PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1113-1121 (doi:10.1542/peds.2005-1528)
Prevalence of Spontaneous Closure of the Ductus Arteriosus in Neonates at a Birth Weight of 1000 Grams or Less
a Department of Pediatrics, Divisions of Neonatal-Perinatal Medicine
c Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas
b Department of Biostatistics, Children's Medical Center, Dallas, Texas
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. Ductus arteriosus (DA) closure occurs within 96 hours in >95% of neonates >1500 g in birth weight (BW). The prevalence and postnatal age of spontaneous ductal closure in neonates
1000 g in BW (extremely low birth weight [ELBW] neonates) remain unclear, as does the incidence of failure to close with indomethacin. Therefore, we prospectively examined the prevalence, postnatal age, and clinical variables associated with spontaneous DA closure, occurrence of persistent patent DA, and indomethacin failure in ELBW neonates. METHODS. Neonates delivered at Parkland Memorial Hospital from February 2001 through December 2003 were studied. Those with congenital heart defects or death <10 days postnatally were excluded. Echocardiograms were performed 48 to 72 hours postnatal and every 48 hours until 10 days postnatally.
RESULTS. We studied 122 neonates with BW of 794 ± 118 (SD) g and estimated gestational age (EGA) of 26 ± 2 weeks. Spontaneous permanent DA closure occurred in 42 (34%) neonates at 4.3 ± 2 days postnatally, with 100% closure by 8 days. These neonates were more mature, less likely to have received antenatal steroids or have hyaline membrane disease (HMD; 52% vs 79%), and more likely to be growth restricted (31% vs 5%) and delivered of hypertensive women. Using regression analysis, EGA and absence of antenatal steroids and HMD predicted ductal closure. Ten (8%) neonates with early DA closure reopened and required medical/surgical closure. Eighty neonates had persistent patent DA; 7 were surgically ligated, and 5 remained asymptomatic, with 4 of 5 closing after 10 days postnatally. Sixty-eight (85%) received indomethacin at 6.2 ± 4 days postnatally; 41% failed therapy and had no distinguishing characteristics.
CONCLUSIONS. Spontaneous permanent DA closure occurs in >34% of ELBW neonates and is predicted by variables related to maturation, for example, EGA and an absence of HMD, whereas indomethacin failure could not be predicated.
Key Words: gestational age • extremely low birth weight • indomethacin therapy • chronic lung disease • fluid therapy
Abbreviations: DA—ductus arteriosus • BW—birth weight • pPDA—persistent patent ductus arteriosus • EGA—estimated gestational age • HMD—hyaline membrane disease • ELBW—extremely low birth weight • PDA—patent ductus arteriosus • ECHO—echocardiogram • CLD—chronic lung disease • OR—odds ratio • CI—confidence interval • SGA—small for gestational age • AGA—appropriate for gestational age
Before birth the ductus arteriosus (DA) is responsible for shunting blood away from the high-resistance pulmonary vascular bed into the systemic circulation. At the time of birth the placental circulation is removed, pulmonary vascular resistance falls, and the pulmonary circulation becomes the sole source of oxygenated blood. Shunting through the DA is no longer necessary and may become detrimental. Closure of the DA occurs in 3 steps: constriction of ductal smooth muscle, hypoxia/ischemia of medial smooth muscle, and, finally, remodeling that results in permanent closure.1 In >95% of neonates exceeding 1500 g in birth weight (BW), the initial phase of DA closure generally occurs within 96 hours and is permanent soon thereafter.2 In contrast, preterm neonates <1500 g in BW are at increased risk of having a persistent patent DA (pPDA) beyond 96 hours postnatally and the absence of remodeling.2–4 This may result in a left-to-right shunt and hyperperfusion of the pulmonary vascular bed, often resulting in decreased lung compliance,5,6 increased need for mechanical ventilation,7 and altered postnatal nutrition and growth.8 Thus, a pPDA may adversely affect morbidity and mortality in an already high-risk population.1
The incidence and pathogenesis of pPDA has been studied in neonates <1500 g in BW.3,4,7,9 In these studies, pPDA varied from 18% to 77% and decreased with increasing BW and estimated gestational age (EGA), the greatest changes occurring after 30 weeks of gestation and 1000-g BW.3,4,7,9 Although several variables have been associated with the occurrence of a pPDA (eg, initial fluid management and volume expansion,3,10 hyaline membrane disease (HMD; ref 11), and infection4,12), most occur by association, and few have been proven to be directly causative.3,10 Survival of neonates 1000 g in BW (extremely low birth weight [ELBW]) and at 30 weeks in EGA has increased in the last 2 decades13; however, the causative factors associated with pPDA and the natural history of DA closure in this very high-risk population are poorly understood.
