Treatment results of stage I and II oral tongue cancer with interstitial brachytherapy: maximum tumor thickness is prognostic of nodal metastasis

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 > or =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 <34 weeks and 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 < 0.0001 by analysis of variance). CONCLUSION: The secretory component of immunoglobulin A in maternal serum does not predict preterm delivery in a low-risk population.     

Identifying twin gestations at low risk for preterm birth with a transvaginal ultrasonographic cervical measurement at 24 to 26 weeks' gestation

OBJECTIVE: Because twins are a high-risk group for preterm birth, many clinicians routinely use prophylactic interventions such as home bed rest, hospital bed rest, oral tocolytics, or home uterine activity monitoring to prevent preterm delivery. We sought to identify twin gestations at low risk for spontaneous preterm birth with transvaginal ultrasonography of the cervix to avoid the unnecessary use of prophylactic interventions in these pregnancies. STUDY DESIGN: We measured cervical length at 24 to 26 weeks' gestation by transvaginal ultrasonography in women with twin gestations referred to our prematurity prevention clinic. Each delivery was classified as (1) spontaneous preterm birth < 34 weeks' gestation, (2) delivery at > or = 34 weeks' gestation with intervention, or (3) delivery at > or = 34 weeks' gestation without intervention. Intervention included strict bed rest at home or in the hospital, either parenteral or oral tocolysis, or both, or home uterine activity monitoring. Indicated preterm deliveries and patients with cerclage were excluded from this analysis. The ability of transvaginal cervical length to predict women who would deliver at > or = 34 weeks without intervention was evaluated. A cervical length of 35 mm was chosen by scatter diagram as the best cutoff to discriminate between the group delivered at term without intervention and the other two groups. RESULTS: Of 85 women with twin gestations who underwent ultrasonographic cervical length measurements at 24 to 26 weeks' gestation, 17 had spontaneous preterm birth at < 34 weeks, 23 were delivered at > or = 34 weeks but required intervention, and 45 were delivered at > or = 34 weeks without intervention. The mean cervical length for those delivered at > or = 34 weeks' gestation without intervention (36.4 +/- 5.8 mm) was significantly greater (p < 0.0001) than the mean for those delivered preterm (27.4 +/- 8.5) and those delivered at > or = 34 weeks' gestation who required intervention (27.7 +/- 10.5 mm). The sensitivity, specificity, and positive and negative predictive values of a cervical length > 35 mm for predicting delivery at > or = 34 weeks' gestation are 49%, 94%, 97%, and 31%, respectively. CONCLUSION: A transvaginal ultrasonographic measurement of the cervix of > 35 mm at 24 to 26 weeks in twin gestations can identify patients who are at low risk for delivery before 34 weeks' gestation.     

Effects of sulphonylureas on the volume-sensitive anion channel in rat pancreatic beta-cells

OBJECTIVE: This study's aim was to determine whether maintenance therapy with terbutaline administered by pump prolongs gestation in women after treatment with intravenous magnesium sulfate tocolysis for suspected preterm labor. STUDY DESIGN: Consenting women with a singleton gestation and intact membranes who had uterine contractions and >1 cm cervical dilation, 80% effacement, or progressive cervical change and whose contractions were successfully arrested with intravenous magnesium were randomly assigned to receive either terbutaline or normal saline solution placebo by subcutaneous infusion pump. Pump therapy was administered with a standardized protocol. Pump therapy was discontinued and parenteral magnesium was resumed if recurrent preterm labor developed while women were on the therapeutic regimen at <34 weeks' gestation and no contraindication for tocolysis existed. If recurrent labor was arrested, pump therapy was restarted according to the original treatment group. A sample size of 48 women was required to detect a 2-week intergroup difference in mean time to delivery. Analyses were based on intent to treat. RESULTS: Fifty-two women received terbutaline (n = 24) or placebo (n = 28). At random assignment the groups were similar with respect to age, race, parity, previous preterm delivery, gestational age, and cervical examination. Overall there was a 1-day difference in mean time to delivery between the groups (terbutaline 29 +/- 22 days and placebo 28 +/- 23 days, P = .78). There were no differences in the rates of preterm delivery at <34 and <37 weeks' gestation. Neonatal outcomes were similar. CONCLUSIONS: Maintenance terbutaline therapy administered by pump does not prolong gestation in women successfully treated for suspected preterm labor.     

