Influence of fetal breathing movements on pulmonary hemodynamics in fetal sheep

During fetal development, pulmonary vascular resistance (PVR) is high, and, as a result, blood flow through the fetal lungs is low. Although PVR markedly decreases at the time of birth, the factors that regulate pulmonary blood flow (PBF) and PVR before and immediately after birth are not clear. Our aim was to examine the relationship between episodes of fetal breathing movements (FBM) and pulmonary hemodynamics during late gestation to further understand the relationship among lung luminal volume, phasic changes in intrapulmonary pressure, and PVR before birth. In chronically catheterized fetal sheep (120-128 d gestation; n = 5; term approximately 147 d), PBF and PVR were measured during periods of FBM and apnea. Episodes of FBM were divided into periods of accentuated (amplitude of >3.5 mm Hg change in tracheal pressure) and nonaccentuated periods of FBM. During accentuated episodes of FBM, mean PBF was increased to 159.5 +/- 23.4% (p < 0.0025) of the preceding apneic period and was associated with a 19.1 +/- 5.2% reduction in PVR. In addition, during accentuated episodes of FBM, the retrograde flow of blood through the left pulmonary artery was reduced to 90.1 +/- 1.0% of the preceding apneic period, which most likely contributed to the increase in mean PBF at this time. Although a change in PBF and PVR could not be detected during nonaccentuated FBM, compared with the preceding apneic period, PBF was linearly and positively correlated with the amplitude (change in pressure) of FBM. We conclude that PVR is decreased and PBF is increased during accentuated episodes of FBM, possibly as a result of phasic reductions in intrapulmonary pressures.     

Prenatal prediction of pulmonary hypoplasia

Pulmonary hypoplasia, although rare, is associated with significant neonatal morbidity and mortality. Conditions associated with pulmonary hypoplasia include those which limit normal thoracic capacity or movement, including skeletal dysplasias and abdominal wall defects; those with mass effect, including congenital diaphragmatic hernia and pleural effusions; and those with decreased amniotic fluid, including preterm, premature rupture of membranes, and genitourinary anomalies. The ability to predict severe pulmonary hypoplasia prenatally aids in family counseling, as well as obstetric and neonatal management. The objective of this review is to outline the imaging techniques that are widely used prenatally to assess pulmonary hypoplasia and to discuss the limitations of these methods.     

Stimulatory effect of theophylline on regulation of fetal breathing movements

We have performed the fetal CO2 response test on eight mature lambs in utero and have found that theophylline is a respiratory stimulant over a wide range of PaO2 and pHa. Theophylline produces significant increase in slope of P100, Pmax, and VEq response curves and significant increase in P100, Pmax, f, and VEq responses at PaCO2, 65 torr. It also produces significant lowering of the naturally high fetal absolute threshold to CO2, i.e., PaCO2 at which breathing starts during the CO2 test. "Offset" threshold, i.e., PaCO2 when breathing stops after the test, is the same with and without theophylline and equal to absolute threshold with theophylline. Our studies indicate that: (1) theophylline lowers fetal threshold and increases sensitivity to CO2; (2) increased sensitivity is expressed mainly by heightened Pmax (i.e., the equivalent of tidal volume) with some contribution of f particularly at high PaCO2; (3) decreased CO2 threshold is best assessed by determination of absolute threshold rather than the conventional x-axis intercept method; (4) the low offset threshold is consistent with our understanding that arousal is a requisite for generation and maintenance of fetal breathing; (5) theophylline is as effective a respiratory stimulant during fetal acidemia and hypoxemia as it is under normal conditions; and (6) a number of serious reservations must be held regarding use of theophylline during low pHa, low PaO2 states.     

The central effects of thyrotropin-releasing hormone on the breathing movements and electrocortical activity of the fetal sheep

The fetal respiratory and electrocortical effects of thyrotropin-releasing hormone (TRH) administered into the lateral cerebral ventricles, have been investigated in chronically catheterized unanesthetized fetal sheep at 125-140 days of gestation. Stimulatory effects on fetal breathing movements were seen at doses as low as a lug bolus. TRH given as a 5-micrograms bolus followed by a 10 micrograms/h infusion for 2 h induced a rapid switch to significantly faster, deeper, and continuous fetal breathing movements, while the electrocorticogram remained episodic. Fetal breathing movements did not stop during hypoxia. TRH given as a 2-micrograms bolus followed by a 4 micrograms/h infusion or as a 5-micrograms bolus followed by a 5 micrograms/h infusion induced the same stimulation of FBMs, but breathing essentially remained episodic, state related and inhibited by hypoxia. As hypothermia presumably induces a surge in TRH secretion at birth it is possible that TRH has some role in the switch from fetal to postnatal breathing patterns.     

