Very few diseases can be treated successfully in utero. Fetal chylothorax, an intrathoracic effusion due to leakage of lymph into the pleural cavity, occurs in 1 in 10,000–15,000 pregnancies. The clinical course of primary chylothorax is highly variable, ranging from complete spontaneous resolution to progression into hydrops, lung hypoplasia, or both.1,2 The overall mortality rate of chylothorax is approximately 50%, with hydrops, preterm delivery, and no treatment being poor prognostic indicators.1,2 The mortality rate of primary chylothorax early in the second trimester is unknown, and spontaneous remission rates have been reported as high as 50%.3,4 In contrast, persistent pleural effusions diagnosed early in second trimester may be associated with a high risk of fetal or neonatal death due to the risk of developing hydrops or lung hypoplasia.2,3,5–7 Pleuroamniotic shunting has been the treatment of choice in fetal chylothorax. However, only two cases have described successful pleuroamniotic shunting in early second trimester.8,9 Pleuroamniotic shunting is a technically difficult procedure, particularly at early gestational age, associated with adverse effects such as preterm labor, which is a poor prognostic factor.1,2 Further, the position of the fetus and the placenta may prevent the procedure. OK-432 is a preparation of Streptococcus pyogenes, which induces a strong inflammatory response and causes pleurodesis in adults with chylothorax.10 OK-432 has additionally been applied for lymphangiomas in newborns and for the intrauterine treatment of cystic hygromas.11–14 Based on successful reports of intrauterine OK-432 treatment of chylothorax in late second trimester,15–17 we introduced a new treatment strategy in 2003 offering intrapleural injections of OK-432 to all fetuses referred to our department with persistent pleural effusions diagnosed in early second trimester. Here, we present the results of our cohort of fetuses treated with OK-432 in the early second trimester due to chylothorax.
MATERIALS AND METHODS
A prospective study of all fetuses (n=7) with pleural effusions in the second trimester (gestational ages 16–21 weeks) referred to our tertiary center of fetal medicine in Denmark (covering Denmark and the southern part of Sweden, with approximately 100,000 births per year) in 2003–2005 (Table 1). Pleural effusions in these fetuses were detected by routine ultrasound examination, which is offered to all women in gestational weeks 16–20 in Scandinavia. No fetuses were determined to have aneuploidy, infections, or structural abnormalities. An observation period of 1–2 weeks between diagnosis and treatment confirmed that all fetuses had persistence or progression of pleural effusions. The fetuses were treated with 0.2–1.0 mg OK-432, which was injected into the pleural cavity using a 21-G needle after, when possible, fully aspirating the pleural effusions. The aspirated fluid was used to determine the nature of the condition, thus the diagnosis of chylothorax was not confirmed before installation of OK-432 to minimize the number of invasive procedures. The dose of OK-432 was initially based on experience in treatment of newborns in the Department of Pediatric Surgery, Rigshospitalet, Denmark.17 During the study, the dose of OK-432 was increased to try to avoid giving further intrathoracic injections. The women were not treated with tocolytics or antibiotics. Chylothorax was confirmed in all cases by cytologic analysis of the aspirated pleural fluid demonstrating that the percentage of lymphocytes and lymphoblasts was more than 95%. No secondary cause of chylothorax was found subsequent to the treatment. After the injections, the fetuses were closely monitored using ultrasound examination, and the treatment was repeated if there were persistent or increasing pleural effusions after 1–3 weeks (Table 1). Outcome variables were remission of pleural effusions, fetal and infant morbidity and mortality, and pregnancy complications.
The parents were informed about the experimental fetal therapy with OK-432 and were counseled regarding the potential benefits and hazards of the treatment, including the uncertainty of long-term adverse effects of the treatment. The parents were also informed about the risk of progression into hydrops and lung hypoplasia as well as the chance of spontaneous remission in approximately 50% of cases. Information about alternative treatment options (serial thoracocentesis and thoracoamniotic shunting) was given. The parents were asked to choose between expectancy and treatment with OK-432. All parents elected to proceed with the option of OK-432 and informed consent was obtained. The Scientific-Ethical Committee, Copenhagen, Denmark, approved the treatments (approval no. (KF) 07 2006–7149).
