The preterm prediction study: granulocyte colony-stimulating factor and spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

OBJECTIVE: Granulocyte colony-stimulating factor is elevated in the amniotic fluid and plasma of women with chorioamnionitis and active preterm labor. We investigated the relationship between plasma granulocyte colony-stimulating factor and subsequent spontaneous preterm birth in pregnant women without symptoms. STUDY DESIGN: We performed a nested case-control study involving 194 women who had a singleton spontaneous preterm birth and 194 matched term control subjects from the patient pool (n = 2929) enrolled in the Preterm Prediction Study. Plasma collected at 24 and 28 weeks' gestation was analyzed for granulocyte colony-stimulating factor, and the results were compared with subsequent spontaneous preterm birth. RESULTS: Compared with term control subjects, women who were delivered of their infants spontaneously at <28 weeks' gestation had increased mean granulocyte colony-stimulating factor values at 24 weeks' gestation (84.7 +/- 38.4 vs 67.7 +/- 28.6 pg/mL; P =.049), and women who were delivered of their infants at <32 weeks' gestation had increased mean plasma granulocyte colony-stimulating factor values at 28 weeks' gestation (80.4 +/- 24.1 vs 55.9 +/- 16.5 pg/mL; P =. 001). At 24 weeks' gestation a granulocyte colony-stimulating factor value >75th percentile in control subjects (approximately 80 pg/mL) was found in 48.9% (23/47) of all women delivered of their infants at <32 weeks' gestation versus 14.9% (7/47) of the term control subjects (adjusted odds ratio, 6.2; 95% confidence interval, 1.8-20. 8). At 28 weeks' gestation a granulocyte colony-stimulating factor value >75th percentile was found in 36.8% (7/19) of women delivered of their infants at <32 weeks' gestation versus 5.3% (1/19) of term control subjects (adjusted odds ratio, 25.7; 95% confidence interval, 1.5-470.4). When measured at 24 or 28 weeks' gestation, granulocyte colony-stimulating factor did not predict spontaneous preterm birth at 32 to 34 weeks' gestation or at 35 to 36 weeks' gestation. CONCLUSION: In pregnant women without symptoms at 24 and 28 weeks' gestation, elevated plasma granulocyte colony-stimulating factor levels are associated with subsequent early (<32 weeks' gestation) spontaneous preterm birth, especially within the next 4 weeks, but not with late spontaneous preterm birth. These data provide further evidence that early spontaneous preterm birth is associated with an inflammatory process that is identifiable by the presence of a cytokine in maternal plasma several weeks before the early spontaneous preterm birth; however, later spontaneous preterm birth is not associated with this process.     

Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy

Adrenocorticotropin (ACTH) and cortisol in plasma were measured weekly from early in gestation through delivery in five women whose pregnancies were normal. During the twelfth week of pregnancy, the concentration of ACTH in plasma of blood samples obtained between 0800 and 0900 hours was 23 +/- 4.6 pg/ml (mean and SEM) and rose progressively to 59 +/- 16 pg/ml at 37 weeks. The levels of ACTH in plasma were significantly lower throughout pregnancy than those found in nonpregnant women. During labor and delivery, ACTH levels rose strikingly to values of 301 +/- 137 pg/ml. As pregnancy advanced, the concentration of cortisol in plasma increased progressively from 149 +/- 34 ng/ml (mean and SEM) at 12 weeks to 352 +/- 90 ng/ml at 26 weeks' gestation but changed minimally thereafter until labor commenced, during which values of 706 +/- 148 ng/ml were achieved. ACTH and cortisol secretory patterns over a 24-hour period were also investigated in one subject during each trimester of pregnancy. Diurnal variations were observed that were qualitatively similar to those seen in nonpregnant women. From the results of these studies, we conclude that ACTH levels are suppressed in plasma of normal pregnant women but are higher in late pregnancy than in early pregnancy. The rise in plasma ACTH concentrations, as pregnancy advances, in spite of increasing levels of plasma cortisol, estrogens, and progesterone, is suggestive of the possibility that a source of ACTH exists that is not subject to negative feedback control, that the clearance of free cortisol increases as pregnancy advances, or that there is an alteration in the metabolism of the ACTH precursor protein produced by the pituitary and/or placenta.     