Indomethacin is widely used as the medical treatment for closure of a pPDA. It mediates its effects, at least in part, by inhibiting local prostaglandin synthesis.14,15 This allows constriction of DA smooth muscle that is necessary for the initiation of DA closure and subsequent permanent closure.16,17 Because indomethacin may have significant adverse effects, for example, renal failure and alterations in organ perfusion, including the brain,18,19 it would be helpful to predict those neonates who might benefit most from its selective use, rather than exposing all neonates to prophylaxis and the associated risks. Furthermore, it is unclear which ELBW neonates are at risk of indomethacin failure. For example, some studies suggest that there are no differences between responders and nonresponders,4 whereas others report that failure is related to EGA and BW.20
Although survival of ELBW neonates has increased significantly,13 there has not been, to the best of our knowledge, a prospective study conducted in ELBW neonates designed to determine the prevalence and age at which a clinically significant patent ductus arteriosus (PDA) occurs after birth, and of those neonates without a clinically significant PDA, the prevalence and age at which spontaneous DA closure occurs and how often this closure is permanent. Furthermore, this population has not been prospectively characterized recently to identify those neonates at risk for pPDA and whether there are factors predictive for the success or failure of indomethacin therapy. Therefore, we designed a prospective study of ELBW neonates within a large in-born delivery population at a single hospital to examine these questions.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
All ELBW neonates delivered between February 2001 and December 2003 (34 months) at Parkland Memorial Hospital in Dallas, Texas, a large community-based hospital with >15500 births annually, were eligible for inclusion in this prospective study. Because the DA closes in >95% of neonates >1500 g in BW within 96 hours postnatally,2 we assumed closure would occur within the first 10 days postnatally and chose that time period to study DA closure. Exclusions included neonates receiving comfort care for extreme prematurity as determined by the clinical team in the NICU (
24 weeks' EGA), those dying in the first 48 hours postnatally, neonates with congenital anomalies, and those with congenital heart disease on the first ECHO. Patients were enrolled after parental consent was obtained. The study was approved by the University of Texas Southwestern Medical Center Institutional Review Board for Human Research.
Protocol
Neonates enrolled into the study received a complete ECHO within 72 hours of birth to determine cardiac anatomy and patency of the DA. Focused ECHO examinations were subsequently performed every other day until 10 days postnatally to evaluate DA patency. When a neonate had documented closure of the DA before 10 days, serial examinations were stopped, and a final ECHO was performed at 10 days to confirm persistent ductal closure. Clinicians caring for the neonates did not have access to study ECHO results. However, in the presence of clinical indications, the clinicians could request the results of studies performed within the previous 24 hours. Clinical care, including the need for treatment of a clinically significant PDA, was determined by the patient care team. Prophylactic ductal closure with indomethacin is not used in our institution, and the need for closure is determined by radiographic (enlarged heart with increased pulmonary vascular markings with or without pulmonary edema), clinical (bounding pulses, increased heart rate, increasing pulse pressure, worsening pulmonary status, and inability to wean mechanical ventilation), and ECHO evidence of a significant ductal left-to-right shunt. If a neonate with previously documented DA closure subsequently developed clinical evidence of reopening of the DA, performance of an ECHO and medical or surgical treatment were decided by the clinical care team. Indomethacin was administered by the clinical care team. Contraindications to medical closure of the DA in our institution include serum creatinine >1.2 mg/dL, oliguria defined as a urine output <1.0 mL/kg per hour in the preceding 8 hours, a platelet count <60000/mm3, evidence of active bleeding diathesis (eg, intracranial hemorrhage), and necrotizing enterocolitis. In the presence of a clinically significant PDA, neonates with contraindications to indomethacin underwent surgical ligation. Indomethacin was administered at a dose of 0.2 mg/kg every 12 hours for 3 doses, as long as the clinical course supported continued doses. Neonates considered indomethacin failures included those that never demonstrated ductal closure during and/or after treatment and those that initially had clinical evidence of closure but subsequently had clinical and ECHO evidence of a recurrent PDA.
