PATHOPHYSIOLOGY OF PREMATURE LABOR,
COMPLICATIONS OF PREMATURITY, AND
PRENATAL DIAGNOSIS OF CONGENITAL ANOMALIES
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Roberto Romero, MD, Head, Unit on Maternal Fetal Medicine, Pathology Unit, Parturition Unit Tinnakorn Chaiworapongsa, MD, Postdoctoral Fellow |
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| Premature birth is the leading cause of perinatal mortality and morbidity worldwide. The Perinatology Research Branch has defined preterm labor as a syndrome and determined that at least 25 percent of all preterm births are born to women with subclinical intrauterine infection. Moreover, we have provided evidence that many premature neonates are critically ill before birth and proposed that the onset of premature labor has survival value in the context of intrauterine infection. We aim to understand the pathophysiology of premature labor and delivery, particularly in the context of intrauterine infection and inflammation. This year, we conducted several studies to explore the role of antibiotic administration in the treatment of intrauterine infection and the value of assessing the concentration of antimicrobial proteins in the detection of intrauterine infection and inflammation. After premature birth, congenital anomalies are the second leading cause of perinatal mortality in the United States. This year, we used four-dimensional ultrasonography for the evaluation of the fetal heart with spatio-temporal image correlation and 3-D ultrasound to quantitate fetal lung volume measurements. Antimicrobial factors in the amniotic fluid of normal women and those with preterm labor and premature rupture of membranes Espinoza, Chaiworapongsa, Romero, Edwin The amniotic cavity is considered a sterile compartment, presumably owing to the innate immune system, and includes the cervical epithelium, cervical mucus plug, chorioamniotic membranes, and cellular components of the decidua, amnion, and chorion, including neutrophils, macrophages, NK cells, and trophoblast. Although intact chorioamniotic membranes are thought to protect against microbial invasion of the cavity (MIAC), this physical barrier alone cannot be responsible for the sterile nature of amniotic fluid in normal pregnancy because bacteria can cross the intact membranes. Indeed, patients with intact membranes can have MIAC, as has been demonstrated in patients in the midtrimester of pregnancy with preterm labor and intact membranes, or even spontaneous labor at term. This suggests that, in addition to the physical barrier, other mechanisms must operate to prevent bacterial proliferation within the amniotic cavity. Antimicrobial peptides, part of the innate limb of the immune response, have been identified in plants, insects, and all vertebrates examined thus far. Neutrophils contain several antimicrobial peptides, including neutrophil defensins (human neutrophil peptides [HNP] 1, 2, and 3), bactericidal/ permeability-increasing protein (BPI), and calprotectin (MRP8/14). The purpose of this study was to determine if amniotic fluid contains immunoreactive antimicrobial peptides (HNP 1-3, BPI, and MRP8/14) and whether their concentration changes with MIAC, parturition, and premature rupture of membranes (PROM). We conducted a series of studies that yielded the following: (1) intraamniotic infection is associated with a significant increase in amniotic fluid concentrations of HNP1-3, BPI, and calprotectin in both women with preterm labor and intact membranes and women with preterm PROM; (2) preterm PROM is associated with a significant increase in amniotic fluid concentrations of HNP 1-3, BPI, and calprotectin; (3) preterm parturition is associated with a significant increase in amniotic fluid concentrations of HNP 1-3, BPI, and calprotectin while term parturition is associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3; and (4) among patients with preterm labor and intact membranes, elevation of amniotic fluid HNP 1-3, BPI, and calprotectin concentrations was associated with intraamniotic inflammation, histologic chorioamnionitis, and short interval to delivery. Espinoza J, Chaiworapongsa T, Romero R, Edwin S, Rathnasabapathy C, Gomez R, Bujold E, Camacho N, Kim YM, Hassan S, Blackwell S, Whitty J, Berman S, Redman M, Yoon BH, Sorokin Y. Antimicrobial peptides in amniotic fluid defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. J Matern Fetal Neonatal Med 2003;13:2-21. The effect of