Objective
The aim of this study was to determine whether sonographic fetal pulmonary artery flow velocity waveforms correlate with amniotic fluid biomarkers of fetal lung maturity.
Study Design
We studied women with singleton pregnancies undergoing clinically indicated amniocentesis for fetal lung maturity at Yale-New Haven Hospital. Fetal pulmonary artery flow velocity measurements, including systolic/diastolic ratio, pulsatility index, resistance index, and acceleration-time/ejection-time ratio were obtained using spectral Doppler ultrasound. Pearson’s correlation coefficient was used to determine the association between fetal pulmonary artery flow velocity parameters and the lecithin/sphingomyelin ratio.
Results
Twenty-nine subjects met study criteria. The acceleration-time/ejection-time ratio was inversely correlated with the lecithin/sphingomyelin ratio (r = −0.76; P ≤ .001). This relationship was maintained after controlling for potential confounders. Other fetal pulmonary artery flow velocity measurements were not associated with the lecithin/sphingomyelin ratio.
Conclusion
There is an inverse correlation between the acceleration-time/ejection-time ratio in the fetal pulmonary artery and the amniotic fluid lecithin/sphingomyelin ratio. This suggests that ultrasound evaluation of fetal pulmonary artery blood flow may be a promising new noninvasive technique to evaluate fetal lung maturity.
Neonatal respiratory distress syndrome (RDS) refers to respiratory compromise presenting at or shortly after delivery related to a deficiency of pulmonary surfactant, a naturally occurring phospholipid required to decrease surface tension within the alveoli to prevent alveolar collapse. Originally described by Avery and Mead in 1959, RDS remains a major cause of neonatal morbidity and mortality. A recent epidemiologic study in the United States estimates that there are 80,000 cases of neonatal RDS each year, resulting in 8500 deaths and hospital costs in excess of $4.4 billion. However, not all infants are at equal risk, as the pulmonary system is among the last of the fetal organ systems to become functionally mature. As such, RDS is primarily, although not exclusively, a disease of premature infants, with an incidence and severity highly dependent on gestational age (GA).
Given the importance of RDS as a cause of neonatal morbidity and mortality, even in late preterm deliveries, a number of biochemical tests have been developed to predict the risk of RDS and assist obstetric care providers in delivery timing. These tests, including, among others, the lecithin/sphingomyelin (L/S) ratio and the presence or absence of phosphatidylglycerol (PG), require amniocentesis, followed by direct or indirect measurement of the surface-active properties of surfactant phospholipids secreted by the fetal lungs into the amniotic fluid. Amniocentesis is an invasive procedure and is associated with a small but real risk to the pregnancy, including preterm premature rupture of membranes, preterm labor, placental abruption, fetomaternal hemorrhage, fetal injury, and (rarely) fetal or even maternal death. Currently, the American College of Obstetricians and Gynecologists recommends that fetal pulmonary lung maturity should be confirmed in a low-risk singleton pregnancy if an elective delivery is being contemplated before 39 weeks of gestation. A noninvasive test for fetal lung maturity (FLM) would be useful to minimize the need for invasive testing and would be more acceptable to women.
We hypothesized that fetal pulmonary artery Doppler velocimetry may be useful to predict FLM. Our hypothesis was based on number of observations. First, the sonographic echogenicity of the fetal lung changes in a predictable pattern throughout pregnancy, which corresponds to morphologic and functional changes in fetal lung development with increasing GA. Second, pulmonary artery Doppler velocimetry has previously been used in an attempt to identify fetuses at risk for pulmonary hypoplasia, albeit with mixed results. Third, pulmonary artery Doppler velocimetry studies have shown that neonates with RDS have increased pressure in their pulmonary vasculature, which decreases after treatment with artificial surfactant. Last, fetal pulmonary artery flow velocity (FPAF) waveforms have been measured throughout normal pregnancy and have been shown to change with advancing GA by some but not by others. Despite these observations, the association between FPAF waveforms and amniotic fluid biomarkers of FLM has not been systematically examined. We examined the relationship between sonographic FPAF waveforms and a standard amniotic fluid biomarker of FLM, the L/S ratio.
Materials and Methods
Study population
This study was approved by the local Human Investigations Committee. Women undergoing clinically indicated amniocentesis for FLM testing at Yale-New Haven Hospital from July 2007–June 2008 were identified and invited to participate in the study. GA was determined by first-trimester ultrasound, certain last menstrual period confirmed by a second-trimester ultrasound, or in vitro fertilization or artificial insemination dating. Exclusion criteria included multiple gestation, fetal growth <10th percentile or >90th percentile for GA, known chromosomal/structural abnormalities, preexisting maternal medical conditions (eg, diabetes, renal disease, hypertensive disorders, and cholestasis), vaginal bleeding, uterine contractions, ruptured membranes, oligohydramnios (defined as a sonographic amniotic fluid index < 5 cm or maximum vertical pocket <2 cm), active infection, and reported illicit drug use. Subjects were excluded from the final analysis if the amniotic fluid samples were visibly stained with either blood or meconium or if a major congenital anomaly was identified after delivery.
