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Microcystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs open fetal resection
Journal of Pediatric Surgery (2012) 47, 36–39
www.elsevier.com/locate/jpedsurg
APSA Papers
Microcystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs open fetal resection Kenneth C. Loh, Eric Jelin, Shinjiro Hirose, Vickie Feldstein, Ruth Goldstein, Hanmin Lee ⁎ Department of Surgery, University of California at San Francisco, San Francisco, CA 94143-0570 Received 24 September 2011; accepted 6 October 2011
Key words: CPAM; CCAM; Fetal surgery; Steroids; CVR; Microcystic
Abstract Background/Purpose: Congenital pulmonary airway malformations (CPAM) are rare lesions often diagnosed during routine prenatal ultrasound. The presence of hydrops fetalis is an indicator of poor prognosis. Here we present a retrospective review of fetuses undergoing either open fetal surgery or steroids for predominantly microcystic CPAM with hydrops fetalis. Method: A retrospective review of patients undergoing open fetal surgery or steroids for CPAM at our institution was performed. The primary outcome was survival. Results: A retrospective review of all patients referred to our institution with the diagnosis of CPAM was performed. Fetuses with predominantly microcystic CPAM and the presence of hydrops fetalis treated with steroid or surgery were included. Thirteen patients were treated with steroids, and 11 patients underwent open fetal surgery. In the steroid group 12 (92%) of 13 fetuses survived to delivery versus 9 (82%) of 11 in the open fetal surgery group. Only 5 (56%) of 9 of the patients in the open fetal surgery group survived to neonatal discharge compared to 10 (83%) of 12 in the steroid group. Conclusions: In the present retrospective study, improved survival was seen in fetuses with hydrops fetalis and predominantly microcystic CPAM treated with steroids when compared with open fetal surgery. Steroids should be considered for first-line therapy in these cases. © 2012 Elsevier Inc. All rights reserved.
Congenital cystic adenomatoid malformations (CCAM), now more correctly referred to as congenital pulmonary airway malformations (CPAMs) are rare lesions usually diagnosed during routine prenatal ultrasound. CPAMs are characterized by abnormal bronchopulmonary development [1]. The natural history of CPAMs are likely related to their growth pattern during embryologic development [2]. Lesion growth may increase or plateau during gestation. The size of
⁎ Corresponding author. Tel.: +1 415 476 4086; fax: +1 415 476 2314. E-mail address: [email protected] (H. Lee). 0022-3468/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.10.015
the lesions and the variable growth behavior results in either the absence of symptoms or the development of non-immune fetal hydrops fetalis. Once fetal hydrops fetalis develops, mortality can reach 100% [3-5]. Treatment with steroids has been reported for microcystic CPAMs. Previous studies have shown a benefit with the use of steroids with survival to birth exceeding 85% [6-8]. Open fetal resection has also been used in cases of large CPAMs with hydrops fetalis, and this has been shown to improve outcome [9-11]. Although outcome is improved in these cases, open fetal surgery carries with it risks of intraoperative and postoperative complications. These complications include fetal bradycardia and demise, postoperative
Mirocystic congenital pulmonary airway malformation chorioamnionitis, amniotic fluid leakage, membrane separation and preterm labor [12]. We previously reported our experience with the use of steroids for microcystic CPAMs with hydrops fetalis [7]. Here we report our results of a retrospective comparison of steroids versus open fetal surgery in the treatment of predominantly microcystic CPAMs with hydrops fetalis.
1. Methods This is an institutional review board–approved retrospective study of all patients referred to the University of California, San Francisco for the diagnosis of CPAM from 1997 to 2010. There was a total of 347 referrals for CPAM during this time. The fetuses from the surgery group were from the time period 1997 to 2001 and the fetuses from the steroid group were from 1997 to 2010. Fetuses with predominantly microcystic CPAM with the presence of hydrops fetalis who were treated with either steroids or surgery were included in the cohort. Microcystic CPAM was defined as N50% echogenic lesions on prenatal ultrasound. Hydrops fetalis was noted by the presence of 2 or more of the following: ascites, integumentary edema, pleural effusion, or placentomegaly. The fetuses that met these criteria were further subdivided into (1) open fetal resection or (2) maternal administration of a single course of betamethasone. Data on patient characteristics included gestational age at diagnosis, CPAM volume to head circumference ratio (CVR) at diagnosis and upon resolution of hydrops, survival to birth, number of neonates on ventilator support at birth, resolution of hydrops, and time to resolution of hydrops. CVR was calculated by dividing the volume of the mass (length × width × height × 0.52) by the head circumference.