The effects of maternal hyperoxia on fetal breathing movements, body movements and heart rate variation in growth retarded fetuses.

In hypoxemic intrauterine growth-retarded fetuses (IUGR) there is a reduction in the incidence of fetal movements and in fetal heart rate variation. A causal relationship with the impairment of fetal oxygenation has been suggested. In 16 IUGR fetuses and in 13 normally grown fetuses maternal hyperoxygenation was applied for 40 min to increase fetal PO2 levels. All IUGR fetuses had abnormal Doppler blood velocity waveforms of the umbilical artery suggesting an impaired uteroplacental exchange. The effect of hyperoxygenation on fetal breathing and body movements and on fetal heart rate was evaluated. In the IUGR fetuses there was a significant increase in fetal breathing and body movements and in heart rate variation during hyperoxygenation as compared to the preceding control period of 40 min. No significant changes in fetal breathing and body movements were found in the normally grown control fetuses. A surprising observation was the increase of the number of heart rate decelerations after discontinuation of the maternal hyperoxygenation. It is concluded that in IUGR fetuses the increase in fetal heart rate variation and the increase in the incidence of breathing and body movements during maternal hyperoxygenation substantiates the relationship between these variables and the oxygenation status of the fetus.     

Neonatal pulmonary hypoplasia with premature rupture of fetal membranes and oligohydramnios

We assessed pulmonary function and compression deformities in 76 preterm infants less than or equal to 34 weeks gestation who had premature rupture of membranes (PROM) for longer than 5 days (mean +/- SD 18.8 +/- 15.4 days, range 6 to 90 days). Twenty-one of the 76 infants had oligohydramnios and positional deformities at birth; however, only two infants met all the criteria for the oligohydramnios tetrad. All 21 required assisted ventilation from the moment of birth. Twenty infants had clinical evidence of pulmonary hypoplasia; 18 of these died. Pulmonary hypoplasia was confirmed by significantly low wet lung weights, low lung DNA content, or low radial alveolar counts in the 13 infants with postmortem examinations. Fifty-five infants with PROM for longer than 5 days did not have positional deformities. Twenty-one required assisted ventilation, of whom 10 had severe oligohydramnios. Eleven of the 21 died; autopsies were performed. All had normal wet lung weights, but seven had significantly decreased radial alveolar counts, implying a less severe but still fatal form of pulmonary hypoplasia. None of the remaining 34 infants had lung disease, and only three had oligohydramnios. We conclude that pulmonary hypoplasia can result from PROM associated with severe oligohydramnios of as short as 6 days duration. Furthermore, fatal pulmonary hypoplasia can occur with little or no external deformation.     

Noninvasive assessment of fetal pulmonary blood flow in experimental pulmonary hypertension in the fetal lamb

The aim of this study was to assess pulmonary arterial blood flow changes induced by the creation of a systemic arteriovenous fistula (120 d gestation) in the fetal lamb using Doppler technique. Doppler echocardiographic assessment of the pulmonary artery blood flow performed 1, 6, and 14 d after surgery showed that mean pulmonary arterial blood flow in the left or right pulmonary artery was 224 +/- 58 mL/min at day 1 in the fistula group, significantly higher than in the control group (113 +/- 22 mL/min; p < 0.01, ANOVA test) whether no difference was found at days 6 and 14. The mean inner diameter of the left pulmonary artery measured on postmortem lung arteriograms compared favorably to the one measured on day 14 at the same level on ultrasound. The mean left pulmonary arterial blood flow, measured at birth on day 14 after surgery, using ultrasonic flow transducer, was not statistically different from the one measured by Doppler on day 14. Our data demonstrate that echocardiography allows accurate assessment of pulmonary arterial blood flow in utero, providing evidence suggesting transient high pulmonary blood flow that did not last >6 d after the creation of a systemic fistula.     