Treatment of severe forms of sickle cell anemia with bone marrow allograft: French experience (15 cases). SFGM

OBJECTIVE: To determine whether home uterine activity monitoring reduces the likelihood of preterm birth in women successfully treated for preterm labor in their current pregnancies. METHODS: Women between 20-34 weeks' gestation who had been treated successfully for preterm labor were solicited to participate in a randomized clinical trial of home uterine activity monitoring versus routine high-risk care. The sample size of 56 was based on power calculations using the results of earlier investigators. Twenty-eight women were randomized to home uterine activity monitoring and 29 were assigned to the type of care appropriate for women discharged after hospitalization for parenteral treatment of preterm labor. One of the routine-care subjects was lost to follow-up. The two groups were comparable in distribution for race, insurance status, multiple gestation, marital status, gestational age at beginning of the study, and incidence of prior preterm birth. RESULTS: The 28 women receiving routine care had a 54% incidence of preterm birth, whereas the incidence was 57% in monitored women (relative risk 1.08, 95% confidence interval 0.6-1.9; P = .79). The incidences of delivery before 32 weeks and 34 weeks also were unaffected by the intervention. CONCLUSION: Home uterine activity monitoring is not effective in reducing the likelihood of preterm delivery in patients successfully treated for preterm labor in their current pregnancies.     

Effect of androstenedione administration on the maternal hypothalamo-pituitary-adreno-placental axis in the pregnant rhesus monkey

To assess the interaction among androgens, placenta, and the hypothalamo-pituitary-adrenal axis we studied effects of androstenedione administered intravascularly to the pregnant monkey on maternal plasma CRH, ACTH, dehydroepiandrosterone sulfate (DHEAS), cortisol, and estradiol concentrations. Ten monkeys (128 +/- 3 days gestation; mean +/- SEM) were instrumented under general halothane anesthesia with maternal femoral artery and venous catheters and uterine electromyogram electrodes. At 137-144 days gestation, baseline maternal femoral artery samples for CRH, ACTH, DHEAS, cortisol, and estradiol measurements were taken at 1.5-h intervals for 7 h starting 2 h before darkness. On the following day, a continuous iv androstenedione infusion (0.3 mg/kg.min at 0.25 ml/h) in 10% intralipid was started at 0930 h in four monkeys; the other six animals received vehicle alone at the same rate starting at the same time. Maternal blood sampling was repeated 1 and 3 days after androstenedione or vehicle administration. Maternal plasma CRH, ACTH, DHEAS, cortisol, and estradiol levels were unaffected by intralipid. In contrast, androstenedione infusion produced a sustained increase in maternal plasma estradiol and a sustained fall in maternal plasma ACTH, but did not affect maternal plasma CRH, DHEAS, or cortisol concentrations. These results provide evidence for negative feedback regulation by androgens at the hypothalamo-pituitary-adrenal axis in the pregnant monkey. Lack of inhibition of maternal plasma CRH after androstenedione administration supports differential regulation of hypothalamic and placental CRH by androgens.     

Activin A and inhibin B in extra-embryonic coelomic and amniotic fluids, and maternal serum in early pregnancy

Activin A and inhibin B levels were measured, using a two-site enzyme immunoassay, in extra-embryonic coelomic fluid, amniotic fluid and maternal serum samples retrieved from 23 healthy pregnant women, at 8 (n=8), 9 (n=8), and 10 (n=7) weeks of gestation. Dimeric activin A and inhibin B were measurable in all samples. Median (+/-SEM) activin A concentrations in coelomic fluid (0.98+/-0.34 ng/ml) were significantly higher than in maternal serum (0.68+/-0.05 ng/ml) and in amniotic fluid (0.09+/-0.04 ng/ml) (P<0.05). Maternal serum activin A levels were significantly higher than amniotic fluid concentrations. Median (+/-SEM) inhibin B concentrations in coelomic fluid (24.32+/-6.02 pg/ml) were significantly higher than in maternal serum (5.94+/-0.97 pg/ml) and in amniotic fluid (6.31+/-1.53 pg/ml) (P<0.05), while no significant difference between maternal serum levels and amniotic fluid concentrations was found. No significant difference in activin A and inhibin B levels in extra-coelomic fluid, amniotic fluid, and maternal serum throughout the 3 weeks of pregnancy was found. The present study showed that coelomic fluid is an important reservoir of activin A and inhibin B, supporting the hypothesis that the extra-embryonic coelom may have a secretory role during the first 11 weeks of gestation.     

Pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone propionate treatment

Systemic corticosteroids prescribed for treatment of pulmonary diseases in preterm, very low birth weight infants caused severe suppression of the hypothalamic-pituitary-adrenal axis and produced serious physiological and metabolic disturbances. However, the effect of inhaled corticosteroids on their pituitary-adrenal functions is not known. We prospectively evaluate the pituitary-adrenal function using the human CRH stimulation test in a cohort of very low birth weight infants at risk for hypothalamic-pituitary-adrenal axis suppression in a double blind, randomized pilot study designed for assessing the efficacy and adverse effects of inhaled fluticasone propionate in newborn preterm infants who required mechanical ventilation for treatment of respiratory distress syndrome. Twenty-five preterm (< 32 gestational weeks), very low birth weight (< 1500 g) infants were randomized to receive inhaled fluticasone propionate (n = 13) or a placebo inhaler (n = 12). The medication was given every 12 h (fluticasone propionate, 1,000 micrograms/day) for 14 days. All surviving infants had their pituitary-adrenal functions assessed by human CRH test on the following morning immediately after completion of the 2-week course. All basal (0 min) and post-stimulation (15, 30, and 60 min) plasma ACTH and serum cortisol concentrations were significantly suppressed in the inhaled fluticasone group compared to their corresponding levels in the placebo group [basal plasma ACTH concentrations (F = 6.0; P = 0.02), poststimulation plasma ACTH concentrations (F > 8.6; P < 0.01), basal serum cortisol concentrations (F = 5.6; P = 0.03), and poststimulation serum cortisol concentrations (F > 15.6; P < 0.001)]. This is the first study in very low birth weight infants that demonstrates unequivocally that cumulative high dose inhaled corticosteroids can induce moderately severe suppression of both the pituitary and adrenal glands. The systemic bioactivity is probably associated with pulmonary vascular absorption, which effectively circumvents the hepatic first pass metabolism. Until the question of safety can be adequately addressed, inhaled fluticasone propionate should be used with cautionin preterm infants.     

Examination of wear in Duraloc acetabular components: two- to five-year evaluation of Hylamer and Enduron liners

BACKGROUND: The purpose was to determine the prognostic value of interleukin (IL) 1-alpha, IL-6 and IL-8 in cervico/vaginal secretion for preterm birth (<37 weeks of gestation) in twin pregnancies. METHODS: The study included screening of 121 women with twin pregnancies with sampling at 24, 26, 28, 30, 32 and 34 weeks of gestation. IL-1alpha, IL-6 and IL-8 was analyzed with ELISA immunoassays. The detection limit was 30 pg/mL for IL-1 and IL-8 and 40 pg/mL for IL-6. Vaginal fluid was smeared and dried for later evaluation of bacterial vaginosis (presence of clue cells). RESULTS: Spontaneous preterm birth occurred in 36 women and 65 women were delivered at term. IL-8 was significantly higher (p=0.03) in samples from women delivered preterm (median 3.72 ng/g mucus, range <0.07-220.00) compared with samples from women delivered at term (median 3.03 ng/g mucus, range <0.08-378.60). At 28 weeks of gestation, IL-8 (cut off 1.75 ng/g mucus) was associated with preterm delivery (relative risk 2.2, CI 95% 1.1-4.5) with a sensitivity, specificity, positive and negative predictive value of 78.8, 45.8, 44.8 and 79.4%, respectively. The levels of IL-1alpha and IL-6 were not significantly associated with preterm birth. Bacterial vaginosis was found in 47/541 (8.7%) samples analyzed. The levels of IL-1alpha and IL-8 were significantly higher in samples positive for bacterial vaginosis than in negative samples (p<0.0001 and p<0.01, respectively). There was no significant association between the level of IL-6 and bacterial vaginosis. CONCLUSIONS: IL-8, but not IL-1alpha and IL-6, was associated with preterm delivery but the relationship was too weak to be of predictive value for preterm birth in twin pregnancies. IL-1alpha and IL-8, but not IL-6, were associated with bacterial vaginosis.     