Plasma immunoreactive beta-endorphin, ACTH and cortisol concentrations in mothers and their neonates immediately after delivery--their relationship to the duration of labor

In 29 cases of vaginal delivery with normal outcome and 4 cases of cesarean section, the concentrations of beta-endorphin, ACTH and cortisol were determined in maternal venous and umbilical venous plasma immediately postpartum. According to duration of labor and mode of delivery the cases examined were classified into three groups: Group A (18 cases) = vaginal delivery of less than 10 hours' duration, Group B (11 cases) = vaginal delivery of more than 10 hours' duration of labor, Group C (4 cases) = cesarean section under general anesthesia. With the exception of one, the deliveries took place at term. The 33 neonates were in a very good clinical state 5 minutes after parturition (11 Saling points as median value). For measurement of the hormone concentrations radioimmunoassays were used. In Group a the mean beta-endorphin concentration in maternal plasma amounted to 150.9 +/- 16.3 pg/ml, that in neonatal plasma to 239.2 +/- 23.5 pg/ml (means +/- SEM). In Group B plasma beta-endorphin, both maternal and neonatal, was slightly higher than in Group A: 153.0 +/- 12.0 pg/ml (maternal) and 260.9 +/- 37.1 pg/ml (neonatal). The differences between maternal and neonatal beta-endorphin levels were statistically significant: Group A p less than 0.01, Group B p less than 0.05; chi 2-test. The mean ACTH concentrations in the plasma of the newborn infants were also found to be considerably higher compared with those in the plasma of their mothers: Group A 78.2 +/- 16.5 pg/ml (maternal) and 98.0 +/- 23.3 pg/ml (neonatal); Group B 98.0 +/- 20.1 pg/ml (maternal) and 165.8 +/- 39.6 pg/ml (neonatal).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma corticotropin-releasing hormone and unconjugated estriol in human pregnancy: gestational patterns and ability to predict preterm delivery.

OBJECTIVE: The purpose of this study was to compare the patterns and timing of the increases in plasma levels of corticotropin-releasing hormone and unconjugated estriol during human pregnancy. STUDY DESIGN: Corticotropin-releasing hormone and unconjugated estriol were measured in serial samples that were collected from preterm subjects and from spontaneous term control subjects who were selected randomly from a study cohort of 297 women. RESULTS: Gestational increases in log corticotropin-releasing hormone and log unconjugated estriol concentrations were best described by linear and cubic polynomial functions, respectively. Plasma unconjugated estriol levels were similar in preterm and term singleton pregnancies at equivalent gestation, whereas corticotropin-releasing hormone was elevated earlier in premature subjects. Mean corticotropin-releasing hormone levels relative to term control subjects (n = 40 women) were shifted forward 16.5 +/- 8.1 days (P =.027, singleton preterm, spontaneous labor; n = 16) and 33.0 +/- 7.9 days (P <.001, singleton preterm, obstetric intervention; n = 10). The corresponding shifts in unconjugated estriol values were -3.8 +/- 2.0 days and -2.7 +/- 5.6 days (both not significant). The prematurity of delivery showed a significant regression on shifts in corticotropin-releasing hormone (P =.004 and P <.001) but not in unconjugated estriol for the 2 groups. The ability to predict prematurity was not significantly improved by regression on corticotropin-releasing hormone and unconjugated estriol shift values together. CONCLUSION: The patterns and timing of gestational changes in corticotropin-releasing hormone and unconjugated estriol differ in humans. The usefulness of corticotropin-releasing hormone as a biochemical preterm marker in singleton pregnancies is not enhanced by the additional measurement of plasma unconjugated estriol.     

Glucagon, insulin and glucose levels in maternal and imbilical cord plasma with studies of placental transfer.

Plasma immunoreactive glucagon, as well as insulin and glucose levels, was measured in 62 women and their infants following a term gestation vaginal delivery. Simultaneously obtained samples were drawn from the maternal antecubital vein (MV), umbilical vein (UV), and umbilical artery (UA). Forty-seven of these subjects were untreated (control) and 15 had received a maternal intravenous injection of 1 mg of glucagon within 40 minutes of delivery. It was shown that the umbilical cord glucagon levels were not different from the maternal levels in the control subjects (mean MU, 181.0; UU, 191.9; UA, 161.0 pg/ml). There was no correlation between the maternal and umbilical glucagon levels or the UV glucagon levels and the insulin or glucose concentrations. Neither the fetal sex, placental weight, or infant weight were correlated with the MV or UV glucagon concentration. Following the glucagon injection, the maternal plasma glucagon levels rose significantly, whereas the umbilical blood values did not change. These results suggest that glucagon does not significantly pass through the human term placenta.     