Retinoic acid fails to reverse oligohydramnios-induced pulmonary hypoplasia in fetal rats

All-trans retinoic acid (ATRA) stimulates platelet-derived growth factor (PDGF)-A expression and enhances alveolarization in rat lungs. On d 16 of gestation, pregnant Sprague-Dawley rats were randomly assigned to either a retinoic acid group (intragastric ATRA at 10 mg/kg body weight) or a vehicle group. We punctured each amniotic sac, and fetuses in the opposite uterine horn served as controls. On d 21 of gestation, the fetuses were delivered by cesarean section. Rats subjected to oligohydramnios exhibited significantly lower lung weights and lung/body weight ratios, and ATRA had no effects on the body or lung weights of oligohydramnios-exposed rats. Lung PDGF-A and -B mRNA expression was significantly lower in oligohydramnios-exposed rats compared with control littermates of maternal vehicle-treated dams. Maternal retinoic acid treatment significantly increased PDGF-A and -B mRNA expression in control and oligohydramnios-exposed rats compared with all rats and oligohydramnios-exposed rats of maternal vehicle-treated dams, respectively. Rats exposed to oligohydramnios exhibited a significantly lower generation of alveolar saccules than did control rats in the maternal retinoic acid- and vehicle-treated groups. In this model, maternal retinoic acid treatment showed no positive effects on oligohydramnios-induced pulmonary hypoplasia in the pseudoglandular stage.     

Low-intensity fetal lungs on MRI may suggest the diagnosis of pulmonary hypoplasia

Background: Pulmonary hypoplasia is a common cause of neonatal death. Despite the recent advances in prenatal diagnosis with US, the diagnosis of pulmonary hypoplasia is difficult. The recent application of fast MR imaging may provide additional valuable information. Objective: To evaluate pulmonary hypoplasia in the fetus with MRI. Materials and methods: The subjects comprised 23 fetuses (18–40 weeks' gestation), including major anomalies diagnosed on fetal ultrasonography (n = 20), maternal abnormality (n = 2) and one normal twin. MRI was performed with a 1.5-T magnet and half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences. MR images were interpreted by three radiologists with special attention to the intensity of the lungs. The lung-to-liver intensity ratio was calculated by means of region-of-interest (ROI) analysis. The diagnosis of pulmonary hypoplasia depended on clinical, surgical and autopsy findings. Results: All fetuses with normal pulmonary development showed high intensity in the lung except for one fetus at 24 weeks' gestational age. All fetuses with pulmonary hypoplasia showed lung of low intensity. Conclusions: Low-intensity fetal lung on MRI imaging indicates pulmonary hypoplasia after 26 weeks' gestation. Received: 10 January 2000 Revised: 28 June 2000 Accepted: 6 March 2001     

The effects of lung distension, oxygenation, and gestational age on fetal behavior and breathing movements in sheep

Lung distension with 100% O2 at a continuous positive airway pressure of 30 cm H2O may induce continuous fetal breathing movements (FBM) in sheep. The objectives of this study were 1) to investigate the relative roles of lung distension and oxygenation and 2) to test the hypothesis that FBM can be induced during labor, when normally they are greatly reduced or absent. We studied 13 chronically instrumented, unanesthetized fetal sheep between 128 and 144 d of gestation (term = 147 +/- 2 d). Each fetus was instrumented to record sleep states, diaphragm electromyogram, blood pressure, arterial pH, and blood gas tensions. The fetal lungs were distended via an in situ endotracheal tube with four different concentrations of O2 (0, 21, 50 and 100%) at a continuous positive airway pressure of 10, 20 and 30 cm H2O in a randomized order. No change in any recorded physiologic variable was observed at 129 +/- 1 or 132 +/- 1 d of gestation. At 135 +/- 1 and 138 +/- 1 d, in response to a continuous positive airway pressure of 30 cm H2O and 100% O2, pH decreased (p = 0.0004 and 0.005, respectively) and arterial O2 tension increased (p = 0.004 and 0.02, respectively). However, increases in 1) breathing time, 2) breathing time/low-voltage electrocortical activity ratio, 3) duration of arousal, and 4) length of single breathing epochs were observed only at 138 +/- 1 d. Lung distension with N2 resulted in a decrease in FBM. Six fetuses were studied during labor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of epidermal growth factor on lung growth in experimental fetal pulmonary hypoplasia

