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Objective: Myometrial oxytocin binding characteristics do not change near term in guinea pigs. We tested the hypothesis that the uterine contractile response to oxytocin does not change near term. Study Design: Chronically instrumented guinea pigs were given graded infusions of oxytocin (n = 19 animals) or saline solution (n = 4 animals) on days 58, 60, and 62 and then daily until delivery (term, 68 days). Uterine contractile response was assessed by the area of the quasi-integrated electromyogram. Concentrations of 13,14-dihydro-15-keto-prostaglandin F 2 α were measured in maternal plasma. Results: The uterine contractile response to oxytocin increased with advancing gestation ( P =.007, random coefficients model) and labor ( P =.005). Plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F 2 α increased during oxytocin infusion ( P Conclusion: The uterine contractile response to oxytocin increases during the 1 to 2 weeks before term in guinea pigs, despite stable myometrial oxytocin receptor density. Oxytocin stimulates the production of prostaglandin F 2 α . (Am J Obstet Gynecol 2003;189:201-7.)

The aim of this study was to determine prospectively whether serum concentrations of corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A (1) predict preterm birth within 10 days of hospital admission or at37 weeks' gestation among women with symptoms of preterm labor and (2) are affected by glucocorticoid therapy.Serum concentrations of corticotropin-releasing hormone and activin A were measured in 94 women with symptoms of preterm labor between 24 and 34 weeks' gestation, and delivery outcomes were monitored. Corticotropin-releasing hormone-binding protein concentrations were measured in 71 of these women. In a subgroup of 15 women the serum analytes were assayed in conjunction with estriol before and 12 to 24 hours after administration of dexamethasone.Forty-six percent (6/13) of the women who were delivered within 10 days of hospital admission had a raised serum corticotropin-releasing hormone level, but the predictive relationship was not significant (chi(2) = 1.7; P =.2). Among the 31 women (including the 6 previously mentioned) who were delivered at37 weeks' gestation, 39% (12/31) had a raised corticotropin-releasing hormone level. Although a raised corticotropin-releasing hormone concentration was positively associated with delivery at37 weeks' gestation (chi(2) = 9; P =.003), the predictive diagnostic value was poor, with sensitivity, specificity, and positive and negative predictive values of 39%, 90%, 67%, and 75%, respectively. The serum concentrations of corticotropin-releasing hormone-binding protein and activin A were unrelated to gestational age at delivery. Dexamethasone markedly lowered the serum estriol level (P.001) but had no effect on concentrations of corticotropinreleasing hormone, corticotropin-releasing hormone-binding protein, and activin A.Serum concentrations of corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A are not clinically useful for the prediction of preterm delivery among women with symptoms of preterm labor and are not affected by administration of glucocorticoids.

OBJECTIVES To determine: 1. whether an alternative definition of gestational hypertension and pre-eclampsia stratifies women according to their risk of maternal and fetal complications; 2. whether pregnancy outcome in women with gestational hypertension differs in the presence or absence of '+' proteinuria; and 3. whether a blood pressure rise of > or = 30/15 mmHg during pregnancy is associated with adverse outcome in women who remain normotensive. DESIGN Prospective, nested case-control study. SETTING Community based. POPULATION Healthy, nulliparous women (n = 1496). METHODS Women recruited into a study investigating serum markers predictive of pre-eclampsia were classified as having gestational hypertension (systolic blood pressure > or = 140 mmHg with a rise of > or = 30 mmHg and/or diastolic blood pressure > or = 90 mmHg with a rise of > or = 15 mmHg) or pre-eclampsia (gestational hypertension plus proteinuria > or = 2+on dipstick or > 0.3 g/24 h). Maternal and fetal complications in gestational hypertension or pre-eclampsia were compared with a control group of 223 randomly selected normotensive women. The main outcome measures were severe maternal disease, preterm birth and small for gestational age infant. RESULTS A stepwise increase in adverse maternal and fetal outcomes occurred in gestational hypertension (n = 117, 7.8%) and pre-eclampsia (n = 71, 4.8%). Severe maternal disease developed in 26.5% (21.4% severe hypertension alone, 5.1% multisystem disease) of women with gestational hypertension and 63.4% (21.1% severe hypertension alone, 42.3% multisystem disease) of women with pre-eclampsia (OR 4.8; 95% CI 2.4-9.5). Preterm birth and small for gestational age infants were more frequent in gestational hypertension (OR 1.7; 95% CI 0.5-5.4, and OR 2.0; 95% CI 1.0-3.7, respectively) and pre-eclampsia (OR 14.6; 95% CI 5.8-37.8, and OR 2.6; 95% CI 1.2-5.3) than in the normotensive group. Among women with gestational hypertension severe maternal disease was more common in women with '+' proteinuria (41.7%) than in those with no proteinuria (15.9%): OR 3.8; 95% CI 1.5-9.8. Pregnancies were uncomplicated in the 27% of normotensive women who had a rise of > or = 30 mmHg systolic blood pressure and/or > or = 15 mmHg rise in diastolic blood pressure. CONCLUSIONS In the nulliparous population studied our definition of gestational hypertension and pre-eclampsia identified women at increasing risk of maternal and fetal complications. In gestational hypertension, the presence of proteinuria '+' was associated with a 3.8-fold increase in severe maternal disease. Normotensive women who have a rise in blood pressure > or = 30/15 mmHg had uncomplicated pregnancies.