2. Results A total of 24 pregnancies met the inclusion criteria for sonographically diagnosed predominantly microcystic CPAM with hydrops fetalis. Of the 24, 11 underwent open fetal resection of the CPAM and 13 received a single course
Table 1
37 of betamethasone. Before 2001, fetuses with microcystic CPAM and hydrops were offered surgery. The patients offered surgery were given steroids in preparation for fetal surgery. In this group, there were 3 patients that subsequently refused surgery. After 2001, all patients with microcystic CPAM and hydrops fetalis were offered steroids first. In the steroid group 12 (92%) of 13 fetuses survived to delivery. Furthermore, 10 (82%) of 12 survived to neonatal discharge (Table 1). There were signs of hydrops in all of the patients in this cohort, and 10 (77%) of 13 had resolution of hydrops before delivery. The mean time to resolution of hydrops was 28 days. The single fetus that did not survive to delivery died at 27 weeks of gestation. The 2 patients who did not survive to neonatal discharge died on day of life 1. Both of these patients were delivered after spontaneous premature rupture of membranes at 24 weeks gestation. All of the non-survivors did not have resolution of hydrops. In the open fetal surgery group, 9 (82%) of 11 fetuses survived to delivery and 5 (56%) of 9 survived to neonatal discharge (Table 1). In contrast to the steroid group, only 2 (18%) of 11 had resolution of hydrops. The mean time to resolution of hydrops was 26 days. The 2 fetuses that had resolution of hydrops survived to neonatal discharge. One of these patients did not require ventilator support. The 2 fetuses that did not survive until delivery died during attempted fetal resection. Most fetuses that did survive to delivery required ventilator support, 8/9 (89%). This is in contrast to only 1 (8%) of 12 in the steroid group. The remainder of neonates who did not survive to discharge died from respiratory failure. There was no significant difference in CVR between the steroid versus the open fetal surgery group at the time of treatment. The mean CVR was 2.95 ± 0.31 for the surgery group and 2.68 ± 0.29 for the steroid group. In addition, no difference in CVR was seen in the nonsurvivors between the 2 groups. The mean decrease in CVR was 0.9 cm 2 ± 0.23 for the steroid group. The mean time between surgery and birth was lower than the time interval between steroid treatment to birth (35.7 ± 9.5 days vs. 87.6 ± 12.6 days, P b .01) (Fig. 1). The mean gestational age at delivery was 34 weeks (range, 24-40) for the steroid group and 31 weeks (range, 28-36) for the open fetal surgery group.
Primary and secondary endpoints comparing steroid versus open fetal surgery in fetuses with predominantly microcystic CCAM
Mean gestational age at delivery (wk) % Survival to birth % Survival to neonatal discharge % Resolution of hydrops CVR (cm 2) total CVR (cm 2) non-survivors Mean gestational age at treatment (wk) Ventilator requirement
Steroids
Open fetal surgery
P
34 12/13 (92%) 10/12 (83%) 10/13 (77%) 2.68 ± 0.29 3.66 ± 0.66 23 (20-26) 1/12 (8%)
31 9/11 (82%) 5/9 (56%) 2/11 (18%) 2.95 ± 0.31 3.02 ± 0.40 24 (20-29) 8/9 (89%)
b.05 .58 .33 b.05 .55 .42 .49 b.001
38
Fig. 1 Time interval between treatment to birth represented in days (*P b .05).