The purpose of this study was (1) to compare the expression of epithelial growth factor receptor (EGFR) in the lung tissues of human fetuses with or without pulmonary hypoplasia, and (2) to investigate the effects of EGF on lung growth in experimental pulmonary hypoplasia in rabbits. Firstly, we investigated the expression of EGFR in lung tissues of human fetuses with or without pulmonary hypoplasia by immunohistochemistry. Secondly, the amniotic fluid was shunted into the maternal abdominal cavity in a group of 12 fetal rabbits, another group (n = 12) received EGF injection (5 microg, i.p.) at day 25 of gestation. The third group (n = 12) was only treated with EGF while littermates not operated on served as the control group (n = 12). On day 29 of gestation, fetuses were delivered by Cesarean section and the lungs removed. The body weight and wet lung and liver weights were measured. As a measure of fetal lung growth, we determined the size of lung acini, the number of terminal airspaces, and diameter of alveoli (n = 6, each groups). We also measured the concentration of phosphatidylcholine (PC) and the lecithin/sphingomyelin (L/S) ratio in lung lavage fluid at birth in some fetuses (n = 6, each groups). In human fetuses with pulmonary hypoplasia, there was a significant decrease in radial alveolar count and expression of EGFR compared with fetuses without pulmonary hypoplasia. Amniotic shunt significantly decreased fetal lung/body weight ratio compared with control. Injection of EGF in the shunted group significantly increased lung/body weight ratio to the control level. The concentration of PC and L/S ratio in lung fluid lavage from rabbit fetuses with hypoplastic lungs was significantly higher than the other three groups. Histopathological examination of fetuses with hypoplastic lungs treated with EGF showed no significant change in the size of acini, number of terminal airspaces or the diameter of alveoli compared with the control group. Our results suggested that EGF was associated with lung growth and maturation of human lung and that treatment of rabbit fetuses with hypoplastic lungs with EGF facilitated lung growth and development.     

Effect of intrauterine repair of diaphragmatic hernia on the accompanying pulmonary hypoplasia in the fetal rabbit

Severe pulmonary hypoplasia precluding the sustenance of life is often found in newborns with prenatally diagnosed congenital diaphragmatic hernia (CDH). In utero repair of the hernia it is thought to be the sole method of salvaging these patients. To study the efficacy and feasibility of in utero repair of CDH, diaphragmatic hernias (DH) were produced successfully in 81 of 90 fetal rabbits by diaphragmatic perforation via a left thoracotomy at 22 days' gestation (term = 31 days). The DHs were repaired successfully in 25 of 50 fetal rabbits at 26 days' gestation. The rabbits with repaired and non-repaired DHs and their litter-mates (the control group) were delivered at 29 days' gestation by cesarean section. Some of the rabbits were killed and subjected to measurements of body and lung weight, determination of the DNA and surfactant (disaturated phosphatidylcholine; DSPC) contents of the lungs, and light and electron microscopic examination of the lung. Some newborn rabbits underwent endotracheal intubation and measurement of pressure-volume curves and pulmonary compliance. The total lung/body weight ratios and total lung DNA contents in the repair group were greater than those in the non-repair Group (P <0.01). There were no differences among the three groups in regard to body weight. When compared with the control group, both the repair and non-repair groups had increased DSPC content (P <0.01 andP <0.05, respectively), although there was no difference between the repair and non-repair groups. Histologically, the thickness of the terminal air spaces was smaller and the size of the lung acini was larger in the repair group than the non-repair group. Electron-microscopically, the number of type 11 lung cells in both the repair and nonrepair groups tended to be larger than that in the control group. When compared with the non-repair group, the repair group showed increased values for pressure-volume curves (P <0.01) and pulmonary compliance (P <0.01). In conclusion, in utero repair of CDHs is effective in improving the hypoplasticity of the lung accompanying this lesion.     

