregnancies showed significantly elevated sEng concentrations (25.9 ng/ml; P < 0.001), but the levels were lower compared with the preeclamptic patients. There was a strong positive correlation between the sEng and sFlt1 concentration (Pearson 0.552; P < 0.01). Similar to sEng, the maternal sFlt1 concentration is highest in the preeclamptic patients (8388 vs. 2602 pg/ml; P < 0.01) but also significantly elevated in the IUGR patients (6952 pg/ml; P < 0.01). CONCLUSIONS: Pregnancy with IUGR, but without maternal symptoms, was characterized by elevated sEng concentrations in circulation. Although this finding is less pronounced when compared with preeclampsia, sEng seems to be involved in different clinical manifestations of placental pathology.     

Amniotic fluid concentrations of dimeric inhibins, activin A and follistatin in pregnancy

OBJECTIVE: The feto-placental unit is the major source of circulating concentrations of inhibin A and activin A in human pregnancy. The aim of this study was to measure the amniotic fluid concentrations of inhibin A, inhibin B, activin A and follistatin in pregnancies bearing male and female fetuses. DESIGN AND METHOD: Amniotic fluid samples collected by amniocentesis were stored at -20 degrees C. Dimeric inhibins, 'total' activin A and 'total' follistatin were measured using specific two-site enzyme immunoassays. Samples were assayed blindly and the information on fetal sex was obtained from the cytogenetics laboratory. RESULTS: Data show that amniotic fluid concentrations of inhibin A, inhibin B and activin A gradually increase with gestation whilst concentrations of follistatin are similar between weeks 15 and 20 of pregnancy. Mean amniotic fluid levels of inhibin A and inhibin B at 16 and 17 weeks gestation and mean activin A levels at 15 and 16 weeks gestation are considerably lower in pregnancies with male (n=24) compared with female (n=28) fetuses. Levels of follistatin are not different in the male and female fetal pregnancies at any studied gestation. CONCLUSIONS: The results indicate that amniotic fluid contains high concentrations of inhibins (A and B), activin A and follistatin in early pregnancy suggesting that these hormones are produced by the fetal membranes and may be involved in the development of the fetus.     

Amniotic fluid testosterone: relationship with cortisol and gestational age

INTRODUCTION: Foetal exposure to testosterone is increasingly implicated in the programming of future reproductive and non-reproductive behaviour. Some outcomes associated with prenatal exposure to testosterone may be predicted from exposure to prenatal stress, suggesting a link between them. The peak serum levels of testosterone in the foetus are thought to be around 14-18 weeks' gestation, and we explored testosterone levels at different gestations. Although best investigated in foetal plasma, this is now difficult because of the decline in frequency of foetal blood sampling; in this study, we used amniotic fluid as a biomarker to investigate foetal exposure. AIMS: To investigate the relationship between amniotic fluid testosterone, amniotic fluid cortisol, foetal gender, and gestational age. METHODS: Paired amniotic fluid and maternal plasma samples were collected from 264 pregnant women undergoing amniocentesis between 15 and 37 weeks' gestation (median 17 weeks [119 days]). Total testosterone and cortisol in amniotic fluid, and total plasma testosterone (maternal) were measured by radioimmunoassay. RESULTS: Amniotic fluid testosterone levels were higher in male than in female foetuses, with a median (interquartile range) of 0.85 nmol/l (0.60-1.17 nmol/l) and 0.28 nmol/l (0.175-0.45 nmol/l), respectively. No relationship between amniotic fluid testosterone and gestational age was detected in either sex. Amniotic fluid testosterone correlated positively with amniotic fluid cortisol in both sexes (r = 0.30 male foetuses, r = 0.33 female foetuses, P < 0.001 for both), and remained significant in multivariate analysis. CONCLUSION: Testosterone in amniotic fluid did not change with gestation in the second and third trimester, raising questions about the timing of the reported early peak in the male foetus. The positive correlation between cortisol and testosterone in amniotic fluid suggests that increased foetal exposure to cortisol may also be associated with increased exposure to testosterone.     