Elevated maternal plasma corticotropin releasing hormone levels in twin gestation

The placenta secretes large amounts of the hypothelamic hormone, corticotropin releasing hormone (CRH) into the maternal and fetal circulation during pregnancy. We and other investigators have shown that during normal pregnancy, maternal plasma CRH levels begin to rise in the second trimester with a dramatic increase in CRH levels during the 5-6 weeks preceding the onset of labor. This rise in maternal plasma CRH is parallel to the rise of placental CRH mRNA which has been reported to occur with gestational maturation. Mechanisms underlying the control of CRH secretion by the placenta have not yet been determined. In twin gestation, increased fetal-placental mass has been shown to be associated with elevated maternal levels of several placental hormones as compared to singleton gestation. We measured maternal plasma CRH in both twin and singleton gestation to investigate whether the larger size of the fetal-placental unit in twin gestation is associated with elevated maternal CRH levels. Seventy-six serial venous blood samples were collected from 20 women with twin gestation and 40 samples were obtained from 27 women with uncomplicated singleton gestation. Gestational age was determined by history of a known last menstrual period and first trimester clinical examination and confirmed by ultrasound examination. CRH was extracted from 1-2 ml plasma with SEP-Pak C18 cartridges and eluted with triethylamine-formic-acid propranolol. CRH was measured by radioimmunoassay (RIA) with human CRH standard and antiserum to human CRH raised in our laboratory. Mean CRH levels were calculated for four week intervals. In both singleton and twin gestation, the maternal plasma CRH levels increased with advancing gestational age. After 29 weeks of gestation, maternal plasma CRH levels in twin gestation were significantly higher than those in singleton gestation (p less than 0.01). At 37 to 40 weeks of gestation, mean maternal CRH was 1167 +/- 237 pg/ml in singleton gestation as compared to 6927 +/- 1725 pg/ml in twin gestation (p less than 0.05). In addition, the rapid rise in plasma CRH levels which occurs near term in singleton gestation, occurred earlier in twin gestation. This early rise in maternal CRH levels persisted when the data from twin pregnancies complicated by preterm labor were removed from the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maternal serum corticotropin-releasing hormone at midgestation in Hispanic and white women

OBJECTIVE: Maternal circulating corticotropin-releasing hormone analysis at midgestation has been proposed as a parameter for the prediction of preterm birth. However, one recent study has reported that corticotropin-releasing hormone concentrations at midgestation differ in the black and white populations. These findings led us to investigate whether other populations have differing concentrations of maternal circulating corticotropin-releasing hormone that may require reference to specific population-based medians for optimal midgestational screening. METHODS: In this study we have defined the mean and median concentrations of maternal circulating corticotropin-releasing hormone in Hispanic and white populations at each gestational week from 14 to 18 weeks of pregnancy, using a sensitive and specific radioimmunoassay. RESULTS: Corticotropin-releasing hormone concentrations were found to be significantly lower in the Hispanic population as compared with whites at 16, 17, and 18 weeks' gestation. The distribution of corticotropin-releasing hormone, expressed as multiples of the median (MoM) using the appropriate ethnicity-related median, was estimated for each gestational week and for each population. No differences were observed in the distribution of the ethnicity-adjusted MoM for Hispanics and whites. CONCLUSION: These data demonstrate that ethnicity is a significant factor affecting corticotropin-releasing hormone concentrations at midgestation in the Hispanic and white populations. The use of ethnicity-specific medians to estimate the ethnicity-specific MoM for the corticotropin-releasing hormone concentrations may enhance the predictive value of midgestational maternal corticotropin-releasing hormone as a screening parameter for the prediction of preterm birth.     