汉防己甲素对先天性膈疝大鼠模型胎仔肺发育不良的影响及意义

目的 探讨产前应用汉防己甲素(TET)对先天性膈疝(CDH)大鼠模型胎仔肺内表面活性蛋白B(SP-B)和增殖细胞核抗原(PCNA)的影响及意义.方法 10只成年雌性SD大鼠配种后,于孕9.5 d随机分为3组:对照组(2只)、膈疝组(4只)和治疗组(4只),膈疝组和治疗组一次性灌胃给予除草醚125 mg/只(溶于2.5ml橄榄油中),对照组灌胃给予等量橄榄油.配种后18.5 d时,治疗组给予30 mg/kg汉防己甲素灌胃(1次/d,连续3 d),膈疝组和对照组给予等量生理盐水.孕21 d对孕鼠行剖宫产,观察胎鼠膈疝形成情况,取出肺组织行HE染色并行图像分析,采用免疫组化染色法检测胎肺内SP-B和PCNA的表达情况.结果膈疝组和治疗组共有48只胎鼠形成膈疝,其致畸率为64.9%,二组之间致畸率差别无统计学意义(P>0.05).膈疝组胎鼠存在肺发育不良,产前给予TET干预,肺组织在形态上有明显改善,外形接近于对照组.正常肺组织中,SP-B在肺泡上皮细胞及远端支气管上皮细胞的胞浆内表达,在膈疝组中未见SP-B表达.治疗组中可见SP-B表达,但低于对照组(P<0.01).PCNA阳性细胞率在对照组与膈疝组的差异无统计学意义(P>0.05),但在治疗组中其表达显著较前二组为低,差异有统计学意义(P<0.01).结论 产前应用TET可诱导CDH胎鼠肺的成熟,促进肺内SP-B表达升高;同时,产前给予TET干预的CDH胎鼠,其肺内PCNA阳性细胞率明显降低,提示TET诱导CDH胎肺的成熟并不是依靠促进细胞增殖来完成的.     

Characterization of the fetal diaphragmatic magnetomyogram and the effect of breathing movements on cardiac metrics of rate and variability

Breathing movements are one of the earliest fetal motor behaviors to emerge and are a hallmark of fetal well-being. Fetal respiratory sinus arrhythmia (RSA) has been documented but efforts to quantify the influence of breathing on heart rate (HR) and heart rate variability (HRV) are difficult due to the episodic nature of fetal breathing activity. We used a dedicated fetal biomagnetometer to acquire the magnetocardiogram (MCG) between 36 and 38 weeks gestational age (GA). We identified and characterized a waveform observed in the raw data and independent component decomposition that we attribute to fetal diaphragmatic movements during breathing episodes. RSA and increased high frequency power in a time-frequency analysis of the IBI time-series was observed during fetal breathing periods. Using the diaphragmatic magnetomyogram (dMMG) as a marker, we compared time and frequency domain metrics of heart rate and heart rate variability between breathing and non-breathing epochs. Fetal breathing activity resulted in significantly lower HR, increased high frequency power, greater sympathovagal balance, increased short-term HRV and greater parasympathetic input relative to non-breathing episodes confirming the specificity of fetal breathing movements on parasympathetic cardiac influence. No significant differences between breathing and non-breathing epochs were found in two metrics reflecting total HRV or very low, low and intermediate frequency bands. Using the fetal dMMG as a marker, biomagnetometry can help to elucidate the electrophysiologic mechanisms associated with diaphragmatic motor function and may be used to study the longitudinal development of human fetal cardiac autonomic control and breathing activity.     

The umbilical artery blood flow velocity waveform in relation to fetal breathing movements, fetal heart rate and fetal behavioural states in normal pregnancy at 37 to 39 weeks

