Monocyte chemoattractant protein-1 and its receptor CCR-2 in piglet lungs exposed to inhaled nitric oxide and hyperoxia.

Monocyte chemoattractant protein-1 (MCP-1), acting through its C-C chemokine receptor 2 (CCR-2), has important roles in inflammation, angiogenesis, and wound repair. The individual and combined effects of inhaled nitric oxide (NO) and hyperoxia on lung MCP-1 and CCR-2 in relation to lung leukocyte dynamics are unknown. Because MCP-1 gene is up-regulated by oxidants, we hypothesized that inhaled NO with hyperoxia will increase MCP-1 production and CCR-2 expression more than either gas alone. We randomly assigned young piglets to breathe room air (RA), RA+50 ppm NO (RA+NO), O(2), or O(2)+NO for 1 or 5 d before sacrifice. Lungs were lavaged and tissues preserved for hybridization studies, Western blotting, histology, and immunohistochemistry. The results show that lung MCP-1 production and alveolar macrophage count were significantly elevated in the 5-d O(2) and O(2)+NO groups relative to the RA group (p < or = 0.05). In contrast, lung CCR-2 abundance was diminished in the O(2) group (p

Neonatal complications of preterm premature rupture of membranes. Pathophysiology and management.

Midtrimester PROM is an infrequent, yet potentially disastrous complication of pregnancy. The most likely neonatal complication is preterm delivery with associated morbidity and mortality risks. Unique neonatal complications following PPROM include skeletal deformations and pulmonary hypoplasia related to prolonged oligohydramnios exposure. A systematic approach to an infant with respiratory insufficiency following PPROM delivery is possible with an understanding of the pathophysiology of pulmonary hypoplasia. Neonatal management should include immediate resuscitation including surfactant replacement, with careful attention to techniques of mechanical ventilation to avoid early volutrauma. Adjunctive therapies directed at pulmonary hypertension may now permit survival of some infants with less severe forms of pulmonary hypoplasia.

The precarious antioxidant defenses of the preterm infant.

Oxygen radicals are considered to be major causative factors in many illnesses of preterm infants. This article reviews the antioxidant defenses in immature animals and preterm infants, and attempts to quantitate their vulnerabilities to oxidants. Sources of oxidants, including hyperoxia, iron, parenteral nutrition, nitric oxide, and prooxidants, and their impact on immature antioxidant defenses are discussed. Genetic manipulations of antioxidant enzymes such as knockout and transgenic mice models are reviewed. The various clinical and investigational antioxidant therapies in animals and humans and difficulties in the design of antioxidant therapy studies are explored.

High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets.

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.

Independent and combined effects of prolonged inhaled nitric oxide and oxygen on lung inflammation in newborn piglets.

Clinical use of nitric oxide (NO) is usually in conjunction with high oxygen concentrations, the effects of which may include lung neutrophil accumulation, apoptosis and upregulation of antioxidant enzyme activity. To define the effects of NO on neutrophils from young piglets and its relationship to lung neutrophil dynamics during hyperoxia we exposed thirty piglets to room air (RA), RA+NO (50 ppm NO), O2 (FiO2> or =0.96) or O2+NO for 5 days. Ten additional animals breathed RA+NO or O2+NO, then recovered in RA for 3 days before sacrifice. Neutrophil CD18 and intracellular oxidant production were measured by flow cytometry. Lung apoptosis were assessed by TUNEL assay. Lung myeloperoxidase, SOD and catalase were measured biochemically. When compared to RA group, there was significant reduction in neutrophil CD18 and intracellular oxidant production in the RA+NO group, but lung MPO was unchanged. The O2 and O2+NO groups did not differ in CD18 expression or in intracellular oxidant production, but had significant increase in lung myeloperoxidase compared to the RA group. Apoptosis increased significantly only in the O2+NO group. The O2 group showed significantly increased lung SOD and catalase activity compared to the RA group, whereas the RA+NO and O2+NO groups did not. We conclude that inhaled NO at 50 ppm decreases neutrophil CD18 expression as well as intracellular oxidant production. However, this effect does not impact lung neutrophil accumulation during concurrent hyperoxia. The combination of NO and O2 exposure produces an increase in lung apoptosis. Finally, NO may prevent upregulation of SOD and catalase activity during hyperoxia, potentially increasing injury.