Adrenomedullin production is increased in normal human pregnancy

OBJECTIVE: Adrenomedullin, a recently discovered vasoactive peptide originally identified in pheochromocytoma, has been found to be increased in the plasma of pregnant women at term. This study was designed to elucidate whether adrenomedullin secretion is dependent on gestational age and the possible source and function of this peptide in human pregnancy. STUDY DESIGN: Adrenomedullin concentrations were determined by RIA in amniotic fluid and maternal plasma obtained from 110 pregnant women between 8 and 40 weeks of gestation. Subjects were stratified into five groups according to gestational age. In term patients (n = 15), adrenomedullin was also measured in the umbilical artery and vein separately. RESULTS: High concentrations of adrenomedullin were present in plasma and amniotic fluid samples from patients in the first, second and third trimester. There was no significant difference in mean maternal plasma concentration of adrenomedullin between the five patient groupings. Amniotic fluid adrenomedullin concentrations decreased from 81.2 +/- 11.7 pg/ml at 8-12 weeks of gestation to 63.7 +/- 6.0 pg/ml at 13-20 weeks of gestation and then increased at 21-28 weeks of gestation to 99.1 +/- 10.4 pg/ml. A further increase was found in samples collected after 37 weeks of gestation (132.6 +/- 10.1 pg/ml). In the umbilical vein, adrenomedullin concentration was higher (P < 0.05) than in the artery (65.7 +/- 6.1 pg/ml and 48.5 +/- 5.2 pg/ml respectively), suggesting that adrenomedullin in the fetal circulation derives from the placenta. CONCLUSIONS: Our results demonstrate the presence of adrenomedullin in maternal plasma and amniotic fluid throughout gestation, and show that its production starts very early in gestation, suggesting that this hormone may have an important role in human reproduction, from implantation to delivery.     

Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns

Little is known about the outcome of pregnancy in women with beta-thalassemia intermedia (TI). Over 10 years, maternal and neonatal outcomes of women with TI followed at a single thalassemia center were reviewed. Nine spontaneous pregnancies in five women with TI were studied. Six pregnancies resulted in live newborns; two were complicated by first-trimester abortions and one by an unexplained intrauterine fetal death at 36 weeks' gestation. Two patients had splenectomy before pregnancy: one required cesarean delivery and splenectomy at 31(2/7) weeks' gestation for worsening hemolytic anemia and thrombocytopenia and another had splenectomy 8 weeks postpartum for symptomatic hypersplenism. Two patients had received transfusions before pregnancy, and two required them for the first time during pregnancy and developed antibodies, which contributed to worsening of their anemia and repeated transfusions. The mean number of transfusions received during pregnancy was 8.0 +/- 5.2 units. The mean lowest hemoglobin level in pregnancy was 5.2 +/- 2.0 g/dl. Cesarean delivery was performed in 42.9% of cases. Mean gestational age at delivery was 36.7+/- 3.1 weeks with intrauterine growth restriction (IUGR) complicating 57.1% of cases. In conclusion, IUGR complicates more than half of pregnancies with TI. Transfusions are needed in most cases, even in non-transfusion-dependent patients. Postpartum splenectomy might be necessary in some patients.     

Ontogeny of foetal exposure to maternal cortisol using midtrimester amniotic fluid as a biomarker

OBJECTIVE: There is increasing evidence that antenatal stress has long-lasting effects on child development, but there is less accord on the mechanisms and the gestational window of susceptibility. One possible mechanism is by foetal exposure to maternal cortisol. To explore this, we investigated the relationship between cortisol in maternal plasma and amniotic fluid, and any moderating influence of gestational age. PATIENTS AND MEASUREMENTS: Two hundred and sixty-seven women awaiting amniocentesis for karyotyping were studied. Samples were collected between 0900 and 1730 h. Gestational age was determined to the nearest day by ultrasound biometry and time of collection noted to the nearest 15 min. Total cortisol was measured by radioimmunoassay in paired amniotic fluid and maternal blood samples (n = 267) [gestation range 15-37 weeks, median 17 weeks (119 days)]. RESULTS: Both maternal and amniotic fluid cortisol levels increased with gestation (r = 0.25, P < 0.001; r = 0.33 P < 0.001, respectively). Amniotic fluid cortisol was positively correlated with time of collection (r = 0.22, P < 0.001) and negatively with maternal age (r =-0.24, P < 0.001). There was a positive correlation between amniotic fluid cortisol with maternal plasma levels (r = 0.32, P < 0.001), which persisted after multivariate analysis controlling for gestation, time of collection and maternal age. The association appeared to be dependent on gestational age, being nonsignificant at 15-16 weeks' gestation and increasing in strength thereafter. CONCLUSION: This study shows a positive correlation between maternal and amniotic fluid cortisol levels, which becomes robust from 17 to 18 weeks onwards. The results provide support for the hypothesis that alterations in maternal cortisol may be reflected in amniotic fluid levels from this gestation.     