Corticotropin-releasing hormone receptor subtype 1 is significantly up-regulated at the time of labor in the human myometrium

Circulating concentrations of CRH rise late in human pregnancy, reaching a peak at labor. The presence of functional CRH receptors, CRH-R1 and CRH-R2, in the human myometrium suggests that CRH may modulate uterine activity. We hypothesized that the number of CRH receptors would be higher in myometrium than fetal membranes (FM) and would change during labor. Myometrial samples were collected from the lower segment (LS) in nonpregnant, preterm (32 +/- 2 weeks), and term (39 +/- 1.6 weeks) pregnant patients before and at labor. Fundus and LS samples were also collected from nonpregnant, pregnant, laboring, and postpartum women. FM were collected at term and at labor. We identified CRH receptors in myometrium and FM by semiquantitative RT-PCR and immunohistochemistry. CRH-R1 messenger ribonucleic acid (mRNA) in the LS was decreased in pregnancy and increased significantly in both preterm and term labor (P < 0.05), but remained unchanged in the fundus. CRH-R2 mRNA was present in 28% of LS myometrium with no change at labor. CRH-R1 and CRH-R2 protein was localized to myometrial smooth muscle in nonpregnant and laboring patients, with lower levels at term. CRH-R1 mRNA was present in chorion and decidua, but CRH-R2 was undetectable in these tissues. We conclude that CRH-R1 is expressed preferentially in myometrium and FM. Changes in CRH receptors during labor are consistent with CRH mediating effects on myometrial activity.     

Maternal plasma D-dimer levels in normal and complicated pregnancies

OBJECTIVE: To evaluate D-dimer as a marker for fibrinolysis in normal and complicated pregnancies using an enzyme-linked immunosorbent assay (ELISA) technique. METHODS: Four groups of pregnant women were enrolled: 17 normal women followed longitudinally from 28-40 weeks' gestation, 14 patients with preterm labor at 28-34 weeks, 17 patients with preeclampsia at term (37-40 weeks), and 14 patients with abruptio placentae (32-40 weeks). We assayed peripheral venous blood samples from each patient for D-dimer levels using a commercial ELISA kit. D-dimer values were calculated by regression analysis using internal standards and controls for each assay. Data were compared using Student t test or analysis of variance with repeated measures. RESULTS: D-dimer values increased slightly with increasing gestational age. Patients with preterm labor, preeclampsia, and abruptio placentae had mean D-dimer values significantly greater than those of controls (P < .003). D-dimer values of the abruption group were approximately twice those of the control group (3393 +/- 2086 versus 1750 +/- 839 ng/dL). CONCLUSION: An increase in fibrinolysis may be associated with the pregnancy complications studied, as reflected by alterations in maternal plasma D-dimer levels.     

Evidence of participation of the soluble tumor necrosis factor receptor I in the host response to intrauterine infection in preterm labor

PROBLEM: This study was conducted to determine whether: (1) the soluble tumor necrosis factor receptor I (sTNF-rI) is present in human amniotic fluid, neonatal urine, and the feto-maternal plasma; (2) there are changes in the concentration of the sTNF-rI in amniotic fluid with gestational age; and (3) microbial invasion of the amniotic cavity (in term and preterm parturition) is associated with changes in amniotic fluid sTNF-rI concentrations. METHOD: Amniotic fluid was retrieved by amniocentesis from 185 women classified into 11 groups according to gestational age (midtrimester, preterm gestation, and term), the presence or absence of labor, spontaneous rupture of membranes and microbial invasion of the amniotic cavity. sTNF-rI was assayed with a sensitive and enzyme-linked immunosorbent assay (ELISA) validated for amniotic fluid. In addition, sTNF-rI concentrations were determined in fetal blood obtained by cordocentesis in preterm gestations (N = 24) or at the time of delivery after spontaneous labor at term (N = 10). sTNF-rI concentrations were also measured in maternal venous and cord blood and neonatal urine (n = 13). RESULTS: sTNF-rI was found to be present in all amniotic fluid samples, maternal blood and fetal blood and neonatal urine samples; sTNF-rI concentrations were higher in the midtrimester than at term (mean +/- SD: 36.2 +/- 12.2 ng/ml versus mean +/- SD: 5.56 +/- 5.72 ng/ml [P < .05]); patients with preterm labor and microbial invasion of the amniotic cavity (with intact or with ruptured membranes) had significantly higher amniotic fluid concentrations of sTNF-rI than patients without microbial invasion; in the absence of microbial invasion, parturition (both term and preterm) was not associated with changes in amniotic fluid concentrations of sTNF-rI; neonatal urine contained the highest concentrations of sTNF-rI of all biological fluids assayed including maternal and neonatal/fetal blood and amniotic fluid. CONCLUSIONS: It was concluded that sTNF-rI is a physiologic constituent of amniotic fluid, as well as of the fetal and maternal plasma; that amniotic fluid sTNF-rI concentrations decrease as a function of gestional age and increases in the concentration of the sTNF-rI are part of the host response to intrauterine infection in preterm parturition.     