Lung elastic tissue maturation and perturbations during the evolution of chronic lung disease.

BACKGROUND: Infants <30 weeks' gestation have difficulty maintaining adequate functional residual capacity after the first week of life without positive end-expiratory pressure. We hypothesized that this is caused, in part, by increased lung elastic recoil. Our aims were to quantitate parenchymal elastic tissue during normal fetal development and in infants born at 23 to 30 weeks' gestation with prolonged survival at risk for chronic lung disease (CLD). METHODS: The controls were 22 to 42 weeks' gestation (n = 71), received ventilator care, and died within 48 hours of birth, plus 7 term infants who died at 43 to 50 weeks' postconceptional age from nonpulmonary causes. Infants who were 23 to 30 weeks' gestation, at risk for CLD, and who lived 5 to 59 days (n = 44), were separated into groups based on respiratory score (SCORE; The integrated area under the curve of the average daily fraction of inspired oxygen x mean airway pressure (cm H(2)O) over the number of days lived). The SCORE groups, <20, 21 to 69 and 70 to 200, related clinically to mild to severe lung disease. The lungs were tracheally perfused and formalin-fixed and total lung volume (TLV) was measured by water displacement. The paraffin-embedded lung blocks were stained with Miller's elastic stain. The parenchyma and parenchymal elastic tissue were point-counted. The absolute elastic tissue was calculated by multiplying TLV by the parenchymal and elastic fractions. Septal width, alveoli and alveolar duct diameters, and internal surface area (ISA) were also measured. RESULTS: In the controls, the volume density of parenchymal elastic tissue and absolute quantity of elastic tissue increased progressively from 22 to 50 weeks. In infants with CLD and SCORE >/=20, the volume density and absolute quantity of elastic tissue increased significantly. Mean absolute elastic tissue in the 20 to 69 group was 0.76 +/- 0.20 cm(3) greater than in the <20 group (0.46 +/- 0.10 cm(3)) who were similar to the controls, and the 70 to 200 group was 1.32 +/- 0.56 cm(3) greater than the 20 to 69 group. Elastic tissue for infants at risk for CLD, as a percent of predicted for same-age controls, rose linearly with increasing SCORE (r = 0.73; r(2) = 0.55). Control TLV and ISA were linearly related to age. Thirty-nine of the 44 CLD-risk infants had TLVs greater than controls. However, 77% with SCORE 20 to 200 had ISAs less than or equal to the control 95% confidence interval. Control septal width decreased sharply from 23 to 30 weeks, then gradually decreased to term. All infants with SCORE 70 to 200 and 80% of those with SCORE 20 to 69 had widths more than the control 95% confidence interval. Control alveolar and duct diameters doubled from 23 to 50 weeks and were significantly greater in infants with SCORES 20 to 200. DISCUSSION: Lung elastic tissue maturation is tightly controlled during fetal development. With increasing SCORE, elastic tissue increased >200%, accounting, in part, for the positive end-expiratory pressure needed to maintain end-expiratory lung volume in infants at risk for CLD. Saccule and duct diameters more than doubled, and septa thickened significantly in CLD. We propose the following sequence to be operative in CLD: at birth, the preterm infant (

Influence of inhaled nitric oxide and hyperoxia on Na,K-ATPase expression and lung edema in newborn piglets.

This study was undertaken to examine the combined effect of nitric oxide (NO) and hyperoxia on lung edema and Na,K-ATPase expression. Newborn piglets were exposed to room air (FiO2 = 0.21), room air plus 50 ppm NO, hyperoxia (FiO2 >/= 0.96) or to hyperoxia plus 50 ppm NO for 4-5 days. Animals exposed to NO in room air experienced only a slight decrease in Na,K-ATPase alpha subunit protein level. Hyperoxia, in the absence of NO, induced both the mRNA and the protein level of Na,K-ATP-ase alpha subunit and significantly increased wet lung weight, extravascular lung water, and alveolar permeability. NO in hyperoxia decreased the hyperoxic-mediated induction of Na,K-ATPase alpha subunit mRNA and protein while wet lung weight, extravascular lung water, and alveolar permeability remained elevated. These results suggest that 50 ppm of inhaled NO may not improve hyperoxic-induced lung injury and may interfere with the expression of Na,K-ATPase which constitutes a part of the cellular defense mechanism against oxygen toxicity.

