Successful resuscitation during fetal surgery.

After in utero resection of a sacrococcygeal teratoma coupled with a transfusion of packed red blood cells, a 23-week-gestation fetus had bradycardia. Chest compressions were begun and epinephrine, atropine, and sodium bicarbonate were given, while the fetus remained bathed in warm saline. After 3 rounds of drugs, and just before withdrawing support, the fetal heart resumed beating and normal cardiac function. Based on to this case, the authors developed a resuscitation protocol for fetal surgery.

Apoptosis in the development of rat and human fetal lungs.

The establishment of an effective pulmonary alveolar-capillary interface occurs during mid to late gestation. This requires an expansion of endothelial, epithelial, and air space compartments with relative thinning of the interstitial compartment. Traditionally, these changes have been attributed to differences in the rate of cell growth in the respective compartments. We hypothesized that apoptosis also participates in this lung remodeling. Using light and electron microscopy, the nucleosomal ladder pattern of DNA digestion, and the detection of apoptotic cells in situ by the TUNEL method (Gavrieli, et al. J. Cell Biol. 1992;119:493-501), we demonstrated the occurrence of apoptosis in fetal lungs in vivo and in explant culture. In the rat fetal lung (RFL) in vivo we detected apoptosis from 16 through 22 d gestation. There was variation in the amount of DNA digestion between fetal lungs, but no correlation with gestational age. The findings in human fetal lungs (HFL) from 15 through 24 wk gestation were similar to those of the RFL; the apoptotic indices for both were about 2 apoptotic cells per thousand, suggesting that a significant percentage of cells are eliminated by this mechanism. In the HFL explant culture system, a rapid and massive wave of apoptosis occurred. In all samples of RFL and HFL examined, apoptosis was restricted to interstitial cells. This work has demonstrated for the first time that apoptosis is a feature of normal fetal lung development and that the process is accelerated in lung explant culture.

Effects of mechanical factors on growth and maturation of the lung in fetal sheep.

Previous fetal studies indicated that endocrine factors control surfactant maturation, whereas mechanical forces affect lung growth, but not surfactant. We altered mechanical forces in fetal sheep lungs at 100-108 days gestation by tracheal ligation (TL, n = 15, 7 successful studies) to accelerate lung growth, transection of cervical spinal cord (TCSC, n = 17, 6 successful studies) to produce lung hypoplasia, or sham operation (n = 11, 6 successful studies). The reasons for the high mortality rates are not known. At delivery (130-142 days), groups were similar in gestational age, weight, and cortisol. Effects on lung growth were similar to, but effects on surfactant differed from, previous reports. TL increased lung growth but decreased saturated phosphatidylcholine (SatPC) and surfactant protein (SP)A and apparently decreased SP-B and relative numbers of alveolar type II cells (based on immunohistochemical studies of 1 animal in each group); TCSC had opposite effects. In contrast to a previous study (J. A. Kitterman, G. C. Liggins, G. A. Campos, J. A. Clements, C. S. Forster, C. H. Lee, and R. K. Creasy, J. Appl. Physiol, 51: 384-390, 1981), SatPC did not correlate with cortisol. We conclude that altering mechanical forces in fetal lung affects not only lung growth but also surfactant maturation and possibly alveolar epithelial differentiation and disturbs the normal correlation between cortisol and surfactant. Associated changes in insulin-like growth factor I (IGF-I; increased by TL, P = 0.003) suggest a possible role for IGF-I in these effects.

The effects of mechanical forces on fetal lung growth.

Abnormalities of fetal lung growth, especially pulmonary hypoplasia, are important causes of neonatal morbidity and mortality. For most clinical conditions associated with abnormal lung growth, studies in experimental animals indicate that these conditions affect the mechanical forces acting on the fetal lung. The major stimulus to growth in the fetal lung is stretch, which is due either to (1) to the constant distending pressure during periods when fetal breathing movements are absent, or (2) the intermittent, repetitive stretch induced by changes in thoracic shape during fetal breathing movements. The mechanisms by which stretch is transduced to a biochemical signal stimulating cell division have not been defined. There are some indications that the mechanical forces that influence lung growth may also affect surfactant, but further studies are needed to define these effects and their possible clinical significance.