3. Discussion Management of microcystic CPAMs diagnosed prenatally can be variable and may include expectant management, steroid treatment, and open fetal surgery [7,11-13]. Open fetal surgery has been used for high-risk lesions with a CVR N1.6 in the presence of non-immune hydrops fetalis [9-11]. However, prenatal resection of CPAM is subject to complications inherent to open fetal surgery with a 50% reported survival [11]. As a result, our group pioneered treating large microcystic CPAM [7,14]. Other groups have also reported on the efficacy of steroids for microcystic CPAMs [6,8]. In the present study, we present a retrospective review of data comparing open fetal resection and steroid treatment for predominantly microcystic CPAM with non-immune hydrops fetalis. Our aim was to determine if indeed there is a benefit with steroid treatment over open fetal resection in this particular type of lesion. We observed in this study survival rates that are consistent with previous reports [7,11]. Specifically, we found the percentage of patients surviving to birth and neonatal discharge was higher in the steroid treatment group when compared to the open fetal surgery group. Although the results were not statistically significant we did see a trend for survival in the steroid group. Interestingly, the difference in survival to birth did not have as pronounced a difference as survival to neonatal discharge. These differences are likely owing to the relative health of the neonates at birth and the level of prematurity. We can explain these findings, in part, by the opposing nature of the two treatments. In contrast to steroid treatment, fetal surgery is invasive and has a high rate of preterm labor. This is evidenced by the lower mean gestational age of the patients in the surgery group. Furthermore, the mean time between surgery and birth was lower than the time interval between steroid treatment to birth. Maternal steroid treatment is noninvasive and does not cause preterm labor. Furthermore,
K.C. Loh et al. the CPAM may involute further throughout gestation and allow for more functional lung tissue at birth. This is further supported by the higher number of neonates on ventilator support in the surgery group suggesting a higher incidence of lung immaturity in this group. Although severity is a possible and likely factor contributing to the differences between the 2 groups, our results show no significant difference between CVR at the time of diagnosis between the 2 groups. Although some groups have used the presence of ascites alone as the definition of hydrops, we used the standard definition of fluid in two or more body parts as the definition of hydrops. We see here that the survivors in the steroid group all had resolution of hydrops. Hydrops in the nonsurvivors were manifested by ascites, pleural effusion, and pericardial effusion. Since hydrops carries a high mortality, it appears that steroids may be used as an alternative to open fetal resection. Therefore, given the higher incidence of prematurity and higher mortality likely related to prematurity in the open fetal surgery group, we advocate that steroids should be used as first-line treatment in patients with predominantly microcystic CPAM and non-immune hydrops fetalis. We recognize that there are several limitations to this retrospective study. There are limitations in follow-up given the tertiary nature of our institution. Given the rare nature of the disease, there are a small number of patients in each group. Variation between practitioners may contribute to conflicting reports in severity. Although there isn't any standard criterion to measure severity of hydrops, we do note that the degree of ascites and integumentary edema was more severe in the surgery group. Therefore, the absence of a defined severity index for hydrops fetalis may confound the data, creating a falsely elevated outcome for steroid treatment. Furthermore, we are limited by the intrinsic difference between the two treatment approaches on fetuses that were referred during two different time periods. However, with only 3 in the steroid group overlapping with the fetal surgery time period, it would not be possible statistically to determine if differences in outcome was owing to a selection bias. In addition, given the small overlap between treatment approaches and the absence of fetal surgery cases after 2001, it is unlikely that the worse outcome in the surgery group is owing to severity. Keeping in mind these limitations, our present findings suggest that treatment with steroids is associated with improved survival in cases of microcystic CPAM with hydrops fetalis. Given the variability in treatment approach between these 2 groups, a prospective trial would be needed to truly compare the 2 therapies.