Compressed air as a source of inhaled oxidants in intensive care units.

Exhaled gas from mechanically ventilated preterm infants was found to have similar oxidant concentrations, regardless of lung disease, leading to the hypothesis that wall outlet gases were an oxidant source. Oxidants in compressed room air and oxygen from wall outlets were assessed in three hospitals. Samples were collected by flowing wall outlet gas through a heated humidifier and an ice-packed condenser. Nitric oxide (NO) was measured in intensive care room air and in compressed air with and without a charcoal filter using a Sievers NOA280 nitric oxide analyzer (Boulder, CO). Oxidants were measured by spectrophotometry and expressed as nMol equivalents of H2O2/mL. The quantity of oxidant was also expressed as amount of Vitamin C (nMol/mL) added until the oxidant was nondetectable. This quantity of Vitamin C was also expressed in Trolox Equivalent Antioxidant Capacity (TEAC) units (mMol/L). Free and total chlorine were measured with a Chlorine Photometer. Oxidants were not found in compressed oxygen and were only found in compressed air when the compression method used tap water. At a compressed room air gas flow of 1.5 L/min, the total volume of condensate was 20.2 +/- 1 mL/hr. The oxidant concentration was 1.52 +/- 0.09 nMol/mL equivalents of H2O2/mL of sample and 30.8 +/- 1.2 nMol/hr; 17.9% of that found in tap water. Oxidant reduction required 2.05 +/-0.12 nMol/mL vitamin C, (1.78 +/- 0.1 x 10(-3) TEAC units). Free and total chlorine in tap water were 0.3 +/- 0.02 mg/mL and 2.9 +/- 0.002 mg/mL, respectively. Outlet gas contained 0.4 +/- 0.06 mg/mL and 0.07 + 0.01 mg/mL total and free chlorine, respectively; both 14% of tap water. When a charcoal filter was installed in the hospital with oxidants in compressed air, oxidants were completely removed. Nursery room air contained 12.4 +/- 0.5 ppb NO; compressed wall air without a charcoal filter, 8.1 +/- 0.1 ppb and compressed air with a charcoal filter 12.5 +/- 0.5 ppb. A charcoal filter does not remove NO. (Table 3) We recommend that all compressed air methods using tap water have charcoal filters at the compression site and the gases be assessed periodically for oxidants.

Airway muscle in infants with congenital diaphragmatic hernia: response to treatment.

BACKGROUND/PURPOSE: Airway muscle hyperactivity and chronic lung disease frequently follow congenital diaphragmatic hernia (CDH) treatment. The aim of this study was to compare the quantity of airway muscle and alveolar ductal artery muscle in CDH infants after various treatments. METHODS: Five groups were studied postmortem: CDH, died within 24 hours, without high ventilatory assistance (n = 3); CDH, various extracorporeal membrane oxgenation (ECMO) durations, without high ventilatory assistance (n = 4); CDH, various ECMO durations, with high ventilatory assistance (n = 7); no CDH, without high ventilatory assistance (n = 12); and no CDH, with high ventilatory assistance and bronchopulmonary dysplasia (BPD) (n = 5). Sections from standardized fixed lungs were immunohistochemically stained for alpha-smooth muscle actin. Muscle surrounding conducting airways from small preterminal bronchioles to bronchi was quantitated in both the ipsilateral and contralateral lungs with computerized image analysis. Similarly, muscle mass was quantitated in alveolar ductal arteries. RESULTS: CDH infants with low ventilatory assistance, regardless of postnatal age, had the same quantity of airway muscle as low ventilatory assistance controls. Infants with CDH and prolonged high ventilatory assistance had significantly more muscle throughout the conducting airways, similar to BPD infants without CDH, even though the CDH infants had significantly less exposure to high ventilatory assistance. With both low and high ventilatory assistance, the quantity of muscle in both the ipsilateral and contralateral lungs was similar. In contrast, small acinar arteries in CDH infants have increased muscle mass at birth. This muscle is decreased by ECMO but persists in CDH infants with high ventilatory assistance. CONCLUSIONS: The authors show that postnatally, CDH infants acquire increased muscle quantity throughout the conducting airways, in both the ipsilateral and contralateral lungs, with relatively short exposure to high ventilatory assistance. The normal decrease in acinar arterial mass that occurs postnatally is delayed in CDH infants with high ventilatory assistance.