Measurements
Data collected prospectively from the maternal and neonatal records included general demographics, the presence of maternal hypertension, use of antenatal steroids, complications of pregnancy, route of delivery, fluid administration in the first week, use of mechanical ventilation or positive airway pressure, presence of HMD, blood pressure regulation and need for treatment with volume expansion and/or pressors, pattern of fetal growth, and the occurrence of chronic lung disease (CLD), which was defined as oxygen requirement at 36 weeks' postconception. The EGA was determined from the obstetric estimate in weeks. The pediatric estimate by modified Ballard examination was used when it differed from the obstetric estimate by >2 weeks.21,22 ECHOs were recorded and the results interpreted and reported by 1 of the authors (CR) without knowledge of other clinical variables.
Data Analysis
Descriptive analyses of the continuous and categorical data were performed using proportions and frequency distributions. Data are presented as means and SDs. Statistical testing of dichotomous variables was performed with Pearson 
2 exact tests. T tests were used for group comparisons of continuous level data. Multivariate forward stepwise logistic regression was used to determine the odds ratio (OR) and confidence intervals (CIs) for predicting the probability of spontaneous closure from a set of hypothesized predictor variables that included EGA, antenatal steroids, HMD, BW, and initial volume expansion as independent predictors. Multivariate forward stepwise logistic regression was also used to predict indomethacin failure.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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During the 34-month study period there were
45000 deliveries at Parkland Memorial Hospital. There were 197 ELBW neonates admitted to the Intensive Care Nursery (Fig 1). Of these, 43 were not approached for enrollment; 33 had extreme prematurity (<500 g BW and EGA 24 weeks) and were admitted for comfort care, 2 had multiple congenital anomalies, and 8 died within 36 hours of birth. Eight neonates were missed during the enrollment period, and consent was refused in 6 cases and refused by an attending physician in 1 case because of instability. Thus, 139 neonates were consented for inclusion in the study. Of these, 17 were subsequently excluded; 10 died <10 days after birth, and 7 had congenital heart disease diagnosed on the initial ECHO (6 with ventricular septal defects and 1 with atrial septal defect). The demographics and characteristics of the 122 neonates in the study population are presented in Table 1. The ethnic distribution mirrors the general delivery population at Parkland Memorial Hospital, which is 75% to 80% Hispanic. Less than half (48%) were exposed to antenatal steroids; of the 64 who did not receive steroids, 21 mothers had hypertensive disease, a contraindication to antenatal steroids in our institution. Eighty-six percent of the neonates were appropriately grown. Only 23% received volume expansion for treatment of hypotension after birth, and 12 of these also required inotropic support in the initial 48 hours, resembling our recent observations in a population of neonates <1500 g in BW.23 Fluid therapy in the initial 48 hours averaged 100 mL/kg per day. HMD was diagnosed in 70% of neonates, 92% of whom received surfactant therapy within 2 hours of birth. Mechanical ventilation or continuous positive pressure was applied to 95% of the total population. By discharge, 53% of neonates were diagnosed with CLD.
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There were 52 neonates who demonstrated spontaneous DA closure by serial ECHO during the first 10 days postnatally. Permanent DA closure was documented in 42 of these neonates, 34% of the total neonates studied, at a mean age of 4.3 ± 2 days. When the cumulative closure rate of this group was examined over time, 50% had closed by
3 days and 100% by 8 days postnatally (Fig 2). Although early DA closure was documented by ECHO in 10 (8.2% of the total) additional neonates, the DA subsequently reopened and required indomethacin therapy (n = 7) and/or surgical ligation (n = 3). The 42 neonates with permanent DA closure within 10 days of life had a greater EGA (27.0 ± 2 vs 25.6 ± 2 weeks; P = .001) but similar BW when compared with the neonates without closure (Table 2). To determine the effect of maturation and development on DA closure, we used EGA as a proxy and divided the neonates into 4 groups. There was a nearly threefold increase in the spontaneous closure rate between <25 and 25 to 26 weeks of EGA and an additional twofold increase after 29 weeks of EGA (Fig 3; P = .002, 2). Although spontaneous DA closure increased from 24% in neonates 501 to 700 g in BW to 43% at 
901 g, BW was not a significant predictive factor for spontaneous DA closure in this population (Fig 4; P = .3), consistent with the univariant analysis noted in Table 2.