References [1] Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 1977;8:155-71. [2] Van Leeuwen K, Teitelbaum DH, Hirschl RB, et al. Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal
Mirocystic congenital pulmonary airway malformation
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12] [13] [14]
presentation, surgical indications, and natural history. J Pediatr Surg 1999;34:794-8. Miller JA, Corteville JE, Langer JC. Congenital cystic adenomatoid malformation in the fetus: natural history and predictors of outcome. J Pediatr Surg 1996;31:805-8. Adzick NS, Harrison MR, Crombleholme TM, et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998;179: 884-9. Vu L, Tsao K, Lee H, et al. Characteristics of congenital cystic adenomatoid malformations associated with nonimmune hydrops and outcome. J Pediatr Surg 2007;42:1351. Peranteau WH, Wilson RD, Liechty KW, et al. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007;22:365. Curran PF, Jelin EB, Rand L, et al. Prenatal steroids for microcystic congenital cystic adenomatoid malformations. J Pediatr Surg 2010;45: 145. Morris LM, Lim FY, Livingston JC, et al. High-risk fetal congenital pulmonary airway malformations have a variable response to steroids. J Pediatr Surg 2009;44:60. Harrison MR, Adzick NS, Jennings RW, et al. Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 1990;336: 965. Adzick NS, Harrison MR, Flake AW, et al. Fetal surgery for cystic adenomatoid malformation of the lung. J Pediatr Surg 1993;28:806. Grethel EJ, Wagner AJ, Clifton MS, et al. Fetal intervention for mass lesions and hydrops improves outcome: a 15-year experience. J Pediatr Surg 2007;42:117. Adzick NS. Open fetal surgery for life-threatening fetal anomalies. Semin Fetal Neonatal Med 2010;15:1. Sauvat F, Michel JL, Benachi A, et al. Management of asymptomatic neonatal cystic adenomatoid malformations. J Pediatr Surg 2003;38:548. Tsao K, Hawgood S, Vu L, et al. Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr Surg 2003;38:508.
Discussion Darrell Cass, MD (Houston, TX): Thank you very much. That was a beautiful presentation and better than the abstract. As you know, at this meeting, our group from Texas Children's presented some data that suggest that in fact the ECHO changes might be a more specific predictor of poor fetal outcome and we suggest that these changes probably should be the primary indication for fetal treatment. We do agree with you that steroids likely play a role in the management of all of these high-risk patients, but we think that hydrops is less specific and that there are some fetuses that will get ascites or scalp edema owing to direct compression of the mass on the cisterna chyli or the thoracic duct leading to passive edema rather than actually heart failure which we think is what we are trying to get to. My question for you is, first, did you have a chance to look at the fetal echo findings in your cohort? The question is how do you know that the group that got the steroids alone was not simply a less sick group that led to their better outcome. We do agree with you that steroids should be the first-line treatment for all fetuses that have high-risk lesions, but fetal surgery likely should be used
39 for those that have ongoing hydrops or worsening fetal heart function despite the steroid application. Loh (response): In regard to your question, our group agrees with the fact that echocardiogram is probably a better indicator of hydrops fetalis and for this particular cohort it is difficult to actually compare in terms of echocardiogram because most of the data is not there, but in the future, I think it would be useful to actually look at echocardiogram as an indicator of severity and that is one of the faults in this paper in that we cannot really use echocardiogram as a severity indicator, and we can only use the standard definition which is two or more fluid body compartments with edema or fluid. Jacob Langer, MD (Toronto, ON): I have just a simple question. It seems to me that you probably treated most of these patients with steroids first and the surgery group were the ones that did not respond to steroids. If you could just tell us how many of the surgery patients started with steroids and if there are a significant number of those that had surgery because they failed steroids, then clearly that is a different group with a higher severity which would explain the worse outcomes in that group. Loh (response): In regards to your question, the cohort of the surgery group was actually a much earlier cohort and a lot of those patients did not receive steroids. They initially went to open fetal surgery and did not initially receive steroids prior to surgery. N. Scott Adzick, MD (Philadelphia, PA): In the past 16 years, we have been referred and have performed evaluations on 1000 fetuses with fetal lung lesions. We have treated 25 with fetal CCAM resection with a link with fetal hydrops and all those were microcystic cases. We have done 46 thoracoamniotic shunt placements for those fetuses with macrocystic lesions, and we have done 22 EXIT to CCAM resections for large lesions latent gestation, so when you think about it, the need for fetal therapy in our experience is about in the 8% to 10% range. What is very telling though is that since we have implemented routine maternal corticosteroid therapy, which is a very straightforward thing to do, for those with a CCAM volume ratio more than 1.4, we have done no fetal CCAM resections in the past three years. I think it has flipped the therapy on its head and is obviously a very benign and straightforward thing to do. Loh (response): I agree with you. I think the same goes for our institution where we have not done an open fetal resection in the past several years. I think the positive thing about steroid treatment is that if a fetus receives steroid treatment and they are refractory to steroid treatment, they can always go to the secondary treatment which is open fetal surgery.