Measurement and characterization of insulin-like growth factor binding protein-3 in human biological fluids: discrepancies between radioimmunoassay and ligand blotting.

The inability to detect insulin-like growth factor binding protein-3 (IGFBP-3) in some circumstances by Western ligand blot analysis has emphasized the need to characterize IGFBPs by both ligand binding and immunological techniques. In this study, we have: 1) characterized and quantified IGFBP-3 in nonpregnancy, pregnancy, and fetal cord serum, follicular, peritoneal, and amniotic fluid, seminal plasma, cerebrospinal fluid (CSF), and urine; 2) established a new IGFBP-3 RIA that detects both intact and fragments of IGFBP-3; 3) identified both intact and fragments of IGFBP-3 by Western immunoblot techniques; and 4) addressed the discordance between Western ligand blot analysis and RIA by assessing fluids for IGFBP proteolytic activity. All fluids examined, except pregnancy serum, CSF, and amniotic fluid, displayed a 44-34-kilodalton (kDa) IGFBP-3 doublet by Western ligand blot analysis. Western immunoblot analysis using specific IGFBP-3 antiserum showed a 44-34-kDa IGFBP-3 doublet and a 28-kDa fragment in nonpregnancy serum, fetal cord serum, follicular fluid, and peritoneal fluid. The immunoreactive 42-38-kDa doublet was faint in urine and seminal plasma. IGFBPs in CSF did not cross-react with IGFBP-3 antiserum. Pregnancy serum and amniotic fluid contained only the 28-kDa fragment when compared against equal volumes of nonpregnancy serum. With the development of an IGFBP-3 RIA, IGFBP-3 could be accurately measured; urine, CSF, and seminal plasma contained the lowest levels of IGFBP-3 at 27 +/- 3 ng/ml (mean +/- SEM), 110 +/- 26 ng/ml, and 209 +/- 56 ng/ml, respectively. In increasing concentration: fetal cord serum contained 753 +/- 101 ng/ml; peritoneal fluid, 1124 +/- 130 ng/ml; follicular fluid, 2356 +/- 211 ng/ml; nonpregnancy serum, 3556 +/- 508 ng/ml; pregnancy serum, 3718 +/- 842 ng/ml; and amniotic fluid, 5150 +/- 688 ng/ml. The measurable concentrations of IGFBP-3 in CSF and the high concentrations measured in pregnancy serum and amniotic fluid conflicted with Western blot analysis. Thus, fluids were assessed for IGFBP proteolytic activity by incubation with a source of IGFBP-3, either nonpregnancy serum or purified IGFBP-3. All fluids displayed some proteolytic activity with either assay. Fluids with little protease activity (nonpregnancy serum, follicular fluid, and urine) showed a close relationship between immunoassayable IGFBP-3 by RIA and IGFBP-3 band intensity by Western ligand blot. Fluids with high proteolytic activity (pregnancy serum, CSF, seminal plasma, peritoneal fluid, and amniotic fluid) gave discrepant IGFBP-3 values between RIA and Western ligand blot.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serum dehydroepiandrosterone sulfate in premature infants and infants with intrauterine growth retardation.

Serum dehydroepiandrosterone sulfate (DHAS) was measured by radioimmunoassay in blood samples obtained in 128 ill newborn infants. Serial sampling was carried out in 40 infants. There were wide ranges found in the values in all gestational age groups, and there were not significant differences in the first day of life between DHAS levels in less than 30 week gestation prematures, 6819 +/- 4631 (SD) ng/ml, and near term or term infants, 4307 +/- 1498 ng/ml. Mean DHAS concentrations did not decline over the first three weeks of life in prematures less than 36 weeks gestation. In six infants, age 35-73 days, and 29-34 weeks gestation at birth, the DHAS concentration was 1068 +/- 138 ng/ml. High concentrations were frequent in prematures less than 33 weeks gestation and could be correlated to epiodes of severe clinical stress. There were no significant differences in serum DHAS levels, on the first day of life, between infants with no hyaline membrane disease, nonfatal hyaline membrane disease and fatal hyaline membrane disease. Intrauterine growth retarded (IUGR) infants, who were greater than 35 weeks gestation, had significantly lower (P less than .032) DHAS levels in the first day of life than normally grown infants. The results show that there is a persistence during the postnatal period of the prominent delta5-3beta-hydroxysteroid production by the adrenal cortex characteristic of the fetus. Low concentrations of serum DHAS in IUGR infants suggest that the fetal zone of the neonatal adrenal cortex is a major source of circulating DHAS in the newborn period.     