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Neonates with spontaneous permanent DA closure tended to have an increased antenatal history of maternal hypertension (Table 2) and, as noted earlier, were less likely to be exposed to antenatal steroids than those with pPDA (P = .02). As a group, they also were more likely to be classified as small for gestational age (SGA; P = .001). Although fewer received antenatal steroids, neonates with DA closure were also less likely to have HMD (P = .004) and to require either surfactant or respiratory support after admission to the intensive care nursery (P
.008). Notably, the EGA of the neonates classified as SGA was 29.2 ± 1.5 compared with 25.6 ± 1.3 weeks (P < .001) for the appropriately grown neonates. Although prior studies suggest that volume expansion and high fluid volume in the first day of life are associated with an increased occurrence of pPDA,3,10 the 2 groups did not differ. Of interest, the prevalence of CLD in neonates with spontaneous DA closure was nearly half of that observed in neonates with pPDA (44% vs 71%; P = .006), and the OR for the developing CLD in the pPDA group was increased 3.4-fold. Using a stepwise regression analysis for prediction of CLD, EGA was the only significant variable (P = .001), whereas HMD and DA closure were borderline (P .079).
To determine whether neonates with spontaneous permanent DA closure could be predicted from our data set, we performed a stepwise logistic regression analysis. The variables tested included obstetric EGA, absence of antenatal steroids and HMD, appropriate-for-gestational-age (AGA) neonates, BW, and the use of volume expansion. EGA (P = .009), the absence of antenatal steroids (P = .034), and HMD (P = .011) were significant predictors, yielding a model 2 of 24.9 (P < .001) and Hosmer and Lemeshow test statistic of P = .402, indicating that these variables improve the prediction of the log odds. Thus, for each week increase in EGA, the odds of having spontaneous permanent DA closure increases 1.5-fold (OR: 1.4; 95% CI: 1.08-1.76), whereas not receiving antenatal steroids (OR: 2.6; 95% CI: 1.08-6.3) or not having HMD (OR: 3.4; 95% CI: 1.3-8.6) had even greater odds for spontaneous DA closure.
We next examined the treatment and outcome of those neonates who had a clinically evident PDA (n = 80) and those that subsequently received indomethacin therapy (n = 68) to determine the efficacy of indomethacin therapy. Seven neonates underwent primary surgical closure because of contraindications for the use of indomethacin (see "Methods" section). Of the 68 that received indomethacin, treatment was provided at a mean age of 6.2 ± 4 days (range: 2–20 days) postnatally. Twenty-eight (41%) did not demonstrate acute or permanent DA closure and subsequently underwent surgical ligation (Table 3). There were no significant differences in the characteristics of the responders and those whose therapy failed, including EGA at delivery, BW, antenatal steroids, fluid therapy, volume expansion, or age at indomethacin therapy (Table 3). Although 100% of neonates 29 weeks in EGA responded to indomethacin, the relationship between EGA and the efficacy of indomethacin was of borderline significance (Fig 5; P = .08). There also was a tendency for decreased surfactant treatment for HMD in the failure group (P = .06). There was no difference in the risk of developing CLD in the 2 groups. As with the univariant analysis, a stepwise logistic regression analysis also failed to identify any predictors for failure of indomethacin therapy.