Changes in fetal plasma corticotropin-releasing hormone during androstenedione-induced labor in the rhesus monkey: lack of an effect on the fetal hypothalamo-pituitary-adrenal axis

Androstenedione infusion to pregnant monkeys leads to premature labor and live delivery. Androstenedione-induced labor also increased placental CRH messenger RNA and peptide to concentrations observed at term in pregnant monkeys. Placental CRH may modulate fetal pituitary-adrenal function during pregnancy in primates. This study tested the hypothesis that androstenedione-induced premature delivery in pregnant monkeys results from androstenedione-induced increases in placental CRH, which stimulate premature activation of the fetal pituitary-adrenal axis. The hypothesis was tested by comparing fetal umbilical vein (FUV) plasma CRH, ACTH, dehydroepiandrosterone sulfate, and cortisol concentrations at cesarean section in fetuses from mothers undergoing spontaneous, term labor (group I), with those in fetuses from mothers undergoing androstenedione-induced, premature labor (group II) and with those from mothers not in labor (group III). In addition, gestation-related changes in maternal plasma CRH concentrations were investigated, and CRH immunoactivity was characterized by Sephadex G50 chromatography in pooled maternal plasma extracts. FUV CRH concentrations were similarly elevated in group I and group II fetuses, compared with group III fetuses. Despite similar FUV blood gases in all fetuses, FUV ACTH and dehydroepiandrosterone sulfate concentrations were higher in group I fetuses than in group II or group III fetuses. The majority of CRH immunoactivity coeluted with synthetic human CRH. Maternal plasma CRH concentrations showed a modest increase with gestation in the rhesus monkey. These data: 1) demonstrate that androstenedione treatment of pregnant monkeys at 0.8 of gestation elevates fetal plasma CRH to similar concentrations measured at term; 2) do not support the hypothesis that androstenedione-induced delivery in the monkey results from premature activation of the fetal pituitary-adrenal axis by placental CRH; but 3) do support a role for activation of the fetal hypothalamo-pituitary-adrenal axis in association with spontaneous term labor in the monkey; and 4) demonstrate important interprimate species differences in maternal CRH physiology.     

Ampicillin-metronidazole treatment in idiopathic preterm labour: a randomised controlled multicentre trial

OBJECTIVE: To determine whether treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour will prolong the gestation and reduce maternal and neonatal infectious morbidity. DESIGN: Randomised controlled double-blind trial. SETTING: Six obstetric departments in the Copenhagen area. POPULATION: One hundred and twelve women with singleton pregnancies, with threatened idiopathic preterm labour and intact amniotic membranes at 26 to 34 weeks of gestation. METHODS: Random allocation to eight days intravenous and oral treatment with ampicillin and metronidazole, or placebo. MAIN OUTCOME MEASURES: Number of days from admission to delivery, gestational age at delivery, rates of preterm delivery, low birthweight, maternal infections and neonatal infections. RESULTS: Treatment with ampicillin and metronidazole was associated with a significant prolongation of pregnancy (admission to delivery 47.5 days versus 27 days, P < 0.05), higher gestational age at delivery (37 weeks versus 34 weeks, P < 0.05), decreased incidence of preterm birth (42% versus 65%, P < 0.05), and lower rate of admission to neonatal intensive care unit (40% versus 63%, P < 0.05), when compared with placebo treatment. Antibiotic treatment had no significant effects on infectious morbidity. CONCLUSIONS: Treatment with ampicillin and metronidazole in women with threatened idiopathic preterm labour significantly prolonged the gestation, but had no effects on maternal and neonatal infectious morbidity.     