Impaired uterine artery blood flow at mid gestation and low levels of maternal plasma corticotropin-releasing factor

OBJECTIVE: Corticotropin-releasing factor (CRF) is a placental neuropeptide that plays a role in the control of uteroplacental blood flow regulation. Because CRF has a relaxant effect on uterine vasculature in pregnant rats, we aimed to evaluate mid-gestation plasma CRF levels in women with impaired uterine artery blood flow. METHODS: Maternal plasma CRF was assayed by specific radioimmunoassay, and uterine artery resistance index (RI) was assessed by Doppler evaluation at 22-24 weeks' gestation in 55 healthy pregnant women, of whom 24 showed a unilateral or bilateral uterine artery notch, reflecting resistance. Statistical analysis was performed by the Kruskal-Wallis test followed by the post hoc Dunn's test and the Spearman rank test. RESULTS: The mean uterine artery RI was significantly (P <.001) higher in women with a notch than in healthy controls. Mean +/- standard error of the mean maternal plasma CRF levels were significantly lower in women with a unilateral (168.45 +/- 27.5 pg/mL; P <.01) or bilateral (186.07 +/- 34.5 pg/mL; P <.001) uterine artery notch than in healthy control pregnant women (375.06 +/- 21.77 pg/mL). Although no difference was found in CRF levels between patients with a unilateral or bilateral uterine artery notch, a significant inverse correlation was found between the mean RI and maternal plasma CRF levels (Spearman r = -0.6540; 95% confidence interval, -0.7865, -0.4640; P <.001). CONCLUSION: Reduced levels of circulating CRF were associated with increased uterine artery resistance, which supports the hypothesis that CRF may regulate uterine artery tone at mid gestation.     

The effects of syphilis on endocrine function of the fetoplacental unit

Several pregnancy complications that are thought to cause chronic intrauterine stress have been found to lead to inappropriate fetal development and reductions in estrogen production. In the current study we sought to evaluate the fetoplacental unit in pregnancies complicated by maternal syphilis (n = 37), with and without fetal infection. Maternal 17 beta-estradiol and estriol levels were reduced during the third trimester in women with syphilis when compared with those in women with uncomplicated pregnancies. Serum progesterone levels were within normal limits or else were increased in women with syphilis. When compared with data in age- and weight-matched control infants of women having no pregnancy complications, umbilical cord serum levels of dehydroepiandrosterone sulfate, the major fetal adrenal precursor of placental estrogens, were subnormal (897 +/- 597 ng/ml, mean +/- SD) in 12 newborn infants with congenital syphilis (33.9 +/- 4.2 weeks' gestation, birth weight 2020 +/- 719 gm); such infants also had excessive serum levels of cholesterol (103 +/- 37 mg/dl). Dehydroepiandrosterone sulfate (1883 +/- 907 ng/ml) and cholesterol (58.1 +/- 13.9 mg/dl) levels were within normal limits in 19 uninfected infants of women with syphilis (38.6 +/- 2.4 weeks' gestation, birth weight 2861 +/- 660 gm). Cortisol levels were increased and estriol levels were decreased in both groups of neonates of women with syphilis compared with those in control neonates. These findings are suggestive that estrogen production often is reduced in pregnancies complicated by syphilis; the reduction in estriol appears to be largely due to reduced fetal adrenal dehydroepiandrosterone sulfate production. The reduction in 17 beta-estradiol levels may be due to alterations in maternal precursor synthesis. Although placental progesterone formation appears to be normal in women with syphilis, a deficiency in placental aromatase activity also is possible.     

Corticotropin-releasing hormone in amniotic fluid during gestation and labor and in relation to fetal lung maturation

Corticotropin-releasing hormone was discovered in the placenta, and its concentration in the maternal plasma was found to increase greatly during the latter half of pregnancy. We studied the concentration of immunoreactive corticotropin-releasing hormone in amniotic fluid in 59 uncomplicated and in 73 complicated pregnancies. The mean (+/- SE) value of corticotropin-releasing hormone in amniotic fluid in uncomplicated pregnancies was significantly higher in the third (24.1 +/- 3.3 pmol/L) than in the second (9.1 +/- 0.7 pmol/L) trimester, but no change was found during labor. In groups matched by gestational age, larger mean values of corticotropin-releasing hormone and cortisol were observed in the group in which the lecithin/sphingomyelin ratio was greater than 2 or the phosphatidylglycerol test was positive than in the group with a lecithin/sphingomyelin ratio less than 2 or a negative phosphatidylglycerol test result. In samples taken at an interval of 1 to 3 weeks, concomitant increases in corticotropin-releasing hormone and cortisol levels were found with the appearance of phosphatidylglycerol. Concentrations of corticotropin-releasing hormone in amniotic fluid were elevated in patients with diabetes and in women with preeclampsia and intrauterine growth retardation. We conclude that the intrauterine release of corticotropin-releasing hormone increases during the last trimester. This may stimulate the fetal pituitary-adrenal axis and promote fetal maturation.     