Effect of inhaled nitric oxide in endothelin-1-induced pulmonary hypertension.

The interaction of two vasoactive substances, the vasoidilator nitric oxide (NO) and the complex-acting peptide endothelin-1 (ET-1), may help explain the pathophysiology of pulmonary hypertension, an important part of many pulmonary disorders in neonates. To understand better the interactions of inhaled NO and ET-1, we investigated the effects of ET-1 infusions with and without inhaled NO in two groups of piglets, one group pretreated with L-nitro-arginine methylester (L-NAME) and the other not pretreated. Inhaled NO (60 ppm) was administered during infusion of 1.0 microgram/kg or 2.5 micrograms/kg of ET-1. In animals not pretreated with L-NAME, the increase in PVR and in SVR induced by either dose of ET-1 was not reduced with administration of NO. The increase in systemic vascular resistance with ET-1 was greater (mean increase of 50% above baseline with 1.0 microgram/kg ET-1 and 100% with 2.5 micrograms/kg ET-1 by 5 min) than the increase in PVR, but the PVR/SVR ratio did not change during ET-1 administration. In contrast, animals pretreated with L-NAME did demonstrate inhibition of ET-1-induced increase in PVR with NO. No differences in effects on SVR were noted. We conclude that ET-1-induced increases in PVR are not diminished by 60 ppm of inhaled NO unless there has been inhibition of endogenous NO production.

Alveolar capillary dysplasia, with and without misalignment of pulmonary veins: an association of congenital anomalies.

Two new cases of alveolar capillary dysplasia (ACD), one without misalignment of the pulmonary vessels (MLV), are reported. They are unique for their association with complex cardiac malformations and asplenia. By reporting these cases we want to stress that ACD is associated with multiple malformations, and that the absence of MLV does not rule out the diagnosis of ACD.

Lung volume, pulmonary vasculature, and factors affecting survival in congenital diaphragmatic hernia.

OBJECTIVES: There is a wide variation in published mortality from congenital diaphragmatic hernia (CDH). The prevailing opinion is that this variation is related directly to the degree of pulmonary hypoplasia. Our aim was to test the hypothesis that other factors are important for outcome. The specific objectives of this study were: 1) to quantitate the degree of lung hypoplasia and pulmonary arterial wall thickness in infants eligible for, and treated with, extracorporeal membrane oxygenation (ECMO), using postmortem analysis of lung DNA, wet lung weight, lung volume, and vessel morphometrics; 2) to correlate the degree of lung hypoplasia and vascular changes with functional tests of oxygenation and estimated right ventricular systolic pressures (RVSP); 3) to determine the minimum lung volume necessary for survival; and 4) to determine contributory clinical factors as potential causes of death in ECMO-treated infants with CDH. METHODOLOGY: We retrospectively analyzed all 90 infants with CDH admitted consecutively over a 9-year period to a children's hospital with an ECMO program. Infants were categorized as lived or died, with or without ECMO. Indication for ECMO was an evolving process; however, in general, it was the therapy of last resort for pulmonary insufficiency. Clinically, the single best oxygenation index before ECMO or CDH repair while on conventional ventilation, and serial echocardiograms before, during, and after ECMO, were obtained. Twelve of 14 infants dying with ECMO and 6 of 12 without ECMO had postmortem examinations. Lung volume, DNA content, wet weights, and arterial wall thickness at the level of alveolar ducts were measured in both lungs. Postmortem morphometric findings were correlated with in vivo tests of cardiopulmonary function and contributory clinical factors in mortality. RESULTS: Sixty-three percent of all infants with CDH and 61% of ECMO-treated infants lived. All infants with CDH requiring ECMO had elevated RVSP/systolic systemic blood pressure ratios before ECMO (0.98 +/- 0.24). Eighty-eight percent of ECMO-treated infants with CDH decreased this ratio to < 0.5 within 14 days, regardless of lung size. However, infants dying with normal ratios still had increased arterial wall thickness and muscle in both lungs. In infants whose lung volume, DNA, and weight were > 45% of values predicted for age-matched controls, the oxygenation index ranged from 4 to 29, significantly less than that in infants with values < 45% of predicted values (range, 25 to 133). We speculate that eight infants with lung volumes > 45% of that for controls died from potentially preventable surgical and medical complications. CONCLUSION: A minimum lung volume of 45% of the value predicted from age-matched controls is required for survival in ECMO-treated infants. The RVSP/systolic systemic blood pressure ratio can be reduced with ECMO to < 0.5 in the majority of infants, even with lung volumes inadequate for survival. We speculate that 9% of infants with adequate lung volume were potentially survivable, but died of medical and surgical complications.