antibiotic therapy on intrauterine infection-induced preterm parturition in rabbits Romero, Chaiworapongsa, Espinoza Microbial invasion of the amniotic fluid cavity and subclinical intrauterine infection have been implicated as mechanisms responsible for preterm labor and delivery. Consequently, investigators have examined whether the administration of antibiotics to women in preterm labor with intact membranes and preterm premature rupture of membranes can prolong pregnancy and improve neonatal outcome. The results from randomized clinical trials and meta-analysis are conflicting. The Cochrane Review concluded that routine use of antibiotics is not effective in preventing preterm parturition with intact membranes. In contrast, animal experiments suggest that, in some instances, antibiotic administration can reduce intra-amniotic bacterial load and preterm delivery as well as improve neonatal survival. One possible explanation for antibiotics' ineffectiveness in humans is that medication must be administered early to be effective and that, when patients present with clinical preterm labor and intraamniotic infection, it is too late to down-regulate the inflammatory response and thus antimicrobial therapy cannot prevent preterm parturition and/or fetal damage. We used a rabbit model of ascending uterine infection to assess whether there is a time-dependent relationship between antibiotic administration and the prevention of preterm parturition. We tested whether rabbits inoculated with E. coli without antibiotic treatment would deliver prematurely. The median inoculation-to-delivery interval was significantly shorter in the infected group than in the control group (36.3 hours [15 to 76.5] versus 219 hours [173 to 240]). Antibiotic administration within 12 hours, but not after 18 hours, of inoculation increased the duration of pregnancy (by reducing the rate of preterm delivery) and neonatal survival (0 versus 71 percent). We found that antibiotic administration can prolong pregnancy and reduce perinatal mortality after an ascending intrauterine infection only if administered early (less than 12 hours) after microbial inoculation. Whether this approach could also reduce neonatal morbidity remains to be determined. The importance of this observation is that it points to the need for the rapid and early identification of intraamniotic infection in humans. Maternal serum of women with preeclampsia reduces trophoblast cell viability: evidence for an increased sensitivity to Fas-mediated apoptosis Chaiworapongsa, Romero; in collaboration with Mor Preeclampsia, or toxemia of pregnancy, has been attributed to the presence of a circulating "toxin" that disappears from peripheral blood after delivery of the placenta. However, the presence, nature, and effects of this toxin have eluded characterization. Increased trophoblast apoptosis has been observed in the placenta of women with preeclampsia, and it is possible that this biological phenomenon is important for the genesis of the disease and is mediated through a soluble factor(s) present in maternal blood. We conducted a study to determine whether serum from women with preeclampsia changes trophoblast viability. We cultured H8 trophoblast cells with serum obtained from normal pregnant women and patients with preeclampsia. We determined cell viability by Cell Titer 96 Assay and Fas sensitivity by treating the cells with an anti-Fas antibody or a blocking anti-Fas Ligand antibody. Serum from normal pregnant women did not affect trophoblast cell viability. In contrast, serum from preeclamptic women reduced trophoblast viability, an effect that was enhanced by treatment with an anti-Fas antibody and reversed by the treatment with a blocking anti-Fas Ligand antibody. We conclude that serum from women with preeclampsia induces cytotoxicity of the first-trimester trophoblast cell line (H8), an effect that appears to be related to changes in trophoblast sensitivity to Fas-mediated apoptosis. The findings suggest that a factor present in maternal blood of patients with preeclampsia may have a role in the genesis of the syndrome. Future studies will aim at determining whether this factor is present before the development of the disease. Neale D, Demasio K, Illuzi J, Chaiworapongsa T, Romero R, Mor G. Maternal serum of women with pre-eclampsia reduces trophoblast cell viability evidence for an increased sensitivity to Fas-mediated apoptosis. J Matern Fetal Neonatal Med 