The physiologic hyperparathyroidism of pregnancy. Is it primary or secondary?

Controversy exists over whether the increase in maternal serum parathyroid hormone levels observed during the second half of pregnancy is due to autonomous parathyroid function or is secondary to changes in maternal serum ionized calcium levels. In order to study this problem further, 9 subjects were followed serially throughout normal pregnancy. Total serum calcium, ionized calcium, parathyroid hormone (PTH), calcitonin, and albumin levels were measured monthly. Six of these subjects had the studies repeated 6 weeks postpartum. Serum ionized calcium levels were found to decrease from 3.81 +/- 0.12 mg/dl to 3.63 +/- 0.18 mg/dl between 21 and 25 weeks' gestation. This decrease was significant at P less than 0.01. The ionized calcium remained in this lower range until term. A significant return to 3.77 +/- 0.1 mg/dl was observed 6 weeks postpartum. Serum PTH levels showed a significant rise after 21 weeks' gestation (P less than 0.05). No serial change in serum calcitonin was observed during pregnancy, although the mean level of the group was significantly higher than in nonpregnant controls (P less than 0.01). The increase in maternal serum PTH observed during pregnancy appears to be due in part to a decrease in maternal serum ionized calcium.     

Relationship between cortisol levels in umbilical cord plasma and development of the respiratory distress syndrome in premature newborn infants.

The aim of this study was to determine whether there is a decrease in fetal cortisol levels associated with the respiratory distress syndrome (RDS). Eighteen newborn infants of less than 37 weeks' gestation who developed moderate to severe forms of RDS did have a significantly lower (P less than 0.02) mean cord plasma cortisol concentration at birth than that observed in 67 unaffected infants of similar gestational age; mean values +/- standard errors were 3.36 +/- 0.42 and 5.58 +/- 0.43 mug per 100 ml, respectively. However, whether or not RDS developed in neonates appeared to depend more upon the degree of prematurity (with a 71.5% incidence in gestations of less than 32 weeks compared to 17.1% in those of 32 to less than 37 weeks) than upon cortisol levels at delivery. Bood cortisol levels in the first days of life of four infants with RDS were considerably increased in comparison to those at birth. Mean cord plasma cortisol concentrations increased with duration of pregnancy, with the previously observed value for term infants (of 37 or more weeks) being approximately twice that for infants of less than 32 weeks' gestation. These findings appear to justify carefully controlled studied with antepartum glucocorticoid administration with the aim of reducing the incidence of RDS in premature newborn infants.     

Immunoreactive corticotropin-releasing hormone in amniotic fluid

Immunoreactive corticotropin-releasing hormone in the amniotic fluid of both human beings and rats was measured by a specific radioimmunoassay. In human subjects the hormone was detectable in all amniotic fluid samples (obtained during the sixteenth and eighteenth weeks of gestation) (2.5 +/- 1.7 fmol/ml, mean +/- SD, n = 17) and the thirty-eighth to fortieth weeks (9.3 +/- 5.4 fmol/ml, n = 24). The levels of concentration of this hormone in this amniotic fluid correlated significantly with the levels in both maternal plasma and placenta for each patient. Gel filtration of amniotic fluid extracts revealed two major peaks of immunoreactive corticotropin-releasing hormone, one at the elution position of the rat hormone and the other at a small-molecular-weight region. Immunoreactive corticotropin-releasing hormone was not detectable in rat amniotic fluid or placenta. We concluded that immunoreactive corticotropin-releasing hormone, which may be derived from the placenta, is present in human amniotic fluid and that its detection in the human placenta but not in rat placentas suggests that the mechanism of corticotropin-releasing hormone gene expression in the placenta is species specific.     