Increased acinar arterial wall muscle in preterm infants with PROM and pulmonary hypoplasia.

Pulmonary hypoplasia (PH), secondary to premature rupture of fetal membranes (PROM), is a frequent cause of pulmonary insufficiency in preterm infants. Pulmonary hypoplasia of diverse causes is usually associated with pulmonary hypertension. The objective of this study was to quantitate the acinar arterial wall thickness and muscularization in preterm infants with PROM that died with PH in comparison to age-matched controls. The left lung and pulmonary vasculature were perfused and fixed in a standard method in 16 infants with PROM and PH, and in 16 controls. In infants with PH, the alveolar ductal artery walls were nearly twice as thick as those of controls, 15.1 +/- 5.1% versus 7.4 +/- 1.3%, p < 0.0001. Ninety-one percent had muscle in the wall compared to 18% of controls. We conclude that infants with PROM and PH have increased pulmonary arterial muscularization, placing them at significant risk to have pulmonary hypertension. For these infants, therapy to reduce pulmonary vascular resistance should be instituted early.

Airway muscle in preterm infants: changes during development.

OBJECTIVE: To quantitate airway muscle changes in infants born at 23 to 41 weeks' gestation (control subjects) and to compare the changes with those in infants with chronic lung disease. METHODS: Fifty-five human lungs (from infants born at 23 to 41 weeks' gestation) were studied: 46 from infants who died of various diseases within 72 hours of birth, and 9 from infants with CLD (infants born at 26.9 +/- 0.5 weeks' gestation, who lived 17 +/- 8 days). All the lungs were perfused via the trachea and pulmonary artery in a standardized protocol. Formalin-fixed tissues in paraffin blocks were cut 5 microns thick. Sections were immunohistochemically stained for alpha-smooth muscle actin. By using computerized image analysis to quantitate images digitized into the computer, we measured the area of muscle, epithelium, airway lumen, and length of basement membrane in 18 airways, from the smallest bronchioles to bronchi, in each infant. RESULTS: Muscle was present at 23 weeks' gestation at all levels of the bronchial tree, and from 25 weeks to term the control lungs had a similar quantity of muscle at any given airway circumference. Relative to airway size, there was more muscle in small airways, less than 1000 microns in circumference, than in larger airways. In airways greater than 1500 microns in circumference, infants with CLD had significantly more muscle than did control lungs. CONCLUSIONS: Airway muscle is present at 23 weeks' gestation at all levels of the conducting airways. The 25-week gestation infants had a quantity of airway muscle relative to airway circumference similar to that of term infants. Preterm infants with CLD who were aged 9 to 29 days have increased airway muscle in airways greater than 1500 microns in circumference. Bronchospasm in very low birth weight infants is possible within the first days of life.

Effects of 8-epi-prostaglandin F2 alpha and U46,619 on pulmonary hemodynamics in piglets.