www.elsevier.com/locate/jpedsurg
APSA Papers
Microcystic congenital pulmonary airway malformation with hydrops fetalis: steroids vs open fetal resection Kenneth C. Loh, Eric Jelin, Shinjiro Hirose, Vickie Feldstein, Ruth Goldstein, Hanmin Lee ⁎ Department of Surgery, University of California at San Francisco, San Francisco, CA 94143-0570 Received 24 September 2011; accepted 6 October 2011
Key words: CPAM; CCAM; Fetal surgery; Steroids; CVR; Microcystic
Abstract Background/Purpose: Congenital pulmonary airway malformations (CPAM) are rare lesions often diagnosed during routine prenatal ultrasound. The presence of hydrops fetalis is an indicator of poor prognosis. Here we present a retrospective review of fetuses undergoing either open fetal surgery or steroids for predominantly microcystic CPAM with hydrops fetalis. Method: A retrospective review of patients undergoing open fetal surgery or steroids for CPAM at our institution was performed. The primary outcome was survival. Results: A retrospective review of all patients referred to our institution with the diagnosis of CPAM was performed. Fetuses with predominantly microcystic CPAM and the presence of hydrops fetalis treated with steroid or surgery were included. Thirteen patients were treated with steroids, and 11 patients underwent open fetal surgery. In the steroid group 12 (92%) of 13 fetuses survived to delivery versus 9 (82%) of 11 in the open fetal surgery group. Only 5 (56%) of 9 of the patients in the open fetal surgery group survived to neonatal discharge compared to 10 (83%) of 12 in the steroid group. Conclusions: In the present retrospective study, improved survival was seen in fetuses with hydrops fetalis and predominantly microcystic CPAM treated with steroids when compared with open fetal surgery. Steroids should be considered for first-line therapy in these cases. © 2012 Elsevier Inc. All rights reserved.
Congenital cystic adenomatoid malformations (CCAM), now more correctly referred to as congenital pulmonary airway malformations (CPAMs) are rare lesions usually diagnosed during routine prenatal ultrasound. CPAMs are characterized by abnormal bronchopulmonary development [1]. The natural history of CPAMs are likely related to their growth pattern during embryologic development [2]. Lesion growth may increase or plateau during gestation. The size of
⁎ Corresponding author. Tel.: +1 415 476 4086; fax: +1 415 476 2314. E-mail address: [email protected] (H. Lee). 0022-3468/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.10.015
the lesions and the variable growth behavior results in either the absence of symptoms or the development of non-immune fetal hydrops fetalis. Once fetal hydrops fetalis develops, mortality can reach 100% [3-5]. Treatment with steroids has been reported for microcystic CPAMs. Previous studies have shown a benefit with the use of steroids with survival to birth exceeding 85% [6-8]. Open fetal resection has also been used in cases of large CPAMs with hydrops fetalis, and this has been shown to improve outcome [9-11]. Although outcome is improved in these cases, open fetal surgery carries with it risks of intraoperative and postoperative complications. These complications include fetal bradycardia and demise, postoperative
Mirocystic congenital pulmonary airway malformation chorioamnionitis, amniotic fluid leakage, membrane separation and preterm labor [12]. We previously reported our experience with the use of steroids for microcystic CPAMs with hydrops fetalis [7]. Here we report our results of a retrospective comparison of steroids versus open fetal surgery in the treatment of predominantly microcystic CPAMs with hydrops fetalis.
1. Methods This is an institutional review board–approved retrospective study of all patients referred to the University of California, San Francisco for the diagnosis of CPAM from 1997 to 2010. There was a total of 347 referrals for CPAM during this time. The fetuses from the surgery group were from the time period 1997 to 2001 and the fetuses from the steroid group were from 1997 to 2010. Fetuses with predominantly microcystic CPAM with the presence of hydrops fetalis who were treated with either steroids or surgery were included in the cohort. Microcystic CPAM was defined as N50% echogenic lesions on prenatal ultrasound. Hydrops fetalis was noted by the presence of 2 or more of the following: ascites, integumentary edema, pleural effusion, or placentomegaly. The fetuses that met these criteria were further subdivided into (1) open fetal resection or (2) maternal administration of a single course of betamethasone. Data on patient characteristics included gestational age at diagnosis, CPAM volume to head circumference ratio (CVR) at diagnosis and upon resolution of hydrops, survival to birth, number of neonates on ventilator support at birth, resolution of hydrops, and time to resolution of hydrops. CVR was calculated by dividing the volume of the mass (length × width × height × 0.52) by the head circumference.