Antenatal findings and treatment, and postnatal conditions of the fetuses treated with OK-432 are shown in Table 1. Total remission of pleural effusions was obtained in all fetuses after one or two intrapleural injections of OK-432 within 3–9 weeks. No adverse effects of the treatment were observed. None of the fetuses developed hydrops, and all experienced an uncomplicated third trimester. All children were born healthy without pleural effusions, lung hypoplasia, or hydrops.
This study investigates the outcome of fetuses with chylothorax treated with OK-432 in the early second trimester. All fetuses obtained total remission of the pleural effusions, and none developed hydrops or lung hypoplasia. All children were born healthy. This high success rate indicates a strong effect of OK-432 in the second trimester. We found that the major criterion for a successful outcome was remission of pleural effusions within a week after the treatment with OK-432. It has previously been indicated by Chen et al18 that complete aspiration is an important requirement for a successful outcome of OK-432. However, in several of our cases, only partial aspiration was obtained, but the treatment was still successful. Speculatively, complete aspiration could increase treatment response of OK-432, because dilution of the medicament could be avoided. The good outcome in cases with only partial aspiration could be because we increased the dosage of OK-432 during the study period. On the basis of these findings, we hesitate to use alternative methods (eg, pleurodesis through the fetal liver) in cases where only partial aspiration through thoracocentesis is possible. Adhesions after OK-432 have also been mentioned as an important requirement for successful OK-432 therapy.18 We also found that the majority of our treatments were followed by adhesions. In two cases, however, adhesions were not visualized, but remission of the pleural effusions was still obtained, although spontaneous remission cannot be excluded. At the time when adhesions are visualized (1–2 weeks after OK-432 treatment), we still consider adhesions less important than the degree of remission of pleural effusions.
OK-432 is an inactivated preparation of Streptococcus pyogenes, and is thought to cause pleurodesis by inducing a strong cellular and cytokine-mediated inflammatory response.10,19–22 The absence of adhesions in cases with complete remission could indicate a direct effect of OK-432 on the lymphatic vessels in addition to pleurodesis. In this study, three fetuses required two injections of OK-432 before remission of chylothorax was obtained. We were unable to identify variables that differed between the first and the second treatment in these three cases. The dose of OK-432 was almost identical in two of the three cases, and partial compared with complete aspiration could not explain the differences. We assign the success of repeated OK-432 injections to an inflammatory response initiated in the first and completed after the second treatment. Therefore, we recommend a second injection of OK-432 if the pleural effusions are stationary or increasing.
In this study, all fetuses were treated with OK-432 before the diagnosis of chylothorax was finally confirmed by cytologic analysis of the aspirated pleural fluid. This strategy was chosen to minimize the number of invasive procedures, and because the fetuses did not have aneuploidy, infections, or structural abnormalities and thus were very likely to have primary chylothorax. The parents were informed about this and accepted the uncertainty.
To date, only seven fetuses worldwide, reported as cases in the literature, have been treated with OK-432 due to primary chylothorax. One fetus had bilateral chylothorax and severe hydrops and died immediately after birth at gestational age 34 weeks.23 However, this fetus was diagnosed late and was not treated with OK-432 until 33 weeks of gestation. The remaining six fetuses were diagnosed in the second trimester (gestational ages 19–25 weeks): One had bilateral chylothorax and severe hydrops and died in utero,18 whereas the remaining five (two complicated by hydrops) had a good outcome (success rate 83%).15–18,24 The treatment procedure in these fetuses differed from ours because 1) repeated thoracocenteses were performed before the installation of OK-432 in contrast to the primary installation of OK-432 in this study and 2) OK-432 was administered at later gestational ages. Despite these differences, the data confirm a high success rate of OK-432 in inducing remission of chylothorax in second trimester. In addition, the data indicate that early administration is essential for optimal treatment response to avoid the development of lung hypoplasia and hydrops, the latter the single most important prognostic factor for poor outcome in fetal chylothorax.3
Fetal chylothorax has an overall spontaneous remission rate of 10–20%,2,3,25,26 but in fetuses with isolated pleural effusions and low gestational age, spontaneous remission rates have been reported as high as 50%.3,4 Although the fetuses in this study had persistence or progression of the pleural effusions and all except two had compression or displacement of the heart and lung at the time of treatment, we cannot exclude that in some cases chylothorax would have undergone spontaneous remission without treatment with OK-432, because our observational period was only 1–2 weeks.