In 19 normal pregnancies between 37 and 39 weeks of gestation, the blood flow velocity waveform (FVW) of the umbilical artery was studied in relation to fetal breathing movements, fetal heart rate (FHR) and the fetal heart rate patterns (FHRPs) A and B. FHRP A is stable, with a narrow oscillation bandwidth, FHRP B shows a wider oscillation bandwidth. Although for state-assessment it is necessary to record three variables simultaneously, the linkage of these variables in the near-term healthy fetus is such, that FHRP A and B may be used for the assignment of behavioural states 1F and 2F. The FVW was characterized by the Pulsatility-Index (PI). Presence of fetal breathing movements strongly disturbed the regularity of the FVW. A significant inverse relationship between FHR and PI was established. A weighted regression coefficient was calculated: PI decreases 0.0075 with an increase of FHR of 1 beat per minute (PI140 = PI / 0.0075(FHR - 140]. The PI was higher during periods of FHRP A as compared to FHRP B. However, this difference disappeared, when the influence of FHR was taken into account by normalising all PIs to a standard heart rate level of 140 bpm. One should perform the umbilical artery blood flow measurements in absence of fetal breathing--(causing irregularity of the FVW) and body movements (because of accompanying FHR accelerations) and FHR should be taken into account when evaluating the FVWs.     

Ultrasonographic prediction of clinical pulmonary hypoplasia: measurement of the chest/trunk-length ratio in fetuses

Pulmonary hypoplasia is involved in patients with various surgical diseases. The aim of this study was to evaluate the clinical usefulness of measurement of the chest/trunk-length ratio (C/T) for predicting pulmonary hypoplasia in patients with congenital anomalies, with the exception of mass-like lesions in the thorax such as diaphragmatic hernia and cystic lung diseases. For measurement of C/T on fetal ultrasound, the sagittal section of the body trunk, including the spine, was analyzed. C/T was calculated as the chest length, defined from the top of the thorax to the top of the diaphragm, divided by the trunk length, defined from the top of the thorax to the bottom of the urinary bladder. From 1986 to 2000, measurements of C/T were undertaken in 49 healthy fetuses from 17 to 37 weeks of gestation and 98 fetuses with congenital anomalies, with the exception of intra-thoracic mass lesions, omphalocele, and fetal hydrops. Pulmonary hypoplasia was clinically assessed by the following criteria: (1) a lung-to-birth-weight ratio of 0.012 or less; (2) patients who required high-frequency oscillatory ventilation with mean airway pressure of 15 cmH(2)O or more with pure oxygen and/or who died presenting respiratory failure without evidences of meconium aspiration, congenital pneumonia, sepsis or hyaline membrane disease. For a predicting value for pulmonary hypoplasia to be obtained, sensitivity, specificity, positive predictive value and negative predictive value were quoted between C/T in patients with pulmonary hypoplasia and those without pulmonary hypoplasia. Healthy fetuses revealed the mean value as 0.38+/-0.03, with no significant change after 20 weeks of gestation. Pulmonary hypoplasia was assessed in 25 fetuses with urethral atresia and stenosis, renal agenesis, polycystic kidney, cloacal anomalies, diaphragmatic eventration, bronchopulmonary foregut malformation, chest deformity, meconium peritonitis and sacrococcygeal teratoma. As a predicting value for pulmonary hypoplasia, 0.32 or less of the maximum value of C/T indicated good accuracy, with a sensitivity of 92.0%, specificity of 95.9%, positive predictive value of 88.5% and negative predictive value of 97.2%. Ultrasonic measurement of C/T is useful in predicting postnatal respiratory conditions with regard to pulmonary hypoplasia.     

Effects of maternal glucose ingestion on human fetal breathing movements at weeks 24 and 28 of gestation

The incidence of human fetal breathing movements was studied in normal pregnancies before and after administration of 50 g glucose or a placebo (water) at 24 and 28 weeks. Glucose or water was given to the same women on two separate days in a randomised order. No significant differences were present among the results on the placebo-day and the control period of the glucose-day at either gestational age. On the glucose-day, the incidence rose significantly from 3.6 to a maximum of 11.6% at 24 weeks, and from 6.7 to 30.2% at 28 weeks. At both ages the maximum was found 90-120 min after the intake of glucose. It is concluded that already at 24 weeks gestation the human fetus reacts with an increase of fetal breathing movements after the administration of glucose to the mother.     

Primary pulmonary hypoplasia in the neonate.

Infants with primary pulmonary hypoplasia with respiratory distress immediately after birth, but usually elude early diagnosis. They have no other abnormalities, but frequently develop signs and symptoms of the PFC syndrome. Roentgenographically, they show small, clear lungs and are prone to develop complicating pneumothoraces. The clinical, roentgenographic, and pathologic features of eight infants with primary pulmonary hypoplasia are presented.