Maternal plasma adenosine and endothelin-1 levels in twin gestation complicated by preeclampsia

The aim of this study was to evaluate the relationship between the vascular resistance in uterine arteries and the maternal release of adenosine and endothelin-1 in twin gestations with and without preeclampsia. Uterine artery Doppler velocimetry and maternal arterial blood sampling were performed in 14 women with normal singleton gestation, nine women with singleton gestation with preeclampsia, eight women with dichorionic twin gestation without preeclampsia and six women with dichorionic twin gestation with preeclampsia at 28–34 weeks’ gestation. In normal singleton gestations, the average maternal uterine arteries pulsatility index (PI), plasma adenosine and endothelin-1 levels were 0.64±0.07, 0.34±0.11 μmol/l and 1.29±0.31 pg/ml, respectively. In preeclamptic singleton gestations, increased vascular resistance in the uterine arteries (PI: 0.85±0.14, P<0.05) and the elevation of maternal arterial plasma adenosine (0.48±0.14 μmol/l, P<0.05) and endothelin-1 levels (1.91±0.55 pg/ml, P<0.05) were observed. In the normal twin gestation group, the average maternal vascular resistance of the uterine arteries (PI: 0.55±0.09) was lower than that in the normal singleton gestation group, while the average plasma adenosine levels (0.47±0.12 μmol/l) were higher than that in normal singleton gestation. On the other hand, significant increased plasma endothelin-1 concentrations (1.87±0.42 pg/ml) were observed in the preeclamptic twin gestation groups without changes in plasma adenosine levels or vascular resistance of uterine arteries. Our results indicate the presence of different mechanisms for the pathogenesis of preeclampsia between twin and singleton gestations. Received: 5 October 2001 / Accepted: 3 December 2001 Correspondence to S. Suzuki     

Plasma ACTH, beta-lipotropin and beta-endorphin in the human fetus and their mother during delivery (author's trans)

Adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) immunoreactivity (IR) and beta-endorphin (beta-EP) immunoreactivity (IR) were measured by high-sensitive radioimmunoassay in maternal and umbilical cord plasma samples which were obtained simultaneously in 12 cases. Mean IR-beta-LPH in maternal (690.1 +/- 138.6 pg/ml, +/- S.E.) and cord venous plasma (1114.8 +/- 94.2 pg/ml) were significantly higher than that of normal adults (93.0 +/- 8.2 pg/ml). Mean IR-beta -EP in maternal (125.8 +/- 24.0 pg/ml) and cord venous plasma (130.6 +/- 20.6 pg/ml) were significantly higher than that of normal adults (6.0 +/- 0.9 pg/ml). There were significant positive correlations between IR-beta-LPH and IR-beta-EP in maternal and cord venous plasma. Mean beta-EP to beta-LPH molar ratio of 0.19 +/- 0.03 in maternal plasma was significantly (p less than 0.05) higher than that of cord venous plasma (0.13 +/- 0.01). There was no significant correlation between the levels of these three hormones in maternal plasma and the levels in cord venous plasma. These data suggest that ACTH, IR-beta-LPH and IR-beta-EP were elevate during labor, delivery responding the stress. Beta-LPH and beta-EP in cord venous plasma were fetal and/or placental origin.     

Interferon gamma expression during human pregnancy and in association with labour.

In this study, the expression of the type 1 cytokine, interferon gamma (IFNgamma) during human gestation and in association with labour was assessed. Immunoreactive (ir) IFNgamma concentrations (ng/ml) were quantified in maternal plasma (n = 136) and amniotic fluid (n = 68). In addition, irlFNgamma content (pg/mg protein) was determined in term gestational tissues (placenta, amnion and choriodecidua, n = 39). In peripheral plasma, irlFNgamma was detected in 34% of all samples assayed. Where detected, the concentration averaged 0.19 +/- 0.03 ng IFNgamma/ml plasma (mean +/- SEM). During pregnancy, irlFNgamma concentrations in maternal plasma declined significantly (p < 0.05). irlFNgamma was identified in all gestational tissues examined and content increased significantly with labour status (p < 0.01). irlFNgamma was not detectable in amniotic fluid (assay sensitivity = 0.02 ng/ml) at any stage of pregnancy. The data obtained are consistent with the hypothesis that, during pregnancy, cell-mediated immunity is suppressed. At term and in association with labour and delivery, lower plasma IFNgamma concentrations and high tissue content may indicate a contributing role for IFNgamma in parturition.     

Uteroplacental blood flow and estrogen production following dehydroisoandrosterone infusion.