2003;13:39-44. Four-dimensional ultrasonography of the fetal heart with spatio-temporal image correlation Chaiworapongsa, Espinoza, Romero Congenital heart disease is the leading cause of birth defect-related infant mortality, with a prevalence ranging from four to 11 per 1,000 births. Prenatal diagnosis remains a major challenge. Four-dimensional (4-D) ultrasonography is a technology that couples motion with three-dimensional (3-D) imaging. Spatio-temporal image correlation (STIC) is a recent advance that allows dynamic multiplanar slicing and surface rendering of heart anatomy. Fetal heart volumes are acquired with a single automated sweep of the transducer. Spatial and temporal information is combined to display dynamic images that can be extracted from volume data sets. Standardized viewing planes, such as the one recommended by the American Institute of Ultrasound in Medicine, can be analyzed. In addition, planes not routinely feasible with two-dimensional (2-D) ultrasonography can be generated. This year, we reported using STIC to examine the fetal heart and for the diagnosis of congenital anomalies. We obtained volume data sets that allowed us to demonstrate the cardiac chambers, moderator band, interatrial and interventricular septae, atrioventricular valves, pulmonary veins, and outflow tracts. With the use of a reference dot to navigate the four-chamber view, we were able to study intracardiac structures simultaneously in three orthogonal planes. We used the same volume data set for surface rendering of the atrioventricular valves. The aortic and ductal arches were best visualized when the original plane of acquisition was sagittal. Volumes could be interactively manipulated to visualize both outflow tracts simultaneously as well as the aortic and ductal arches. We generated novel views of specific structures. Dynamic multiplanar slicing and surface rendering of the fetal heart are feasible with STIC technology. One good-quality volume data set, obtained from a transverse sweep, can be used to examine the four-chamber view and the outflow tracts. This novel method may assist in the evaluation of fetal cardiac anatomy. M, Romero R. Four-dimensional ultrasonography of the fetal heart using spatio temporal image correlation. Am J Obstet Gynecol 2003;189:1792-1802. Three-dimensional color power imaging of fetal hepatic circulation Kalache, Romero, Chaiworapongsa, Espinoza; in collaboration with Lee The anatomy and physiology of the fetal hepatic system are complex. Yet their evaluation is of considerable importance in assessing the hemodynamic status of a critically ill fetus. Furthermore, congenital anomalies of this circulatory system are relatively common and difficult to identify with conventional 2-D imaging techniques. We set out to determine how automated 3-D power Doppler ultrasonography defines the normal anatomy of the fetal portosystemic and umbilical venous systems and identifies fetal hepatic vascular anomalies. In a prospective study, we imaged the hepatic and umbilical venous systems in 390 fetuses with 2-D ultrasonography and color and spectral Doppler imaging and observed vascular abnormalities in eight of the fetuses. The anomalies were absent ductus venosus (n=4); direct connection between the umbilical vein and the right atrium (n=2); and direct connection between the umbilical vein and the inferior vena cava (n=2). The study demonstrated that 3-D color power Doppler ultrasonography can be used to image normal fetal hepatic and portal circulation and to identify anomalies of the fetal portosystemic and umbilical venous systems. Kalache K, Romero R, Goncalves LF, Chaiworapongsa T, Espinoza J, Schoen ML, Treadwell MC, Lee W. Three-dimensional color power imaging of the fetal hepatic circulation. Am J Obstet Gynecol 2003;189:1401-1406. Lee W, Kalache KD, Chaiworapongsa T, Londono J, Treadwell MC, Johnson A, Romero R. Three- dimensional power Doppler ultrasonography during pregnancy. J Ultrasound Med 2003; 22:91-97. Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique Kalache, Espinoza, Chaiworapongsa, Romero; in collaboration with Lee Prenatal diagnosis of pulmonary hypoplasia is a major clinical challenge. The diagnosis is made at autopsy by demonstrating low lung weight and a low lung-to-body ratio. Several fetal biometric parameters have been used to predict the likelihood of lethal pulmonary hypoplasia of the newborn; however, nearly all parameters developed thus far are less than optimal. 