2. Results A total of 24 pregnancies met the inclusion criteria for sonographically diagnosed predominantly microcystic CPAM with hydrops fetalis. Of the 24, 11 underwent open fetal resection of the CPAM and 13 received a single course
Table 1
37 of betamethasone. Before 2001, fetuses with microcystic CPAM and hydrops were offered surgery. The patients offered surgery were given steroids in preparation for fetal surgery. In this group, there were 3 patients that subsequently refused surgery. After 2001, all patients with microcystic CPAM and hydrops fetalis were offered steroids first. In the steroid group 12 (92%) of 13 fetuses survived to delivery. Furthermore, 10 (82%) of 12 survived to neonatal discharge (Table 1). There were signs of hydrops in all of the patients in this cohort, and 10 (77%) of 13 had resolution of hydrops before delivery. The mean time to resolution of hydrops was 28 days. The single fetus that did not survive to delivery died at 27 weeks of gestation. The 2 patients who did not survive to neonatal discharge died on day of life 1. Both of these patients were delivered after spontaneous premature rupture of membranes at 24 weeks gestation. All of the non-survivors did not have resolution of hydrops. In the open fetal surgery group, 9 (82%) of 11 fetuses survived to delivery and 5 (56%) of 9 survived to neonatal discharge (Table 1). In contrast to the steroid group, only 2 (18%) of 11 had resolution of hydrops. The mean time to resolution of hydrops was 26 days. The 2 fetuses that had resolution of hydrops survived to neonatal discharge. One of these patients did not require ventilator support. The 2 fetuses that did not survive until delivery died during attempted fetal resection. Most fetuses that did survive to delivery required ventilator support, 8/9 (89%). This is in contrast to only 1 (8%) of 12 in the steroid group. The remainder of neonates who did not survive to discharge died from respiratory failure. There was no significant difference in CVR between the steroid versus the open fetal surgery group at the time of treatment. The mean CVR was 2.95 ± 0.31 for the surgery group and 2.68 ± 0.29 for the steroid group. In addition, no difference in CVR was seen in the nonsurvivors between the 2 groups. The mean decrease in CVR was 0.9 cm 2 ± 0.23 for the steroid group. The mean time between surgery and birth was lower than the time interval between steroid treatment to birth (35.7 ± 9.5 days vs. 87.6 ± 12.6 days, P b .01) (Fig. 1). The mean gestational age at delivery was 34 weeks (range, 24-40) for the steroid group and 31 weeks (range, 28-36) for the open fetal surgery group.
Primary and secondary endpoints comparing steroid versus open fetal surgery in fetuses with predominantly microcystic CCAM
Mean gestational age at delivery (wk) % Survival to birth % Survival to neonatal discharge % Resolution of hydrops CVR (cm 2) total CVR (cm 2) non-survivors Mean gestational age at treatment (wk) Ventilator requirement
Steroids
Open fetal surgery
P
34 12/13 (92%) 10/12 (83%) 10/13 (77%) 2.68 ± 0.29 3.66 ± 0.66 23 (20-26) 1/12 (8%)
31 9/11 (82%) 5/9 (56%) 2/11 (18%) 2.95 ± 0.31 3.02 ± 0.40 24 (20-29) 8/9 (89%)
b.05 .58 .33 b.05 .55 .42 .49 b.001
38
Fig. 1 Time interval between treatment to birth represented in days (*P b .05).