The effects of systemic infusions of dehydroisoandrosterone on uterine blood flow and the plasma concentration of estrogen in ovine pregnancy were studied in 7 pregnant ewes 52 to 128 days of gestation. Uterine blood flow increased 17.8% after a systemic infusion of dehydroisoandrosterone of 4.67 mg +/- 0.3. Maximum blood flows occurred 111 min +/- 5.8 after injection of dehydroisoandrosterone. The increase in flow (milliliter/minute) was greatest after 100 days of gestation. Plasma estrone concentrations increased from 67.9 pg/ml to 201 pg/ml, while estradiol rose from 42.6 pg/ml to 115 pg/ml (P less than 0.001). Estriol was not detected.     

Cortisol levels in umbilical cord plasma in relation to labor and delivery.

Cortisol was determined by a competitive protein-binding method in umbilical cord plasma from pregnancies of 37 or more weeks' gestation. In 162 cases of vaginal delivery following spontaneous labor the mean +/- S.E. of cortisol values was 7.43 +/- 0.29 mug per 100 ml. of plasma. This cortisol level was not significantly different from that observed in 51 cases of vaginal delivery after oxytocin-induced labor (6.53 +/- 0.49 mug per 100 ml.) or in 47 cases of delivery by emergency cesarean section following labor (6.21 +/- 0.66 mug per 100 ml.). The mean cortisol level in cases of elective cesarean section with no prior labor (4.67 +/- 0.60 mug per 100 ml.) was significantly less than the value for vaginal delivery after spontaneous or induced labor. The cord plasma and amniotic fluid concentrations of cortisol in a pregnancy complicated by fetal anencephaly and terminated at 44 weeks by induction were normal. It is concluded that labor and vaginal delivery resulted in a significant increase in cord plasma cortisol levels but there was no significant difference between spontaneous and induced labors. These findings do not support the hypothesis that a surge in fetal cortisol production immediately precedes and initiates spontaneous labor in human pregnancy.     

Ontogeny of human fetal plasma progesterone, deoxycorticosterone, and deoxycorticosterone sulfate

The concentrations of progesterone, deoxycorticosterone (DOC), and deoxycorticosterone sulfate (DOC-SO4) were determined in mixed umbilical cord plasma of abortuses and newborn infants delivered between 18 and 42 weeks' gestation. A wide range of values among individual samples was found for progesterone (224 to 2,152 ng/ml), DOC (1.6 to 10.4 ng/ml), and DOC-SO4 (17 to 154 ng/ml). Levels of progesterone and DOC in mixed umbilical cord plasma were not correlated; those of DOC and DOC-SO4 were positively correlated significantly (r = 0.3945, P less than 0.001). Whereas the mean plasma levels of DOC were similar throughout gestation, significant variation, as a function of gestational age, was found for progesterone and DOC-SO4, with levels of these steroids generally being higher near term than earlier in gestation. The administration of glucocorticosteroids to the mother resulted in a significant decrease (p less than 0.001) in plasma concentrations of DOC and DOC-SO4 in the newborn infant; levels of progesterone in umbilical cord plasma were not affected by maternal glucocorticosteroid treatment. These results suggest that the fetal adrenal glands play a direct, or possibly an indirect, role in the production of the DOC and DOC-SO4 that is present in the fetal compartment. In addition, since fetal plasma levels of progesterone are quite high throughout gestation, the potential exists for circulating progesterone to serve as a precursor for adrenal and extra-adrenal production of DOC and DOC-SO4.     

Oxytocin in maternal and fetal blood.

Radioimmunoassayable plasma oxytocin (OT) has been measured in maternal and fetal blood. Simultaneous samples were obtained in maternal forearm venous blood and in umbilical venous and arterial blood in 29 patients at term delivery. In addition, maternal forearm venous blood samples were also obtained 10 minutes prior to delivery. Mean OT level in maternal plasma at delivery was 82 +/- 12 muU/ml, and at 10 minutes prior to delivery the mean OT level was 90 +/- 11 muU/ml. The umbilical arterial plasma OT showed 95 +/- 12 muU/ml and the umbilical vein plasma OT was 60 +/- 10 muU/ml. Oxytocin levels higher in maternal blood than in fetal blood were found with the following incidence: In 51% of samples there was more OT in maternal venous blood than in umbilical arterial blood, and in 84% of samples there was more OT in maternal blood than umbilical vein blood. During the postpartum period, the mean maternal plasma OT was 66 +/- 8 muU/ml for the first day, and 50 +/- 9 muU/ml and 54 +/- 9 muU/ml for the second and third days, respectively. This study indicates that both the fetus and the mother are active producers of oxytocin.