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It is of interest that 5 neonates not included in the cumulative closure rate or the treatment groups were noted by serial ECHO to have never closed their DA by 10 days postnatally. Moreover, they were not diagnosed by their clinical care team on the basis of clinical signs or chest radiograph. These neonates remained asymptomatic and, therefore, remained clinically undetected. Only 2 were observed to subsequently close their DA, whereas 2 were discharged, having never been detected as having a pPDA; the fifth died unrelated to the absence of documented DA closure.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Survival of the ELBW neonate has increased significantly in the past 2 decades.13 This has resulted in the recognition of medical problems specific to these neonates that might contribute to increases in morbidity and mortality. One of these entities has been the occurrence of pPDA.2,11,24 However, it remains unclear to what extent these complications occur by association, for example, because of prematurity, rather than the result of having a pPDA. Nonetheless, some have recommended the aggressive closure of the DA in ELBW neonates in the hope of preventing the associated morbidities, in particular CLD and poor growth.25 It is unclear, however, what proportion of ELBW neonates have the potential to undergo spontaneous DA closure and when after birth this occurs or what number remain asymptomatic. Knowledge of this and the variables that place these neonates at risk for pPDA may provide important insights into these issues and, importantly, permit a more selective approach to the treatment and study of pPDA. In the present study, we have shown for the first time that in a predominantly Hispanic population at least a third of ELBW neonates undergo spontaneous and permanent DA closure, this occurs later than reported in older and larger neonates, 8% may reopen their DA after ECHO evidence of initial closure, and the predictors of permanent DA closure relate primarily to the stage of fetal development and maturation. However, we were unable to detect what factors, if any, relate to the failure of medical therapy with indomethacin.
In our study, 34% of ELBW neonates were observed by serial ECHO to have spontaneous permanent DA closure after birth. Unlike larger, older neonates,2 this was more likely to occur after 96 hours, at which time 40% remained patent but were neither clinically nor radiographically evident. In fact, 100% closure did not occur in these asymptomatic neonates until 8 days postnatally. This number increases to 39% if we include the 5 neonates who had a pPDA beyond 10 days postnatally but remained asymptomatic and either closed later or were never clinically detected. One might argue, therefore, that early prophylaxis with indomethacin, that is, in the first 1 to 3 days after birth, involves the unnecessary treatment of a relatively large group of asymptomatic ELBW neonates with a drug known to have short-term adverse effects on blood flow to tissues remote from the DA, including the brain.18,19,26 In view of these observations, there may be benefit in using scheduled ECHO examinations at 7 to 8 days, much like serial head ultrasounds, to determine those that should be considered for medical therapy. However, even this should be approached cautiously, because2% had a prolonged pPDA but remained asymptomatic, similar to the term neonate. Finally, 10 neonates with ECHO evidence of early closure reopened their DA, and based on clinical signs, all subsequently required treatment. In contrast to the findings of Keller et al,27 there were no signs of residual shunting by color flow mapping in these neonates.
It may be beneficial to predict which ELBW neonates are likely to spontaneously close their DA permanently and those at risk for pPDA. This would permit the design of studies to determine the actual impact of pPDA with a significant left-to-right shunt on morbidity, for example, CLD, and mortality and to establish appropriate treatment regimens to close the DA in neonates at risk for complications of extreme prematurity. In prior studies of neonates 1500 g in BW, there was an inverse relationship between BW and EGA and the occurrence of pPDA.3,4 A 5-year analysis of data in our neonatal intensive care database also demonstrated this; however, the greatest impact was observed after 1000 g. When neonates >1000 g BW were excluded in the present study, there was no relationship between BW and pPDA. In contrast, there was a very significant increase in permanent DA closure as EGA advanced and a more than threefold increase in the rate of pPDA as EGA decreased. In addition, the likelihood of DA closure increased in the absence of HMD. These observations strongly imply that DA closure and pPDA are primarily a maturational phenomenon occurring in parallel with other developmentally regulated processes, for example, lung maturation. In recent studies of DA smooth muscle, changes in contractile protein expression were developmentally regulated and consistent with this thesis.28 Interestingly, neonates with permanent DA closure were more likely to be SGA and delivered of women with hypertensive disease of pregnancy, raising a question of the effects of intrauterine stress on ductal closure. Although SGA had been suggested as a marker for advances in lung development, Tyson et al29 disproved this thesis when they examined HMD. When we examined the SGA neonates with DA closure, they had a greater EGA, indicating that they were older and more mature, providing additional support for a developmental cause of pPDA, as well as spontaneous closure. Interestingly, BW was a poor surrogate for the prediction of pPDA or closure. This difference from earlier studies, which included neonates >1000 g in BW, could reflect the dramatic fall in prevalence of pPDA in this BW group, ie, <5% to 10%.3,4 Thus, BW should be cautiously used as a means of categorizing ELBW neonates for studies related to developmental or maturational changes.