OBJECTIVE: Our purpose was to determine whether the secretory component of immunoglobulin A in maternal serum predicts delivery before 34 weeks' gestation. STUDY DESIGN: Primigravid women of an urban population in New Zealand were recruited at booking into a prospective longitudinal nested case control study ( n = 1651; after exclusions and withdrawals, n = 1511). Serum was collected at 8 to 12 weeks, 15 to 18 weeks, 21 to 24 weeks, 28 to 30 weeks, and 36 to 38 weeks of gestation and 6 weeks post partum. Concentrations of the secretory component of immunoglobulin A were determined by enzyme-linked immunosorbent assay in all women who were delivered preterm ( n = 53) and in controls randomly selected from women delivered at ≥37 weeks' gestation ( n = 178). RESULTS: Serum concentrations of the secretory component of immunoglobulin A were similar in women delivered at term or preterm throughout pregnancy ( n = 21 delivered at n = 32 at 34 to 36.9 weeks, incidence 3.5%). Receiver-operator characteristic curves showed no discriminating ability of the secretory component of immunoglobulin A. Smokers had 50% higher concentrations than nonsmokers did ( p CONCLUSION: The secretory component of immunoglobulin A in maternal serum does not predict preterm delivery in a low-risk population. (Am J Obstet Gynecol 1998;178:535-9.)

Prostaglandin production in amnion and decidua is considered important for human parturition. We investigated in pregnant guinea pigs, a species similar to women in regard to the endocrinology of pregnancy, whether the production rates of PGE2 and PGF2 alpha in various intrauterine tissues are compatible with a role in parturition. Net production rates were measured at 45, 55 and 65 days of gestation and during labor in amnion, chorion, myo-endometrium, the outer layer of the myometrium, the site of placental implantation, and placenta. Net production rates in amnion increased between 45 days and labor (30-fold for PGE2 and 8-fold for PGF2 alpha, P0.0001). During labor, the production rates in amnion of PGE2 (P = 0.006) and PGF2 alpha (P = 0.019) were higher than at 45, 55, and 65 days of gestation. In myo-endometrium, the production rates of PGF2 alpha were higher at 65 days of gestation than at 55 days and during labor (P = 0.046). Addition of arachidonic acid (10(-5) M) increased production of PGE2 and/or PGF2 alpha in all tissues (P0.05) except placenta. In amnion, the response to arachidonic acid increased with advancing gestation. This suggests that 1) PGE2 and PGF2 alpha produced by amnion have a potential role in the initiation and maintenance of labor, 2) PGF2 alpha produced by myo-endometrium has a potential role in the initiation of labor, 3) cyclooxygenase(s) are not rate-limiting except in placenta, and 4) the expression of cyclooxygenase in amnion increases with advancing gestation.