Prostaglandin E2 decreases fetal breathing movements, but not pulmonary blood flow, in fetal sheep.

Fetal breathing movements are vital for normal fetal lung growth. Inhibition of these fetal breathing movements is associated with pulmonary hypoplasia. Pulmonary hypoplasia also occurs subsequent to alterations in other factors, such as a significant decrease in pulmonary blood flow. The prostaglandin system is known to have profound effects on both fetal breathing movements and on the pulmonary vascular system. We studied six late-gestation chronically instrumented fetal sheep by using an electromagnetic flow transducer around the left pulmonary artery to determine whether a decrease in fetal breathing movements, subsequent to a continuous infusion of prostaglandin E2 (PGE2), is associated with a decrease in pulmonary blood flow. A continuous PGE2 infusion of 0.88 +/- 0.11 microgram.kg-1.min-1 over 120 min led to a significant decrease in fetal breathing movements (control 40.5 +/- 3.6%, infusion 3.3 +/- 1.6%; P < 0.001). In contrast, the PGE2 infusion had no effect on mean left pulmonary artery blood flow (control 27.7 +/- 9.3 ml.min-1.kg-1, infusion 23.8 +/- 7.0 ml.min-1.kg-1. The PGE2 infusion demonstrated central effects in the percentage of time the fetus was in high-voltage electrocortical activity (control 41.9 +/- 2.5%, infusion 56.5 +/- 5.4%; P < 0.05) and in the amount of time spent in low-voltage electrocortical activity without fetal breathing movements (control 17.5 +/- 2.7%, infusion 40.2 +/- 4.8%; P < 0.05). A significant decrease in the fetal heart rate during the infusion was seen with no effect on either the systemic or pulmonary blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhibition of prostaglandin synthesis on breathing movements and pulmonary blood flow in fetal sheep.

During transition from fetal to extrauterine life, respiration increases in incidence and magnitude as pulmonary blood flow dramatically increases. To determine whether alterations in pulmonary blood flow in utero are directly related to alterations in fetal breathing movements (FBM), we studied six chronically instrumented fetal sheep late in gestation to assess the effects of continuous FBM caused by a 4-h infusion of meclofenamate, a prostaglandin synthase inhibitor, on mean pulmonary blood flow to the fetus. We found a striking increase in FBM from 46 +/- 15% (SD) of the time during control to > 85% of the time by 1 h (P < 0.001), with the fetuses exhibiting continuous FBM by the last 1 h of infusion. The mean pulmonary blood flow also increased significantly during the first 90 min of the infusion as the incidences of FBM were increasing (26 +/- 14 and 56 +/- 23 ml.min-1.kg-1 for control and infusion, respectively; P < 0.01). Despite the simultaneous initial increase in FBM and mean pulmonary blood flow, the increase in left pulmonary artery blood flow was not sustained and decreased back to baseline by 2 h, even though the incidence of FBM continued to increase at this time. During the infusion, the mean pulmonary blood flow was not different between the presence or absence of FBM. There were no changes in fetal heart rate or pulmonary or systemic blood pressures during the infusion nor in arterial pH or blood gas tensions. We conclude that this increase in mean pulmonary blood flow in utero was not solely related to the increase in breathing movements.

Mode of delivery in pregnancies complicated by preeclampsia with very low birth weight infants.