Previously, we3 and others10 reported that initial fluid management and early volume expansion directly impacted the subsequent occurrence of pPDA and the need for treatment. This was not observed in the present study, reflecting our clinical practice of using low fluid volumes and selected volume expansion.3,23 We continue to restrict fluids to low-BW neonates, using urine output, electrolyte balance, and weight loss to determine the need for increases in fluid delivery. This allows for a 12% to 14% weight loss in the first week without detrimental aspects as noted by Lorenz et al30 some years ago. We also use established ranges in blood pressure based on EGA rather than BW, as discussed above, to determine the need for volume expansion or pressor agents, resulting in a lower use than reported by others.23,31
Antenatal steroids are reported to decrease the sensitivity of the DA to prostaglandin E2 and to reduce the occurrence of pPDA.32–35 In our study, neonates undergoing spontaneous permanent closure were less likely to have received antenatal steroids. We hypothesized that this was related to our practice of deferring antenatal steroid administration to women with hypertensive disorders, which may have modified the likelihood of spontaneous DA closure. There was a trend toward an association between maternal hypertension and the spontaneous closure group (26% vs 13%), but this was not significant. However, there was a fivefold to sixfold higher incidence of SGA neonates delivered by these women. As noted earlier, SGA neonates as a group were delivered later in pregnancy and, thus, were developmentally more mature and more likely to undergo spontaneous permanent closure. Nonetheless, being SGA did not contribute to the regression analysis for predicting DA closure, possibly reflecting that the study was not powered to address this question. On the other hand, the absence of antenatal steroid exposure in the SGA group was predictive and might be considered a proxy for EGA.
Our failure rate of indomethacin therapy, 41%, was similar to prior reports.36–39 In these studies, predictive factors for indomethacin success included BW and postnatal age at the time of treatment.20 In the present study, EGA, BW, and age at treatment did not influence the response to indomethacin. In fact, there were no predictive variables other than surfactant therapy that distinguished the 2 groups by univariant or logistic regression analyses. This may reflect our practice to move directly to ductal ligation in neonates with renal dysfunction, intracranial hemorrhage, or considered to be beyond the age of efficacy, that is, >12 to14 days postnatally. Although our results suggest that predictive variables were not present to separate these 2 groups, this may reflect insufficient numbers in the 2 groups.
In the present study, we have characterized for the first time the prevalence and age at which DA closure occurs spontaneously and permanently in a large cohort of inborn predominantly Hispanic ELBW neonates, as well as the prevalence of a clinically significant PDA in need of closure. We have shown that the likelihood of DA closure is developmentally regulated, increasing with advanced EGA. We also have provided an age at which Doppler flow ECHO can be used to determine whether spontaneous closure has occurred and in whom medical and/or surgical closure should be considered in the absence of clinical signs. Notably, our data suggest that in asymptomatic neonates, the clinical and radiographic signs of pPDA may not identify all neonates with a pPDA and should be used in conjunction with planned Doppler flow ECHO similar to the use of cranial ultrasound for the diagnosis of intracranial hemorrhage.40,41 This will permit the clinician to more accurately identify all neonates with pPDA and may help determine who should be considered for DA closure. Finally, it is now possible to design studies to reexamine the use of prophylactic indomethacin and the actual effects of pPDA on morbidities previously related by association, for example, CLD, necrotizing enterocolitis, and abnormalities of neurodevelopmental outcome.
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ACKNOWLEDGMENTS |
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This study was funded in part by a training grant from Forest Pharmaceuticals (to Dr Brown) and the George L. MacGregor Professorship in Pediatrics.
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FOOTNOTES |
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Accepted Sep 28, 2005.
Address correspondence to Charles R. Rosenfeld, MD, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail: charles.rosenfeld{at}utsouthwestern.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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