There is no consensus in the literature on optimal antenatal management of chylothorax, due the rarity and the variable clinical course of the disease, as well as the suboptimal treatment possibilities, which have included thoracocentesis or pleuroamniotic shunting or both.3 Because rapid reaccumulation of pleural effusions occurs after only hours of thoracocentesis, serial thoracocenteses are mandatory and often have no effect on fetal or neonatal death.1,3 Pleuroamniotic shunting has been shown effective in providing long-term intrauterine drainage after gestational week 22,2,3,27–32 and shunting was shown to be effective in early second trimester (gestational weeks 17 and 19) in two case reports.8,9 However, it is a technically difficult procedure because of the relatively large gauge of the instruments needed for placing the shunts, and shunt replacements are often required. Further, the position of the fetus and the placenta may prevent the procedure. Finally, pleuroamniotic shunting implies a risk of adverse effects, such as infection, bleeding, maternal or fetal organ trauma, preterm rupture of membranes, and preterm labor, the last being an important prognostic factor for poor outcome in fetuses with chylothorax.1,2,31
Although some fetuses with chylothorax may be treated unnecessarily, we believe that OK-432 treatment of early persistent chylothorax is justified to prevent hydrops and lung hypoplasia, in particularly because 1) OK-432 injection is a simple and relatively low-risk procedure and 2) no adverse effects of OK-432 were observed in this or other studies,16–18,23,24,33 except one report of transient fetal tachycardia.15 Nevertheless, further studies are needed to differentiate fetuses with chylothorax in the early second trimester undergoing spontaneous remission from those benefiting from OK-432. Additionally, long-term postnatal follow-up of the children treated with OK-432 is needed and ongoing.
We found intrapleural injections of OK-432 to induce remission in all fetuses with persistent chylothorax diagnosed early in the second trimester. OK-432 is a promising therapy for selected cases with persistent chylothorax early in the second trimester.
1. Longaker MT, Laberge JM, Dansereau J, Langer JC, Crombleholme TM, Callen PW, et al. Primary fetal hydrothorax: natural history and management. J Pediatr Surg 1989;24:573–6.
2. Weber AM, Philipson EH. Fetal pleural effusion: a review and meta-analysis for prognostic indicators. Obstet Gynecol 1992;79:281–6.
3. Aubard Y, Derouineau I, Aubard V, Chalifour V, Preux PM. Primary fetal hydrothorax: a literature review and proposed antenatal clinical strategy. Fetal Diagn Ther 1998;13:325–33.
4. Klam S, Bigras JL, Hudon L. Predicting outcome in primary fetal hydrothorax. Fetal Diagn Ther 2005;20:366–70.
5. Castillo RA, Devoe LD, Falls G, Holzman GB, Hadi HA, Fadel HE. Pleural effusions and pulmonary hypoplasia. Am J Obstet Gynecol 1987;157:1252–5.
6. Inselman LS, Mellins RB. Growth and development of the lung. J Pediatr 1981;98:1–15.
7. Smoleniec J, James D. Predictive value of pleural effusions in fetal hydrops. Fetal Diagn Ther 1995;10:95–100.
8. Grisaru-Granovsky S, Seaward PG, Windrim R, Wyatt P, Kelly EN, Ryan G. Mid-trimester thoracoamniotic shunting for the treatment of fetal primary pleural effusions in a twin pregnancy. A case report. Fetal Diagn Ther 2000;15:209–11.
9. Lam H, Yates R, Jauniaux E. Successful early in utero management of fetal hydrothorax in a twin pregnancy. Prenat Diagn 2003;23:221–4.