The aims of this study were to examine data from an institution at which the goal has been to pursue vaginal delivery in patients with a preterm gestation and preeclampsia and to test the hypothesis that labor does not increase the risk of poor outcome for the preterm infant of a mother with preeclampsia. An analysis of all singleton infants born live who weighed 1500 gm or less and who were born to mothers with preeclampsia or eclampsia from 1975 to 1990 was undertaken. The infants who were delivered by cesarean section without labor and with a reassuring fetal assessment were compared with the infants who went through labor. Of 116 women with singleton pregnancies with preeclampsia and an infant who weighed 1500 gm or less, 54.3% were delivered by cesarean section without labor, 31.0% because of nonreassuring fetal assessment and 23.3% (group 1) because of other indications. Of the patients allowed to labor (group 2), 47.2% had cesarean sections because of fetal intolerance of labor and 32.1% were delivered vaginally. Of the patients who were delivered vaginally, 75% had an unfavorable Bishop's score at the outset of the induction. There was no significant difference between groups 1 and 2 for a number of immediate and long-term outcome variables except for a lower incidence of respiratory distress syndrome in the infants who went through labor. On the basis of these limited data a trial of labor should be considered in carefully selected women with preeclampsia who have very-low-birth-weight infants.

Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero.

Fetal lungs normally produce fluid that flows through the upper airway into the amniotic fluid. In fetuses with congenital diaphragmatic hernia (CDH), obstructing the flow of lung fluid may expand the lungs and propel the viscera from the chest, alleviating the pulmonary hypoplasia associated with CDH. To test this hypothesis, left-sided diaphragmatic hernias were created in sixteen 75-day-gestation fetal lambs (full-term, 145 days). At 120 days, the trachea was ligated in eight lambs; it was left unligated in the other eight. At 135 to 140 days, the fetuses were delivered, and a tracheostomy performed. Newborns were ventilated for 1 hour and then killed. Blood gas analysis was performed at 0,5,20,40, and 60 minutes. Lung dry weight, DNA, protein, and lipid analyses, as well as plasma cortisol measurements were performed. At autopsy, in the ligated lambs, the abdominal viscera was reduced from the thorax; however, the unligated lambs had viscera completely occupying the left chest. The lungs of the ligated lambs had a higher dry weight (4.22 +/- 1.37 g/kg v 1.95 +/- 0.59 g/kg; P =.001), DNA (193.8 +/- 90.5 mg/kg v 91.5 +/- 66.4 mg/kg; P = .02), and protein (1798 +/- 691.6 mg/kg v 766.6 +/- 201 mg/kg; P = .004). Lung saturated phosphatidyl choline (SPC) levels, DNA:protein ratio, and plasma cortisol were not different between the groups. Neonatal Po2 at 60 minutes was higher in the ligated group (179.4 +/- 127.0 mm Hg v 60.9 +/- 62.4 mm Hg; P < .05), and Pco2 was lower (44.1 +/- 21.4 v 83.9 +/- 23.5; P < .05) in the ligated group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of fetal breathing movements on pulmonary blood flow in fetal sheep.

In the fetus, normal lung growth requires both fetal breathing movements (FBM) and adequate pulmonary blood flow. We postulated that FBM intermittently increase pulmonary blood flow and may stimulate lung growth through that effect. To test the hypothesis that normal intermittent FBM cause associated intermittent increases in pulmonary blood flow, we studied eight chronically instrumented fetal sheep (gestational ages 125-143 d) on 34 occasions (total study time = 65.7 h). Each fetus had a cuff electromagnetic flow transducer around the left pulmonary artery, electrocortical electrodes, and catheters in the trachea, main pulmonary artery, carotid artery, and amniotic cavity. Mean blood flow though the left pulmonary artery averaged 59 +/- 8 mL/min (mean +/- SEM; per kg: 25 +/- 4 mL/kg/min) and was similar in both the presence (61 +/- 9 mL/min) and absence (57 +/- 7 mL/min) of FBM and during both high and low voltage electrocortical activity. In contrast, in utero phasic pulmonary blood flow varied with FBM, increasing during the inspiratory phase and decreasing during the expiratory phase. Both pulmonary and systemic vascular pressures showed changes in the opposite directions. Arterial pH and blood gas tensions were normal and did not change with FBM or electrocortical activity. We conclude that FBM do not increase mean blood flow through the left pulmonary artery; thus, it is unlikely that FBM stimulate lung growth through changes in pulmonary blood flow.