Publisher Summary This chapter discusses oxytocin in parturition of guinea pigs, humans, and other species. Oxytocin is unlikely to have a regulatory role in the onset of labor in guinea pigs. This is suggested by the lack of any influence of oxytocin receptor blockade on the timing of the onset of labor, the lack of any significant change in the binding characteristics of myometrial oxytocin receptors, and the gradual, and not sudden, increase in the oxytocin dose-response toward term. The fact that oxytocin is an unlikely trigger of labor is not limited to guinea pigs. In rats, oxytocin receptor blockade had no effect on gestational length at doses that inhibited the response to exogenous oxytocin. In women, oxytocin receptor density in myometrium does not increase significantly, plasma concentrations of oxytocin do not increase markedly, and oxytocin peptide in intrauterine tissues do not change at the onset of labor. Birth is a vital event for both offspring and parturient. Although oxytocin is not the trigger of labor in guinea pigs, it is indispensable for the normal progress of labor. Without oxytocin, the survival of this species would be in jeopardy.

Objective: We sought to determine whether total secretory component in serum is increased in women in whom preeclampsia subsequently develops. Study Design: Serum samples were collected serially throughout pregnancy and post partum from nulliparous women (N = 1496). Serum concentrations of total secretory component were measured by an enzyme-linked immunosorbent assay in all women in whom preeclampsia developed (n = 71) and a randomly selected group of normotensive women (n = 83). Results: Secretory component increased with smoking ( P =.0003) and with gestation ( P =.0001). In the whole group secretory component was not different in women with preeclampsia ( P =.10), but there was a significant interaction of smoking, gravidity, and preeclampsia ( P =.04). Among the women who smoked, secretory component was lower in women in whom preeclampsia subsequently developed compared with those who remained normotensive ( P =.02). This difference was significant from 15 to 19 weeks' gestation. Conclusion: Very high serum concentrations of secretory component in smokers may protect against the development of preeclampsia and may indicate the involvement of mucosal tolerance. (Am J Obstet Gynecol 2000;183:136-9.)

Serum inhibin A and activin A concentrations increase in pre-eclampsia. We investigated the time courses of the changes in relation to the onset of the maternal syndrome and if their measurement could be useful for clinical prediction particularly in relation to early onset disease, the most severe of the clinical presentations. Serial samples were taken from 1496 healthy nulliparae. Changes in activin A and inhibin A were analysed in women with: early onset pre-eclampsia (n = 11), pre-eclampsia delivering at 34-36 weeks (n = 14), term pre-eclampsia (n = 25) and gestational hypertension (n = 25); and in a subset with uncomplicated pregnancies (n = 25). Serum inhibin A and activin A were increased in all groups prior to pre-eclampsia, before 20 weeks in those with early onset pre-eclampsia. Screening efficacy was determined at 15-19 and 21-25 weeks in all women who developed pre-eclampsia (n = 70) and randomly selected controls (n = 240). Predictive sensitivities were low (16-59%) but much better for early onset pre-eclampsia: 67 and 44% at 15-19 weeks and 89 and 89% at 21-25 weeks for inhibin A and activin A respectively. Hence, serum inhibin A and activin A concentrations increase before the onset of pre-eclampsia at gestational ages that depend on when pre-eclampsia develops. On their own such measures are unlikely to prove efficient for screening.

To test whether beta-adrenergic mechanisms and the sympathetic nervous system are involved in the synergistic action of thyrotropin-releasing hormone (TRH) and cortisol on lung maturation, fetal sheep (n = 32) were infused from 121 to 128 days of gestation with saline, TRH + cortisol, TRH + cortisol + beta-adrenergic blocker, or TRH + cortisol after chemical sympathectomy with 6-hydroxydopamine. TRH + cortisol increased lung distensibility and stability and alveolar concentrations of saturated phosphatidylcholine two- to threefold over control fetuses. beta-Adrenergic blockade prevented the increase in distensibility in response to TRH + cortisol. Sympathectomy did not impair the increase in distensibility and stability in response to TRH + cortisol but inhibited the increase in alveolar total phospholipids. Tissue concentrations of saturated phosphatidylcholine increased in TRH + cortisol-treated fetuses after either sympathectomy or beta-adrenergic blockade. We concluded that during lung maturation by TRH + cortisol 1) sympathetic mechanisms are requisite for surfactant release, 2) nonneurogenic beta-adrenergic mechanisms are requisite for the maturation of the mechanical properties of the lung and 3) stimulation of surfactant synthesis is independent of beta-adrenergic action and the sympathetic nervous system.