3. Discussion Management of microcystic CPAMs diagnosed prenatally can be variable and may include expectant management, steroid treatment, and open fetal surgery [7,11-13]. Open fetal surgery has been used for high-risk lesions with a CVR N1.6 in the presence of non-immune hydrops fetalis [9-11]. However, prenatal resection of CPAM is subject to complications inherent to open fetal surgery with a 50% reported survival [11]. As a result, our group pioneered treating large microcystic CPAM [7,14]. Other groups have also reported on the efficacy of steroids for microcystic CPAMs [6,8]. In the present study, we present a retrospective review of data comparing open fetal resection and steroid treatment for predominantly microcystic CPAM with non-immune hydrops fetalis. Our aim was to determine if indeed there is a benefit with steroid treatment over open fetal resection in this particular type of lesion. We observed in this study survival rates that are consistent with previous reports [7,11]. Specifically, we found the percentage of patients surviving to birth and neonatal discharge was higher in the steroid treatment group when compared to the open fetal surgery group. Although the results were not statistically significant we did see a trend for survival in the steroid group. Interestingly, the difference in survival to birth did not have as pronounced a difference as survival to neonatal discharge. These differences are likely owing to the relative health of the neonates at birth and the level of prematurity. We can explain these findings, in part, by the opposing nature of the two treatments. In contrast to steroid treatment, fetal surgery is invasive and has a high rate of preterm labor. This is evidenced by the lower mean gestational age of the patients in the surgery group. Furthermore, the mean time between surgery and birth was lower than the time interval between steroid treatment to birth. Maternal steroid treatment is noninvasive and does not cause preterm labor. Furthermore,
K.C. Loh et al. the CPAM may involute further throughout gestation and allow for more functional lung tissue at birth. This is further supported by the higher number of neonates on ventilator support in the surgery group suggesting a higher incidence of lung immaturity in this group. Although severity is a possible and likely factor contributing to the differences between the 2 groups, our results show no significant difference between CVR at the time of diagnosis between the 2 groups. Although some groups have used the presence of ascites alone as the definition of hydrops, we used the standard definition of fluid in two or more body parts as the definition of hydrops. We see here that the survivors in the steroid group all had resolution of hydrops. Hydrops in the nonsurvivors were manifested by ascites, pleural effusion, and pericardial effusion. Since hydrops carries a high mortality, it appears that steroids may be used as an alternative to open fetal resection. Therefore, given the higher incidence of prematurity and higher mortality likely related to prematurity in the open fetal surgery group, we advocate that steroids should be used as first-line treatment in patients with predominantly microcystic CPAM and non-immune hydrops fetalis. We recognize that there are several limitations to this retrospective study. There are limitations in follow-up given the tertiary nature of our institution. Given the rare nature of the disease, there are a small number of patients in each group. Variation between practitioners may contribute to conflicting reports in severity. Although there isn't any standard criterion to measure severity of hydrops, we do note that the degree of ascites and integumentary edema was more severe in the surgery group. Therefore, the absence of a defined severity index for hydrops fetalis may confound the data, creating a falsely elevated outcome for steroid treatment. Furthermore, we are limited by the intrinsic difference between the two treatment approaches on fetuses that were referred during two different time periods. However, with only 3 in the steroid group overlapping with the fetal surgery time period, it would not be possible statistically to determine if differences in outcome was owing to a selection bias. In addition, given the small overlap between treatment approaches and the absence of fetal surgery cases after 2001, it is unlikely that the worse outcome in the surgery group is owing to severity. Keeping in mind these limitations, our present findings suggest that treatment with steroids is associated with improved survival in cases of microcystic CPAM with hydrops fetalis. Given the variability in treatment approach between these 2 groups, a prospective trial would be needed to truly compare the 2 therapies.