Transient severe respiratory distress mimicking pulmonary hypoplasia in preterm infants.

Three preterm infants are described who had respiratory failure immediately after birth. For each, historical factors (extrauterine abdominal pregnancy; ruptured membranes with oligohydramnios for 14 weeks; congenital diaphragmatic hernia) and the initial postnatal course were suggestive of pulmonary hypoplasia. However, with vigorous resuscitation each infant showed rapid improvement in pulmonary status for several hours. Two infants survived with no apparent pulmonary sequelae; the third had almost complete resolution of pulmonary disease but died from gastrointestinal complications. Thus some infants with historical and clinical indicators of severe pulmonary hypoplasia do not have hypoplastic lungs and respond favorably to resuscitation. The causes of the respiratory distress and of its rapid resolution are not known. On the basis of this experience, even infants with historical factors suggesting pulmonary hypoplasia and with postnatal respiratory distress should receive vigorous resuscitation.

Sympathectomy and beta-adrenergic blockade during lung maturation stimulated by TRH and cortisol in fetal sheep.

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.

Effects of acute oligohydramnios on respiratory system of fetal sheep.

Prolonged oligohydramnios, or a lack of amniotic fluid, is associated with pulmonary hypoplasia and subsequent perinatal morbidity, but it is unclear whether short-term or acute oligohydramnios has any effect on the fetal respiratory system. To investigate the acute effects of removal of amniotic fluid, we studied nine chronically catheterized fetal sheep at 122-127 days gestation. During a control period, we measured the volume of fluid in the fetal potential airways and air spaces (VL), production rate of that fluid, incidence and amplitude of fetal breathing movements, tracheal pressures, and fetal plasma concentrations of cortisol, epinephrine, and norepinephrine. We then drained the amniotic fluid for a short period of time [24-48 h, 30.0 +/- 4.0 (SE) h] and repeated the above measurements. The volume of fluid drained for the initial studies was 1,004 +/- 236 ml. Acute oligohydramnios decreased VL from 35.4 +/- 2.9 ml/kg during control to 22.0 +/- 1.6 after oligohydramnios (P less than 0.004). Acute oligohydramnios did not affect the fetal lung fluid production rate, fetal breathing movements, or any of the other measured variables. Seven repeat studies were performed in six of the fetuses after reaccumulation of the amniotic fluid at 130-138 days, and in four of these studies the lung volume also decreased, although the overall mean for the repeat studies was not significantly different (27.0 +/- 5.2 ml/kg for control vs. 25.5 +/- 5.5 ml/kg for oligohydramnios). Again, none of the other measured variables were altered by oligohydramnios in the repeat studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of very-low-birth-weight infants exposed to beta-sympathomimetics in utero.

In this study we examined neonatal and early childhood outcomes after intrauterine exposure to beta-sympathomimetic agents on infants with birth weights less than or equal to 1500 gm. The hospital courses and anthropomorphic, developmental, and neurologic development of 201 infants exposed to one or more beta-sympathomimetic agents (isoxsuprine, 33; ritodrine, 70; terbutaline, 43; combination, 55) were analyzed and compared with those of 130 control infants of similar birth weight. One hundred and seventy-seven infants had follow-up to 1 year of age, 101 to age 3, and 58 to age 4. When treatments consisting of a single beta-sympathomimetic or no treatment were compared, there were no statistically significant overall differences found in growth and development or in most of the short-term measures of infant well-being. However, significant overall differences with no evidence of confounding by time-related effects were found for the following; mortality, none greater than terbutaline; maximum positive inspiratory pressure when respiratory distress syndrome was present, none greater than terbutaline; neonatal trauma, terbutaline greater than ritodrine. Other differences were found in conjunction with evidence of time-related confounding, or within specific time intervals. It should be noted that these differences are not necessarily due to effects of the different treatments, as the data are observational.