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P 相似文献   

Human placental growth hormone,insulin-like growth factor I and -II,and insulin requirements during pregnancy in type 1 diabetes

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P < or = 0.021). Serum hPGH correlated to serum IGF-I from wk 24- 35, and changes in IGF-I followed the increase in hPGH between wk 26-35 (r(s) = 0.53; P < 0.001), as did IGF-II (r(s) = 0.37; P = 0.008). Changes in IGF-I and IGF-II between wk 26-35 also correlated to the birth weight z-score (P < or = 0.020), but only hPGH remained significant in multiple regression analysis. Similar results were found in the subgroup delivering at term. Interestingly, the increase in hPGH was not correlated to the increase in insulin requirements, nor was any consistent relationship revealed during each gestational period. In conclusion, our study suggests a role for hPGH in the regulation of both IGFs and fetal growth in type 1 diabetes. In contrast, the increase in insulin requirements during pregnancy in type 1 diabetic subjects could not be related to hPGH levels.     

Differential regulation of visfatin and adiponectin in pregnancies with normal and abnormal placental function

OBJECTIVE: There is compelling evidence that insulin resistance may play a pivotal role in the development of pregnancy complications including pre-eclampsia and intrauterine growth restriction (IUGR). As dysregulation of visfatin and adiponectin is found in insulin resistance, both adipokines might contribute to pregnancy disorders. PATIENTS AND METHODS: Plasma levels of visfatin and adiponectin were quantified in second-trimester pregnancies with abnormal uterine perfusion and in third-trimester pregnancies with IUGR as compared to healthy controls. RESULTS: Mean plasma adiponectin levels were significantly increased in women with pathological perfusion (7078 +/- 789 ng/ml) as compared to normal uterine perfusion (4481 +/- 1183 ng/ml) (P < 0.05) whereas visfatin plasma concentrations were not different between these groups. Visfatin levels were significantly elevated in women with IUGR (140.1 +/- 10 ng/ml) as compared to patients with normal outcome (65.5 +/- 11 ng/ml) (P < 0.05). By contrast, adiponectin plasma concentrations were not significantly altered in women with IUGR. CONCLUSIONS: Our data support the view that the adipokines visfatin and adiponectin are differentially regulated in pregnancy complications.     

Involvement of fibrinolytic factors in mid trimester amniotic fluid with development of severe early-onset preeclampsia

Impaired placental development is a well-known pathogenesis in preeclampsia. The present study was undertaken to elucidate the involvement of fibrinolytic factors in amniotic fluid in midtrimester with development of severe early-onset preeclampsia. Amniotic fluid was obtained by amniocentesis at 15 to 18 weeks of gestation. All specimens were retrospectively identified according to the hospital records as coming from gestations that later had severe early-onset preeclampsia (severe preeclamptic group, n = 9) or gestations with normal outcomes (control group, n = 73). Fibrinolytic factors such as tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and t-PA-PAI-1 complex (PAI-C) of specimens were measured by enzyme-linked immunoassay. In the control group, concentrations of t-PA as well as PAI-1 in amniotic fluid remained at similar levels from 15 to 18 weeks, although PAI-1 levels were more than 10 times higher compared with t-PA levels. Levels of t-PA and PAI-1 in the severe preeclamptic group were not different from those of the control group. PAI-C levels gradually decreased from 15 through 18 weeks of gestation in the control group. PAI-C levels of the severe preeclamptic group were significantly lower than those of the control group (55.5 +/- 18.0% versus control; mean +/- standard deviation [SD], p <0.001). PAI-C, as the most specific indicator of the early stage of fibrinolytic activities, showed lower levels in midtrimester amniotic fluid in the severe preeclamptic group, suggesting fibrinolytic activities of amniotic fluid may have a significant role in the development of severe early-onset preeclampsia via impaired placental development in the latent stage of preeclampsia.