Maternal records were matched to neonatal charts and demographic and outcome data abstracted. Maternal charts were reviewed for gestational dating criteria, indication for amniocentesis, results of L/S ratio and PG testing, date of delivery, maternal ethnicity, and the presence of medical complications. Neonatal records provided information on infant sex, birthweight, Apgar scores, results of chest radiographs if performed, and newborn intensive care unit (NICU) course. Infants who remained in the well-baby nursery were assumed not to have RDS, and no further data were collected. For those infants admitted to the NICU, data were collected on the duration of oxygen requirement; duration of NICU admission; and the diagnoses of RDS, transient tachypnea of the newborn, persistent pulmonary hypertension, bronchopulmonary dysplasia, pneumothorax, and other neonatal complications, including retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, and sepsis. Neonatal RDS was diagnosed by the presence of at least 2 of the following 3 criteria: (1) evidence of respiratory compromise (tachypnea, retractions, and/or nasal flaring) shortly after delivery and a persistent oxygen requirement for longer than 24 hours; (2) administration of exogenous pulmonary surfactant; and/or (3) radiographic evidence of hyaline membrane disease.
FPAF waveforms
After obtaining written consent, FPAF waveforms were obtained using spectral Doppler ultrasound immediately before clinically indicated amniocentesis for FLM testing. In each case, the ultrasound examination also confirmed fetal well-being, GA, amniotic fluid volume, and estimated fetal weight (EFW).
A standardized protocol was used for FPAF waveform measurements. All measurements were performed by a single provider (H.A.) using a Voluson E8 Expert ultrasound (General Electric Medical Systems, Milwaukee, WI) equipped with a 3–5 MHz convex array sector transducer. The low-cut filter was set at 50 MHz to record diastolic blood flow. Women were placed in the semirecumbent position, and a systematic examination of the fetal heart was performed (including 4-chamber view and outflow tracts) to exclude a major structural heart defect. The technique for FPAF waveform measurements was similar to that previously described by Chaoui et al. An axial plane through the fetal thorax was used to achieve the 4-chamber view of the heart. The main pulmonary artery was followed to the point where it divides into the right and left branches by rotating the transducer from the 4-chamber view to the short-axis view of the heart. The FPAF waveform measurements were taken within the proximal portion of the main pulmonary artery ( Figure 1 ). The sample volume gate was adjusted to 3 mm, and the angle of insonation was maintained at <15°. The blood flow waveform was displayed while scanning at a speed of 100 cm/s. The shortest time interval that could be measured was 1 ms.
Doppler velocimetry of the main pulmonary artery, which we measured, provides a characteristic waveform, which allows it to be distinguished from a signal emanating from the ductus arteriosus. The main pulmonary artery was recognized by the Doppler waveform. Differentiation from the ductus arteriosus waveform was important to avoid error. Unlike the pulmonary artery, the ductus arteriosus waveform is characterized by a rounded, full, and triangular-shaped systolic blood flow that is best described as “dome-like.” The ductus arteriosus also has a greater diastolic flow and peak velocity than the pulmonary artery. Signals emanating from the pulmonary arteries, on the other hand, are characterized by a sharp systolic peak blood flow with a needle-like appearance, commonly referred to as a “spike and dome” pattern. A small “notch” of reversed flow is also seen at the end of systole. The “spike” component of systolic blood flow is made up of a rapid acceleration and deceleration phase that corresponds with ventricular systole. The diastolic phase begins with a brief reversal of blood flow (notch) caused by closure of the pulmonary valves. Thereafter, blood flow continues in a forward (positive) direction throughout ventricular diastole, albeit at a lower velocity ( Figure 2 , A).
Three consecutive pulmonary artery waveforms with corresponding measurements were acquired for each fetus and these measurements were averaged. To obtain consistent waveform images, all samplings were performed when the fetus was at rest without body or breathing movements. A number of different parameters were measured from the FPAF waveform, including the systolic/diastolic (S/D) ratio, pulsatility index (PI), resistance index (RI), and the acceleration-time/ejection-time ratio (At/Et). At refers to the time interval from the beginning of ventricular systole to the achievement of peak velocity. Et refers to the time interval from the beginning to the end of ventricular systole ( Figure 2 , B). Calculation of the At/Et ratio minimizes the influence of heart rate on the individual parameters.
FLM testing
Amniotic fluid samples obtained at amniocentesis were analyzed by thin-layer chromatography using the Helena Fetal-Tek 200 (Helena Laboratories, Beaumont, TX) method. At the same time, the presence or absence of a band in the PG area was routinely reported. Because these were all clinically indicated tests, the L/S ratio and PG results were available to the obstetric care provider and were used in clinical decision making. At our institution the L/S ratio cutoff to predict pulmonary maturity is ≥2.5 for nondiabetic women.
Statistical analysis
Data were analyzed using the SPSS 15 statistical software package (SPSS, Inc, Chicago, IL). The relationship between the various parameters of the FPAF waveform (including S/D ratio, PI, RI, and At/Et ratio) and measurements of FLM (L/S ratio and PG) were tested and expressed using the Pearson’s correlation coefficient. Partial correlation was used to calculate an adjusted correlation coefficient, taking into account potential confounding variables. To analyze intraobserver reproducibility of the FPAF measurements, observations were repeated 3 times at 5-minute intervals in 10 fetuses by a single examiner (H.A.). The intraobserver coefficient of variation for At/Et ratio was 6.3%. Statistical significance was accepted at a P value < .05.
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