Graham C. Liggins

Lupus anticoagulant and pregnancy

A subset of women with a high rate of fetal wastage is identifiable among those with serologic but not necessarily clinical evidence of connective tissue disease. The presence of lupus anticoagulant in the plasma of a pregnant woman serves as a marker for a high rate of fetal wastage and risk of thrombosis. Lupus anticoagulant is best identified by the activated partial thromboplastin time or kaolin clotting time and can be specifically confirmed by the platelet neutralization procedure. Review of the obstetric literature indicates a total of 49 women with 160 unsuccessful pregnancies and 13 live births. Prednisone in immunosuppressive doses (40 to 60 mg/day) combined with low-dose aspirin (75 mg/day) has been demonstrated to be effective in suppressing activity of lupus anticoagulant in pregnant women and successful pregnancies have been obtained with this treatment. Lupus anticoagulant should be excluded in women with suspected collagen disease, with repeated early abortions and all unexpected late fetal losses.

Steroid and Growth Hormone Levels in Premature Infants After Prenatal Betamethasone Therapy to Prevent Respiratory Distress Syndrome

Summary: Prenatal maternal therapy with glucocorticoid reduces the incidence of respiratory distress syndrome (RDS) in premature infants. To investigate the effects of this treatment on the fetal endocrine system, we determined serum concentrations of betamethasone, cortisol, dehydroepiandrosterone sulfate, growth hormone, and prolactin in cord blood of 215 treated infants and 117 untreated infants of 26–36 wk of gestation. Cortisol levels are suppressed within 6 hr of betamethasone treatment, decrease to 45% of the concentration in untreated infants (8.4 μg/dI), and return to normal by 7 days. Dehydroepiandrosterone sulfate is reduced maximally by 65% and returns to normal concentrations (123.5 μg/dI) in 7½ days. The suppression of both steroids was similar after treatment with 12 mg betamethasone (acetate and phosphate) daily 2 times or with 6 mg betamethasone (alcohol) twice daily 4 times. Peak betamethasone levels were higher after the 12 mg dose, but the two-treatment regimens produced a similar total exposure of the fetus to elevated serum glucocorticoid activity for 2½ days and decreased plasma activity for the subsequent 4½ days. Treated infants with low cortisol concentrations at birth increased their cortisol levels severalfold after birth in response to either intrapartum asphyxia or RDS.Betamethasone therapy did not affect cord serum prolactin levels, but the concentration of growth hormone was reduced at all gestational ages. The suppression was greatest (53% decrease) among infants of 28<32 wk, and, among older infants, there was a subsequent increase above control levels between 2 and 4 days after treatment.This study indicates that prenatal betamethasone treatment causes a transient suppression of fetal growth hormone and presumably those pituitary hormones which regulate steroid production by both the definitive and fetal zones of the fetal adrenal. However, the suppression of fetal cortisol does not interfere with the pituitary-adrenocortical response to stress after birth.Speculation: We speculate that the results of betamethasone treatment on the fetal endocrine system described here may represent only some of the effects which exogenous corticosteroids have on the human fetus. Continuing research in this area will further the understanding of the role of glucocorticoids during development, and will help in establishing the safest and most efficacious treatment regimen for prevention of RDS.

Prolactin in umbilical cord blood and the respiratory distress syndrome

Prolactin was measured in umbilical cord serum obtained from 77 newborn infants of gestational age 28 to 40 weeks. A positive correlation with gestational age was demonstrated. Between 30 and 36 weeks of gestation the elevation of the regression line of the concentration of cord PRL versus gestation age was significantly lower (P less than 0.05) for those infants who developed respiratory distress syndrome compared to the regression line for infants who did not develop RDS. Between 32 and 33.5 weeks, the mean +/- SEM cord PRL concentration in infants who developed RDS (101.7 +/- 9.5 ng/ml) was significantly less (P less than 0.025) than the PRL concentration in those who did not develop RDS (161.8 +/- 18.9 ng/ml). Cord PRL did not correlate with cord cortisol or dehydroepiandrosterone sulfate concentrations. Cord growth hormone concentrations did not show any relationship to the occurrence of RDS. Serum PRL was not suppressed in a further 114 infants whose mothers were treated prenatally with betamethasone. These findings raise the possibility of a role of PRL in fetal lung maturation.

Human amnion metabolism

The energy stores of human term amnion include glycogen (2.2 +/- 0.3 mumoles of glucose per gram, mean +/- S.E.) and ATP (0.13 +/- 0.2 MM.). Histologic structure and biochemical functions were preserved during incubations of amnion for 120 minutes at 37 degrees C. in a defined medium simulating amniotic fluid; glycogen concentrations were maintained at control values, and the concentration of ATP usually remained at 85 to 100 per cent of control values. Glucose utilization during the first 60 minutes of incubation was linear at a rate of 70.0 +/- 3.0 nmoles per minute per gram of tissue. It is concluded that amnion is a highly metabolically active tissue that can be maintained in a viable state in a suitable medium.