Meclofenamate does not affect lung development in fetal sheep.

Prostaglandins may be involved in some aspects of fetal lung development, including surfactant metabolism, tracheal fluid production, and possibly lung growth. In the fetus, during the days before delivery, plasma PGE2 concentration increases and concurrently, tracheal fluid production decreases and surfactant production increases. To determine whether the increase in PGE2, specifically plasma PGE2 concentration, is responsible for these changes, we continuously infused the prostaglandin synthetase inhibitor, meclofenamate (0.7 mg/h per kg), into 8 fetal sheep for 5-13 days before delivery; 5 control fetuses received a continuous infusion of solvent for 5-11 days before delivery. Meclofenamate infusion significantly decreased plasma PGE2 concentrations until the day of delivery. However, meclofenamate did not affect tracheal fluid production or its decrease before delivery, fetal plasma cortisol concentration, surfactant content of tracheal fluid and lung tissue, organ weights, lung weights, or lung DNA and protein content. We conclude that the changes in lung development during the days before delivery are not dependent on the usual high fetal plasma concentration of PGE2 or its increase before delivery.

Meclofenamate increases ventilation in lambs.

To investigate the effects of the prostaglandin synthetase inhibitor, meclofenamate, on postnatal ventilation, we studied 11 unanaesthetised, spontaneously-breathing lambs at an average age of 7.9 +/- 1.1 days (SEM; range 5-14 days) and an average weight of 4.9 +/- 0.5 kg (range 3.0-7.0 kg). After a 30-min control period we infused 4.23 mg/kg meclofenamate over 10 min and then gave 0.23 mg/h per kg for the remainder of the 4 h. Ventilation increased progressively from a control value of 515 +/- 72 ml/min per kg to a maximum of 753 +/- 100 ml/min per kg after 3h of infusion (P less than 0.05) due to an increased breathing rate; the effects were similar during both high- and low-voltage electrocortical activity. There were no significant changes in tidal volume, heart rate, blood pressure, arterial pH or PaCO2, the increased ventilation resulted from either an increase in dead space ventilation or an increase in CO2 production. This study indicates that meclofenamate causes an increase in ventilation in lambs but no changes in pH of PaCO2. The mechanism and site of action remain to be defined.

Synergism of cortisol and thyrotropin-releasing hormone in lung maturation in fetal sheep.

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.

Physiological factors in fetal lung growth.

Adequate pulmonary function at birth depends upon a mature surfactant system and lungs of normal size. Surfactant is controlled primarily by hormonal factors, especially from the hypophysis, adrenal, and thyroid; but these have little influence on fetal lung growth. In contrast, current data indicate that lung growth is determined by the following physical factors that permit the lungs to express their inherent growth potential. (a) Adequate intrathoracic space: lesions that decrease intrathoracic space impede lung growth, apparently by physical compression. (b) Adequate amount of amniotic fluid: oligohydramnios retards lung growth, possibly by lung compression or by affecting fetal breathing movements or the volume of fluid within the potential airways and airspaces. (c) Fetal breathing movements of normal incidence and amplitude: fetal breathing movements stimulate lung growth, possibly by stretching the pulmonary tissue, and do not affect mean pulmonary blood flow but do induce small changes in phasic flow; these changes are probably too slight to influence lung growth. (d) Normal balance of volumes and pressures within the potential airways and airspaces: in the fetus, tracheal pressure greater than amniotic pressure greater than pleural pressure. This differential produces a distending pressure which may promote lung growth. Disturbing the normal pressure relationships alters the volume of fluid in the lungs and distorts lung growth, which is stimulated by distending the lungs and is impeded by decreasing lung fluid volume. The mechanisms by which these factors affect lung growth remain to be defined. Fetal lung growth also depends on at least a small amount of blood flow through the pulmonary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)