Non-cyclooxygenase-derived prostaglandin F2- (PGF2)-like compounds can be formed by membrane lipid peroxidation. We sought to characterize one member of this class of compounds, 8-epi-PGF2 alpha, for its biological properties on the pulmonary vasculature in young piglets. We first compared 8-epi-PGF2 alpha to a thromboxane (Tx) mimetic, U46,619, to determine relative pulmonary vasoconstrictive effects. We next determined if the vasoconstriction induced by both agonists would be reversed by 50 ppm of inhaled nitric oxide (NO). We also determined the degree of inhibition of U46,619 and of 8-epi-PGF2 alpha by a Tx receptor antagonist, SQ 30,741. Anesthetized, ventilated piglets (18 +/- 2 days, 3.7 +/- 0.5 kg) were infused with randomly selected doses of U46,619 and of 8-epi-PGF2 alpha to describe dose-response curves plotting pulmonary vascular resistance (PVRi) against dose. When a maximal dose was achieved, inhaled NO (50 ppm) was administered. Results for the calculated PVRi (mm Hg/l/ min/kg) are as follows (mean +/- SD): for U46,619, baseline value: 43 +/- 10, peak dose: 165 +/- 46, and peak dose with NO: 73 +/- 33; for 8-epi-PGF2 alpha, baseline value: 38 +/- 9, peak dose: 138 +/- 30, and peak dose with NO: 72 +/- 25, and for both drugs, PVRi at peak dose was greater than at baseline (p < 0.001). PVRi at peak dose plus NO also remained elevated above baseline (p < 0.05; repeated measures ANOVA). The Tx receptor antagonist SQ 30,741 (1-10 mg/kg) inhibited U46,619-induced pulmonary vasoconstriction completely; however, the 1 mg/kg dose provided only 90% inhibition against 8-epi-PGF2 alpha. We conclude that 8-epi-PGF2 alpha can contribute to pulmonary vasoconstriction in young piglets in a dose-dependent reversible manner and that it acts primarily via pulmonary vascular Tx receptors.

Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes.

OBJECTIVE: Our purpose was to determine prospectively whether sequential ultrasonographic assessment of amniotic fluid volume (< 1 cm vertical pocket constitutes severe oligohydramnios), in conjunction with other readily available clinical data, could predict the occurrence of pulmonary hypoplasia and neonatal mortality in pregnancies complicated by second-trimester premature rupture of membranes. STUDY DESIGN: Singleton pregnancies complicated by premature rupture of membranes at < 29 weeks' gestation were prospectively monitored by weekly ultrasonographic assessments. Stepwise multiple logistic regression analysis was used to determine the independent predictive value of ultrasonographically determined factors in the development of lethal pulmonary hypoplasia, neonatal mortality, and skeletal deformations. RESULTS: Neonatal mortality and pulmonary hypoplasia were statistically predicted by gestational age at rupture of membranes and interaction of premature rupture of membranes of > 14 days' duration with severe oligohydramnios. The occurrence of skeletal deformations was related to the interaction of duration of premature rupture of membranes and severe oligodramnios (p < 0.0001). Fetal breathing, fetal movements, and thoracic circumference/abdominal circumference ratios were not predictive of outcome. CONCLUSIONS: Both duration of severe oligohydramnios exposure and gestational age at premature rupture of membranes were independent significant predictors of increased neonatal risk. Severe oligohydramnios > 14 days after premature rupture of membranes at < 25 weeks' gestation has a predicted neonatal mortality of > 90%.

Familial pulmonary lymphatic hypoplasia associated with fetal pleural effusions.

Two siblings born with pleural effusions died of pulmonary insufficiency. The infant born with fetal hydrops at 30 weeks of gestational age lived 45 minutes. The lung weights were mildly hypoplastic on postmortem examination. The sibling, born at 37 weeks of gestational age lived 8 days. Postmortem lung weights were normal, but the infant had a congenital heart anomaly consisting of a complicated vascular ring. Morphometric analysis of both infants indicated relatively normal lungs except for interlobular septal lymphatic hypoplasia, apparently a specific, previously unrecognized cause of fetal pleural effusions.