Purification and characterization of a uterine phospholipase inhibitor that loses activity after labor onset in women

Gravidin, a protein that inhibits release of arachidonic acid from human decidual cells, was purified from amniotic fluid. The protein has a molecular weight of 58 to 60 kilodaltons, an isoelectric point of 8.4, and physical characteristics that are indistinguishable from those of inhibitor II previously described. Activity was determined in a dispersed decidual cell system that released arachidonic acid in response to either histamine or calcium ionophore and in a cell-free assay of phospholipase A2. Protein purified from incubates of chorion obtained after the onset of labor was significantly less active than that from chorion obtained before the onset of labor.

Growth, Elastin Concentration, and Collagen Concentration of Perinatal Rat Lung: Effects of Dexamethasone

Abstract: The ontogenesis of elastin and collagen accumulation and growth of the lung were studied in Wistar rats from day 18 of gestation until day 30 postnatally. Dexamethasone phosphate 0.1 mg or normal saline solution every 8 h for three doses was injected into pregnant rats on day 17. The effects of treatment, age, and sex on lung wet weight, lung dry weight, body weight, DNA, protein and desmosine (estimated by radioimmunoassay), and hydroxyproline were determined in the offspring. Dexamethasone inhibited lung growth and, to a lesser extent, body weight gain. While lung wet weight, lung dry weight, and body weight remained significantly reduced until postnatal day 15, the lung weight/body weight ratio was depressed only until postnatal day 5. The lung dry weight/lung wet weight ratio was decreased on day 20 of gestation and at birth. DNA concentration remained slightly but significantly reduced throughout the study period. Desmosine but not hydroxyproline concentration was lower after dexamethasone treatment during the period of rapid postnatal desmosine accumulation (day 10 p < 0.05, day 15 p < 0.01, day 20 p = 0.06).

Preterm delivery is not predicted by serial plasma estradiol or progesterone concentration measurements

Previous studies suggest that plasma estradiol-17 beta and progesterone concentration values differ between patients who deliver before term and those who deliver at term. To determine if these values would aid in preterm delivery risk prediction, we measured plasma estradiol-17 beta and progesterone concentrations serially in 90 patients at high risk for preterm delivery. Measurements from 17 patients who developed documented preterm labor and/or were delivered before term were compared to the tenth and ninetieth percentiles of 42 patients who were delivered at term. The sensitivity of these measurements to predict preterm delivery was very low. Also, the mean plasma estradiol-17 beta and progesterone concentrations in patients with preterm labor who had term deliveries and in patients with preterm labor that progressed to preterm delivery were not different from each other or from patients delivering at term. No change in plasma estradiol-17 beta or progesterone concentration was noted preceding labor. We conclude that serial measurements of plasma estradiol-17 beta and progesterone concentrations do not improve preterm delivery risk prediction.

Elastin and Collagen in the Fetal Sheep Lung. II. Relationship to Mechanical Properties of the Lung

ABSTRACT.: 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. Desmosinc 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)>1.5 ml/g wet weight and at 5 cm H2O (V5)>0.8 ml/g] and in seven fetuses whose lungs remained nondistensible and unstable (V40<0.6 ml/g and V5<0.4 ml/g). Alveolar saturated phosphatidylcholine was five times higher (p < 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. Desmosinc (p < 0.0001) and hydroxyproline (p < 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 Estimation of Elastin in Fetal Tissues by Radioimmunoassay of Isodesmosine

A radioimmunoassay was developed for the determination of isodesmosine as the tetraacetyl derivative. Isodesmosine tetraacetate conjugated with bovine albumin was injected into rabbits which developed useful titers of antibodies after five months. The radioligand for the assay was prepared by acetylating isodesmosine with [3H] acetic anhydride. The bound ligand was separated from free ligand by coprecipitation with human gamma-globulin in 46% saturated ammonium sulfate solution. The sensitivity of the assay was 2 ng isodesmosine. The antiserum was specific for isodesmosine tetraacetate and only desmosine tetraacetate gave appreciable cross-reactivity (4%). The assay was found to be suitable for the accurate estimation of elastin in small samples (5 mg dry weight) of rat and ovine fetal lung tissue and for elastin degradation products in amniotic fluid (0.5 ml).

Elastin and collagen in the fetal sheep lung. I. Ontogenesis.

ABSTRACT.: 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 IIfold in nondissected parenchyma, dissected (free of tubular structures of >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.