2000). We have recently discoveredthat the web-based calculator (http://cebm.jr2.ox.ac.uk/docs/2 2table.html) uses an incorrect formula to calculate confi-dence intervals for sensitivity. We present revised Tables IIIand IV below. Confidence intervals were recalculated usingthe software Confidence Interval Analysis (2000). Thisresulted in the same point estimates, but wider confidenceintervals and minor alterations to post-test probabilities.We would like to thank Ed Juszczak (Centre for StatisticalMedicine, Institute of Health Sciences, Oxford, UK) for hisadvice and help in reanalysing the data.

The paper reviews the effects on lung maturation of glucocorticoids in animals and humans and presents relevant recent findings from the author's laboratory. It is now well established that antenatal glucocorticoid treatment reduces the incidence and severity of the respiratory distress syndrome (RDS) in prematurely born infants. The recommended doses of glucocorticoids produce fetal glucocorticoid activity levels similar to those of newborns with RDS or prolonged rupture of the membranes. Extensive follow-up studies have shown that adverse effects on child development are unlikely to occur. It is also evident that a significant number of fetuses do not respond to the treatment, which is of particular consequence in fetuses of less than 28 weeks gestation. These fetuses are less likely to respond to glucocorticoid therapy that fetuses between 28 and 32 weeks gestation and are at a higher risk of developing complications due to their immaturity. In fetal sheep, there is a similar decrease in the efficacy of glucocorticoids on lung maturation with decreasing gestational age. Simultaneous infusion of cortisol, triiodothyronine and prolactin but not of any of these hormones administered singly or in combination of two produced mature lungs in fetal sheep of 125 days gestation. Similar results were obtained with thyrotropin releasing hormone (TRH) and cortisol. It remains to be seen whether the combined administration of glucocorticoids and TRH accelerates lung maturation in human fetuses.

The relationship between elastin and collagen concentration and indices of lung maturation was studied in the lungs of fetal sheep. Fetal sheep of 124 days gestation were infused for 84 h with cortisol, triiodothyronine, prolactin, or epidermal growth factor alone or in combination. Pressure-volume curves with air were performed on the lungs and saturated phosphatidylcholine was measured in lung washes. Desmosine and hydroxyproline were determined in lung tissue in seven hormone-treated fetuses that displayed distensible and stable lungs similar to term lungs [volume of air at 40 cm H2O (V40) greater than 1.5 ml/g wet weight and at 5 cm H2O (V5) greater than 0.8 ml/g] and in seven fetuses whose lungs remained nondistensible and unstable (V40 less than 0.6 ml/g and V5 less than 0.4 ml/g). Alveolar saturated phosphatidylcholine was five times higher (p less than 0.001) in distensible than in nondistensible lungs, but attained less than 20% of term values. Desmonsine and hydroxyproline concentrations in parenchyma, pleura, and trachea of nondistensible, unstable lungs were similar to intact controls of 125 days gestation and those in distensible, stable lungs were similar to controls of 137 days gestation. Desmosine (p less than 0.0001) and hydroxyproline (p less than 0.001) concentrations in parenchyma of distensible, stable lungs were higher than those of nondistensible, unstable lungs. We speculate that increased distensibility of the fetal lung in response to treatment with hormones is attributable in part to changes in the composition of connective tissue.

The ontogenesis of elastin (desmosine), collagen (hydroxyproline), and DNA concentrations and their rates of increase were studied in fetal sheep lungs from day 60 until term. Elastin increased 13-, 17-, 63- and 11- fold in nondissected parenchyma, dissected (free of tubular structures of greater than 0.1 mm diameter) parenchyma, pleura, and trachea, respectively. Collagen increased 2.1-, 1.8-, 5- and 3-fold, respectively, in the four tissues. A sharp rise in elastin occurred after day 100. The rate of increase in elastin was greater in dissected than in nondissected parenchyma while the reverse was true for collagen. The steepest rise of elastin concentration occurred in the pleura after day 125. DNA concentration peaked on day 125 and was lowest at term. These findings are consistent with 1) the onset of a steep rise in elastin accumulation during the canalicular period, 2) the development of a rigid, mainly collagenous structure of the central airways and blood vessels and a distensible peripheral "gas-exchange tissue," rich in elastin, 3) an important role of elastin in the function of the visceral pleura, and 4) a peak of mitotic activity during the early alveolar period.