3D ultrasound may improve the estimation of fetal organ size. In addition, rotational measurement of volume has now become possible through the recent introduction of a software tool named VOCAL (Virtual Organ Computer-Aided AnaLysis, 3D View). The software allows volume calculation by rotating the organ of interest around a fixed axis through a number of sequential steps. We studied 32 fetuses with a variety of conditions at risk for pulmonary hypoplasia. We acquired 3-D volume data sets of the fetal lungs by using a commercially available ultrasound system and separately calculated the right and left lung volumes by using VOCAL and the multiplanar technique. We determined the level of agreement between two independent observers in categorizing the 3-D volume data set as measurable or nonmeasurable and evaluated the interobserver and intermethod variabilities for both methods. The intermethod variability was excellent, demonstrating substantial agreement between the results of both approaches. Fetal lung estimation with VOCAL had a significantly higher interobserver variability than the multiplanar technique. Interobserver agreement in categorizing lung volume data sets as measurable or nonmeasurable was lower when VOCAL was used. Fetal lung volume measurements can be undertaken interchangeably by using the multiplanar technique or the rotational method with VOCAL. However, the latter was less reproducible (lower degree of agreement and significantly higher interobserver variability) than the former. Kalache KD, Espinoza J, Chaiworapongsa T, Londono J, Schoen ML, Treadwell MC, Lee W, Romero R. Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique. Ultrasound Obstet Gynecol 2003;21:111-118. Genetic sonography: an option for women of advanced maternal age who are screen-negative following triple-marker maternal serum screening Romero; in collaboration with DeVore The prenatal detection of trisomy 21 is a major goal in prenatal care for families seeking antenatal diagnosis. Several approaches are available, including (1) routine offering of amniocentesis to women age 35 and over; (2) maternal serum screening and identification of patients at risk; and (3) a combination of the previous two with a sonographic examination of the fetus. Trisomy 21 is often associated with phenotypic abnormalities detectable with ultrasound. We conducted a study to determine whether conducting genetic ultrasound to patients 35 years and older who are screen-negative following maternal serum triple-marker screening is cost-effective and results in an increase in the detection rate of trisomy 21. We determined the detection rate and cost of detecting trisomy 21 in women 35 years and older, who were managed as follows: universal genetic amniocentesis; maternal-serum triple-marker screening followed by amniocentesis only in high-risk women (risk greater than 1:90); genetic ultrasound in women who were screen-negative; and genetic amniocentesis in patients with an abnormal genetic ultrasound. We concluded that offering genetic ultrasound followed by amniocentesis to patients 35 years and older who were originally screen-negative following triple-marker maternal serum screening for the diagnosis of trisomy 21 is cost-effective and results in a higher overall detection rate for trisomy 21. DeVore GR, Romero R. Genetic sonography: an option for women of advanced maternal age who are screen-negative following triple-marker maternal serum screening. J Ultrasound Med, 2003; 22:1191-1199. GENERAL REFERENCES Bytautiene E, Vedernikov YP, Saade GR, Romero R, Garfield RE. Effect of histamine on phasic and tonic contractions of isolated uterine tissue from pregnant women. Am J Obstet Gynecol 2003;188:774-778. Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch S, Thaler HT, Romero R. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol 2002;187:1137-1142. Romero R, Chaiworapongsa T, Espinoza J, Gomez R, Yoon BH, Edwin S, Mazor M, Maymon E, Berry S. Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes. Am J Obstet Gynecol 2002;187:1125-1130. COLLABORATORS Greggory DeVore, MD, ALFIGEN-The Genetics Institute, Pasadena CA Robert Garfield, MD, University of Texas Medical Branch at Galveston, Galveston TX Wesley Lee, MD, William Beaumont Hospital, Royal Oak MI Gil Mor, MD, Yale University School of Medicine, New Haven CT For further information, contact romeror@mail.nih.gov |
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