Oocyte donation to women of advanced reproductive age: pregnancy results and obstetrical outcomes in patients 45 years and older

We analysed the results of oocyte donation to women of advanced reproductive age (> or = 45 years old) and followed their pregnancies through to delivery in order to assess obstetrical outcomes. Patients (n = 162) aged 45-59 years (mean +/- SD; 47.3 +/- 3.4 years) underwent 218 consecutive attempts to achieve pregnancy. Oocytes (16.2 +/- 7.2 per retrieval) were provided by donors < or = 35 years old. Cleaving embryos (8.2 +/- 4.8 zygotes/couple) were transferred transcervically (4.5 +/- 1.1 per embryo transfer) to recipients prescribed oral micronized oestradiol and intramuscular progesterone. Following oocyte aspiration there were six instances of non-fertilization (2.8%) and 212 embryo transfers. A total of 103 pregnancies was established for an overall pregnancy rate (PR) of 48.6%, which included 17 preclinical pregnancies, 12 spontaneous abortions, and 74 delivered pregnancies (clinical PR 40.6%; delivered PR 34.9%). Multiple gestations were frequent (n = 29; 39.2% of pregnancies) and included 20 twins, seven triplets, and two quadruplets. Two of the triplet and both of the quadruplet pregnancies underwent selective reduction to twins. Antenatal complications occurred in 28 women (37.8% of deliveries) and included preterm labour (n = 9), gestational hypertension (n = 8), gestational diabetes (n = 6), carpel tunnel syndrome (n = 2), pre-eclampsia (n = 2), HELLP syndrome (n = 2), and fetal growth retardation (n = 2). 48 (64.8%) deliveries were by Caesarean section. The gestational age at delivery for singletons was 38.3 +/- 1.3 weeks (range 35-41 weeks), with birth weight 3218 +/- 513 g (range 1870-4775 g); twins 35.9 +/- 2.0 weeks (range 32-39 weeks), birth weight 2558 +/- 497 g (range 1700-3450 g); and triplets 33.5 +/- 0.7 weeks (range 32-34 weeks), birth weight 1775 +/- 190 g (range 1550-2100 g). Neonatal complications (4.6% of babies born) included growth retardation (n = 2), trisomy 21 (n = 1), ventricular septal defect (n = 1), and small bowel obstruction (n = 1). There were no maternal or neonatal deaths. We conclude that oocyte donation to women of advanced reproductive age is highly successful in establishing pregnancy. However, despite careful antenatal screening, obstetrical complications are common, often secondary to multiple gestation.     

Levels of corticotropin-releasing hormone messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus and proopiomelanocortin mRNA in the anterior pituitary during late gestation in fetal sheep

CRH regulates POMC gene expression and subsequent ACTH biosynthesis and release. In sheep, the preterm rise in fetal plasma ACTH commences at approximately 125 days gestation (dGA; 147 dGA = term), preceding the initiation of adrenocortical steroidogenesis. We hypothesized that an increase in CRH expression in the hypothalamic paraventricular nucleus (PVN) and POMC expression in the anterior pituitary in the late gestation sheep fetus may precede adrenal cortex maturation. Fetal sheep were obtained at 105-107 (n = 4), 128-130 (n = 5), and 138-140 (n = 4) dGA. Hypothalami were cryosectioned and subjected to in situ hybridization for ovine CRH mRNA. In all dGA groups, expression of CRH mRNA was observed throughout the rostrocaudal extent of the fetal PVN. The midrostral region of the fetal PVN where the dorsal and ventral divisions of the rostral PVN merge to form a single structure was selected for quantification. The number of copies of CRH probe hybridized per micron 3 were determined to estimate the quantity of hybridized CRH mRNA; the mean estimated CRH mRNA copy number per micron 3 midrostral PVN were 0.064 +/- 0.012 (105-107 dGA), 0.237 +/- 0.048 (128-130 dGA), and 0.108 +/- 0.034 (138-140 dGA; mean +/- SEM copies per micron 3 PVN). CRH mRNA signal significantly increased between 105-107 and 128-130 dGA (P < or = 0.05); 138-140 dGA levels of mRNA were not different from either 105-107 or 128-140 dGA levels. Regional variation in CRH mRNA levels were observed within the midrostral PVN between groups; at 138-140 dGA, a population of lateral midrostral PVN neurons maintain CRH mRNA levels greater than 105-107 dGA (P < 0.05), similar to those at 128-130 dGA. Fetal anterior pituitary RNA was subjected to Northern analysis for POMC mRNA. POMC mRNA levels in fetal anterior pituitaries were 14.1 +/- 2.2 (105-107 dGA), 28.9 +/- 10.9 (128-130 dGA), and 43.2 +/- 6 (138-140 dGA; mean +/- SEM arbitrary units). A significant increase (P < or = 0.05) was observed at 138-140 dGA compared to levels at 105-107 dGA. We conclude CRH mRNA levels in the fetal PVN increase coincident with increased POMC gene expression and the late gestation rise in fetal plasma ACTH. We speculate that a neuroendocrine stimulus at the fetal PVN may precipitate increased levels of CRH mRNA, initiating the maturation of the fetal hypothalamic-hypophyseal-adrenal axis, thus inducing the events of labor and delivery in sheep.     

A corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep

In sheep, corticotropin-releasing hormone (CRH) can stimulate the fetal release of ACTH to produce a cortisol surge which leads to the onset of parturition. We tested the hypothesis that fetal CRH is a primary factor in the onset of parturition in sheep by using a Type I CRH receptor antagonist, antalarmin, to block the endogenous action of CRH. Pregnant ewes were cannulated at 130-135 days of gestation. Five catheters were placed into the amniotic sac, fetal femoral artery, fetal tarsal vein, maternal jugular vein and carotid artery. After 5 days' recovery, blood samples from maternal and fetal vessels were collected at the following times: a day before the start of infusion, at [-1, 0, 1, 2, 4, 8 and 24]h, on the first day of infusion, and thereafter daily throughout a 10-day infusion. Animals (n=6 per group) received infusions into a fetal vein of either a vehicle comprising 1:1 mixture of ethanol and polyethoxylated castor oil (Cremophor EL) or antalarmin (50 g/L) in the vehicle at a rate of 0.3 mL/h. The plasma samples were assayed for ACTH and cortisol using commercial RIA kits. Fetuses infused with vehicle delivered at a mean gestational age of 141.8 +/- 0.9 days compared with antalarmin-infused sheep at 148.8 +/- 1.6 days (P = 0.0036, unpaired Student's t-test). Fetal ACTH and cortisol did not change in the antalarmin-infused sheep after 3 days' infusion compared to significant increases in vehicle-infused sheep (P=0.004 and P = 0.016 respectively, ANOVA). These data show that CRH receptor antagonism in the fetus can delay the onset of parturition. It supports the hypothesis that hypothalamic CRH drives fetal production of ACTH and is essential for the onset of parturition triggered by a surge in fetal cortisol.     

A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy

Maternal serum concentrations of inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC-related inhibin forms, total follistatin, steroids and gonadotrophins were measured longitudinally in six normal singleton pregnancies. Maternal venous blood was collected randomly during a spontaneous follicular phase prior to donor insemination, at 5, 7, 9, 11, 16, 20, 24, 28, 32 and 36 weeks after the first missed menses and in the early puerperium. Steroid and gonadotrophin profiles conformed to previous reports. While at week 5 of gestation inhibin-A, activin-A and follistatin concentrations were similar to those at the follicular phase, all three increased progressively (P < 0.001) to maximal concentrations in week 36: approximately 48-fold (3740 +/- 1349 ng inhibin-A/ml), approximately 22-fold (6109 +/- 1443 ng activin-A/ml) and approximately 10-fold (3563 +/- 418 ng follistatin/ml) higher. Pro-alphaC concentrations reached a maximum in weeks 5 (approximately 5-fold, P < 0.001) and 36 (1027 +/- 174 pg/ml, P < 0.01). Inhibin-B (71 +/- 23 pg/ml prior to pregnancy) was undetectable (<12 pg/ml) between week 5-16 of gestation but increased slightly in the third trimester (26 +/- 7 pg/ml in week 36). Activin-AB was undetectable throughout pregnancy. Post-partum concentrations of inhibin-A (41 +/- 12 ng/ml), inhibin-B (<12 pg/ml), activin-A (950 +/- 149 pg/ml), pro-alphaC (128 +/- 22 pg/ml) and follistatin (990 +/- 79 ng/ml) were substantially lower than at week 36 of gestation. The activin-A:follistatin ratio increased from 0.5 in week 5 to 1.8 in week 36, suggesting that more free activin-A is available in the maternal circulation during late pregnancy.     

Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy

OBJECTIVE: Corticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. During pregnancy corticotropin-releasing hormone is synthesized in large amounts by the placenta and released into the maternal and fetal circulations. Various endocrine, autocrine, and paracrine roles have been suggested for placental corticotropin-releasing hormone. The aim of this study was to prospectively assess the relationship between maternal plasma concentrations of corticotropin-releasing hormone in the early third trimester of pregnancy and the length of gestation in two groups of deliveries, with and without spontaneous labor. STUDY DESIGN: In a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples were collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record. RESULTS: Maternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length. CONCLUSION: These findings support the premise that placental corticotropin-releasing hormone is potentially implicated in the timing of human delivery in at least two ways. First, placental corticotropin-releasing hormone may play a role in the physiology of parturition. Premature or accelerated activation of the placental corticotropin-releasing hormone system, as reflected by precocious elevation of maternal corticotropin-releasing hormone levels, may therefore be associated with earlier onset of spontaneous labor and resultant delivery. Second, placental corticotropin-releasing hormone may be a marker of antepartum risk for preterm delivery and therefore an indirect predictor of earlier delivery. The implications of these findings are discussed in the context of the neuroendocrinology of placental corticotropin-releasing hormone and human parturition. Furthermore, the role of corticotropin-releasing hormone as a possible effector of prenatal stress in producing alterations in the timing of normal delivery is detailed.     

A boy with X-linked hyper-IgM syndrome and natural killer cell deficiency

OBJECTIVE: To compare the efficacy of nifedipine with ritodrine in the management of preterm labor. METHODS: One hundred eighty-five singleton pregnancies with preterm labor were assigned randomly to either ritodrine intravenously (n = 90) or nifedipine orally (n = 95). The principal outcome assessed was delay of delivery. RESULTS: Ritodrine was discontinued in 12 patients because of severe maternal side effects, and their results were excluded from further analysis. More women in the ritodrine group delivered within 24 hours (22 versus 11, P = .006), within 48 hours (29 versus 21, P = .03), within 1 week (45 versus 36, P = .009), and within 2 weeks (52 versus 43, P = .005) compared with those receiving nifedipine. There were significantly fewer maternal side effects in the nifedipine group. Apgar scores and umbilical artery and vein pHs were similar in both groups. The number of admissions to the neonatal intensive care unit (NICU) in the nifedipine group was significantly lower than in the ritodrine group (68.4 versus 82.1%, P = .04). CONCLUSION: Nifedipine in comparison with ritodrine in the management of preterm labor is significantly associated with a longer postponement of deliver, fewer maternal side effects, and fewer admissions to the NICU.     

Maternal hematologic changes during pregnancy and the effect of iron status on preterm delivery in a West Los Angeles population

This study was conducted to document the prevalence of anemia and high hematocrit during pregnancy and examine their effect on delivering preterm in a predominantly Hispanic population. The sample consisted of women receiving prenatal care from the public health clinics in the West Los Angeles from 1983 to 1986 (n = 7589). Multivariate logistic regression was used to isolate the role of anemia and high hematocrit from other factors that may influence birth outcome. The prevalence of anemia was approximately 9% at the initiation of prenatal care and at 28-32 weeks' gestation. Only anemia at 28-32 weeks was significantly associated with a preterm birth, even after adjusting for several confounders [Adjusted Odds Ratio (AOR) 1.83 95% Cl = 1.21, 2.77]. A high hematocrit that occurred in 9.6% of the population at 28-32 weeks was inversely associated with a preterm birth (AOR 0.78, 95% Cl = 0.44, 1.39). There was little differentiation of these risk factors when analyzing the etiological pathways of a preterm birth. These results indicate for the first time in a predominantly Hispanic population that despite routine iron supplementation, anemia still occurs in pregnant women and it can predict a preterm delivery.