Hemodynamic consequences of sustained (one hour) hypocalcemia and hypercalcemia (plasma ionized calcium concentration [Ca++] maintained approximately 60% below or above normal, encompassing the clinical range) were studied and the influence of beta blockade on these hemodynamic alterations examined in 16 anesthetized, closed-chest dogs. Alterations in [Ca++] were associated with directionally similar changes in mean arterial pressure, whereas on the average cardiac output remained unchanged. Thus, the peripheral vasculature played an important role in the hemodynamic response to alterations in [Ca++]. The state of beta adrenergic activity was an important determinant of the hemodynamic response to hypocalcemia. Prior to beta blockade, hypocalcemia was associated with decreased systemic vascular resistance, whereas after beta blockade with propranolol hydrochloride, systemic vascular resistance was not different from control except at the five-minute observation period, and cardiac output and stroke volume fell.

The effects of fetal infusions of cortisol and thyrotropin-releasing hormone (TRH) singly and together on pressure-volume relationships and saturated phosphatidylcholine (SPC) concentrations in the lungs were studied in 28 fetal sheep delivered at 128 days of gestation. Four groups each of 7 fetuses were infused with either saline (for 156 h), TRH (25 micrograms/h in 60-s pulses for 156 h), TRH (for 156 h) combined with cortisol (1 mg/h for 84 h), or cortisol (for 84 h). Cortisol had no effect on SPC concentrations, whereas both TRH and cortisol plus TRH increased the concentration of SPC in lavage fluid but not lung tissue. Neither cortisol nor TRH significantly affected lung distensibility [V40; 0.64 +/- 0.04 and 0.57 +/- 0.10 (SE) ml/g, respectively, vs. 0.41 +/- 0.03 ml/g in controls] or stability (V5; 0.24 +/- 0.01 and 0.35 +/- 0.07 ml/g vs. 0.24 +/- 0.03 ml/g), whereas treatment with a combination of the two hormones was associated with a fourfold increase in V40 (1.70 +/- 0.16 ml/g) and V5 (1.03 +/- 0.15 ml/g). Since raised concentrations of cortisol, triiodothyronine, and estradiol-17 beta (treatment with cortisol) had no effect on V40 and V5, whereas similar hormonal changes associated with elevated prolactin levels (treatment with cortisol plus TRH) had marked effects, we conclude that prolactin plays an essential part in the synergism of cortisol and TRH.

Cortisol has minimal effects on lung maturation in fetal sheep before 130 days gestation. To test whether there is enhancement of cortisol action by other hormones, cortisol (F), triiodothyronine (T3), epinephrine (E), prolactin (PRL), and epidermal growth factor (EGF), alone or in combination, were infused into fetal sheep for 84 h between 124 and 128 days gestation. A mixture of F + T3 + PRL, but not any combination of two hormones, increased both distensibility [1.71 +/- 0.12 (SE) ml of air/g wet wt at 40 cmH2O, V40] and stability (1.16 +/- 0.09 ml of air per g wet wt at 5 cmH2O, V5) to near full-term values, above values resulting from treatment with F alone (0.91 +/- 0.12 and 0.43 +/- 0.09 ml/g, P less than 0.01). Only F had an effect when given alone, V40 increasing (P less than 0.05). Treatment with F + T3 (0.81 +/- 0.18 ml/g) and F + E (0.77 +/- 0.07 ml/g) increased V5 above values obtained with F alone (P less than 0.05). Alveolar saturated phosphatidylcholine (SPC) was higher after treatment with F + T3 (161 +/- 52 micrograms/g), F + T3 + PRL (156 +/- 53 micrograms/g, P less than 0.05), and F + E (113 +/- 40 micrograms/g, P = 0.07) than after F (12 +/- 3 micrograms/g). We conclude that F, T3, and PRL have a synergistic effect on the development of distensibility and stability of the ovine fetal lung.