References [1] Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 1977;8:155-71. [2] Van Leeuwen K, Teitelbaum DH, Hirschl RB, et al. Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal
Mirocystic congenital pulmonary airway malformation
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12] [13] [14]
presentation, surgical indications, and natural history. J Pediatr Surg 1999;34:794-8. Miller JA, Corteville JE, Langer JC. Congenital cystic adenomatoid malformation in the fetus: natural history and predictors of outcome. J Pediatr Surg 1996;31:805-8. Adzick NS, Harrison MR, Crombleholme TM, et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998;179: 884-9. Vu L, Tsao K, Lee H, et al. Characteristics of congenital cystic adenomatoid malformations associated with nonimmune hydrops and outcome. J Pediatr Surg 2007;42:1351. Peranteau WH, Wilson RD, Liechty KW, et al. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007;22:365. Curran PF, Jelin EB, Rand L, et al. Prenatal steroids for microcystic congenital cystic adenomatoid malformations. J Pediatr Surg 2010;45: 145. Morris LM, Lim FY, Livingston JC, et al. High-risk fetal congenital pulmonary airway malformations have a variable response to steroids. J Pediatr Surg 2009;44:60. Harrison MR, Adzick NS, Jennings RW, et al. Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 1990;336: 965. Adzick NS, Harrison MR, Flake AW, et al. Fetal surgery for cystic adenomatoid malformation of the lung. J Pediatr Surg 1993;28:806. Grethel EJ, Wagner AJ, Clifton MS, et al. Fetal intervention for mass lesions and hydrops improves outcome: a 15-year experience. J Pediatr Surg 2007;42:117. Adzick NS. Open fetal surgery for life-threatening fetal anomalies. Semin Fetal Neonatal Med 2010;15:1. Sauvat F, Michel JL, Benachi A, et al. Management of asymptomatic neonatal cystic adenomatoid malformations. J Pediatr Surg 2003;38:548. Tsao K, Hawgood S, Vu L, et al. Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr Surg 2003;38:508.
Discussion Darrell Cass, MD (Houston, TX): Thank you very much. That was a beautiful presentation and better than the abstract. As you know, at this meeting, our group from Texas Children's presented some data that suggest that in fact the ECHO changes might be a more specific predictor of poor fetal outcome and we suggest that these changes probably should be the primary indication for fetal treatment. We do agree with you that steroids likely play a role in the management of all of these high-risk patients, but we think that hydrops is less specific and that there are some fetuses that will get ascites or scalp edema owing to direct compression of the mass on the cisterna chyli or the thoracic duct leading to passive edema rather than actually heart failure which we think is what we are trying to get to. My question for you is, first, did you have a chance to look at the fetal echo findings in your cohort? The question is how do you know that the group that got the steroids alone was not simply a less sick group that led to their better outcome. We do agree with you that steroids should be the first-line treatment for all fetuses that have high-risk lesions, but fetal surgery likely should be used
39 for those that have ongoing hydrops or worsening fetal heart function despite the steroid application. Loh (response): In regard to your question, our group agrees with the fact that echocardiogram is probably a better indicator of hydrops fetalis and for this particular cohort it is difficult to actually compare in terms of echocardiogram because most of the data is not there, but in the future, I think it would be useful to actually look at echocardiogram as an indicator of severity and that is one of the faults in this paper in that we cannot really use echocardiogram as a severity indicator, and we can only use the standard definition which is two or more fluid body compartments with edema or fluid. Jacob Langer, MD (Toronto, ON): I have just a simple question. It seems to me that you probably treated most of these patients with steroids first and the surgery group were the ones that did not respond to steroids. If you could just tell us how many of the surgery patients started with steroids and if there are a significant number of those that had surgery because they failed steroids, then clearly that is a different group with a higher severity which would explain the worse outcomes in that group. Loh (response): In regards to your question, the cohort of the surgery group was actually a much earlier cohort and a lot of those patients did not receive steroids. They initially went to open fetal surgery and did not initially receive steroids prior to surgery. N. Scott Adzick, MD (Philadelphia, PA): In the past 16 years, we have been referred and have performed evaluations on 1000 fetuses with fetal lung lesions. We have treated 25 with fetal CCAM resection with a link with fetal hydrops and all those were microcystic cases. We have done 46 thoracoamniotic shunt placements for those fetuses with macrocystic lesions, and we have done 22 EXIT to CCAM resections for large lesions latent gestation, so when you think about it, the need for fetal therapy in our experience is about in the 8% to 10% range. What is very telling though is that since we have implemented routine maternal corticosteroid therapy, which is a very straightforward thing to do, for those with a CCAM volume ratio more than 1.4, we have done no fetal CCAM resections in the past three years. I think it has flipped the therapy on its head and is obviously a very benign and straightforward thing to do. Loh (response): I agree with you. I think the same goes for our institution where we have not done an open fetal resection in the past several years. I think the positive thing about steroid treatment is that if a fetus receives steroid treatment and they are refractory to steroid treatment, they can always go to the secondary treatment which is open fetal surgery.