10. Shimizu J, Hayashi Y, Oda M, Morita K, Arano Y, Nagao S, et al. Treatment of postoperative chylothorax by pleurodesis with the streptococcal preparation OK-432. Thorac Cardiovasc Surg 1994;42:233–6.
11. Sasaki Y, Chiba Y. Successful intrauterine treatment of cystic hygroma colli using OK-432. A case report. Fetal Diagn Ther 2003;18:391–6.
12. Sanlialp I, Karnak I, Tanyel FC, Senocak ME, Buyukpamukcu N. Sclerotherapy for lymphangioma in children. Int J Pediatr Otorhinolaryngol 2003;67:795–800.
13. Hall N, Ade-Ajayi N, Brewis C, Roebuck DJ, Kiely EM, Drake DP, et al. Is intralesional injection of OK-432 effective in the treatment of lymphangioma in children? Surgery 2003;133:238–42.
14. Watari H, Yamada H, Fujino T, Okuyama K, Sagawa T, Makinoda S, et al. A case of intrauterine medical treatment for cystic hygroma. Eur J Obstet Gynecol Reprod Biol 1996;70:201–3.
15. Tanemura M, Nishikawa N, Kojima K, Suzuki Y, Suzumori K. A case of successful fetal therapy for congenital chylothorax by intrapleural injection of OK-432. Ultrasound Obstet Gynecol 2001;18:371–5.
16. Okawa T, Takano Y, Fujimori K, Yanagida K, Sato A. A new fetal therapy for chylothorax: pleurodesis with OK-432. Ultrasound Obstet Gynecol 2001;18:376–7.
17. Jorgensen C, Brocks V, Bang J, Jorgensen FS, Ronsbro L. Treatment of severe fetal chylothorax associated with pronounced hydrops with intrapleural injection of OK-432. Ultrasound Obstet Gynecol 2003;21:66–9.
18. Chen M, Shih JC, Wang BT, Chen CP, Yu CL. Fetal OK-432 pleurodesis: complete or incomplete? Ultrasound Obstet Gynecol 2005;26:791–3.
19. Katano M, Morisaki T. The past, the present and future of the OK-432 therapy for patients with malignant effusions. Anticancer Res 1998;18 (5D):3917–25.
20. Ogita S, Tsuto T, Nakamura K, Deguchi E, Tokiwa K, Iwai N. OK-432 therapy for lymphangioma in children: why and how does it work? J Pediatr Surg 1996;31:477–80.
21. Terashima M, Takagane A, Abe K, Kuboi M, Asahi H, Saito K. Changes of cytokine levels in ascitic fluid after intraperitoneal administration of OK-432 or CDDP [in Japanese]. Gan To Kagaku Ryoho 1994;21:2326–9.
22. Tsuchiya I, Kasahara T, Yamashita K, Ko YC, Kanazawa K, Matsushima K, et al. Induction of inflammatory cytokines in the pleural effusion of cancer patients after the administration of an immunomodulator, OK-432: role of IL-8 for neutrophil infiltration. Cytokine 1993;5:595–603.
23. Chen M, Chen CP, Shih JC, Chou HC, Yu CL, Wang BT, et al. Antenatal treatment of chylothorax and cystic hygroma with OK-432 in nonimmune hydrops fetalis. Fetal Diagn Ther 2005;20:309–15.
24. Tsukihara A, Tanemura M, Suzuki Y, Sato T, Tanaka T, Suzumori K. Reduction of pleural effusion by OK-432 in a fetus complicated with congenital hydrothorax. Fetal Diagn Ther 2004;19:327–31.
25. Devine PC, Malone FD. Noncardiac thoracic anomalies. Clin Perinatol 2000;27:865–99.
26. Pijpers L, Reuss A, Stewart PA, Wladimiroff JW. Noninvasive management of isolated bilateral fetal hydrothorax. Am J Obstet Gynecol 1989;161:330–2.
27. Ayida GA, Soothill PW, Rodeck CH. Survival in non-immune hydrops fetalis without malformation or chromosomal abnormalities after invasive treatment. Fetal Diagn Ther 1995;10:101–5.
28. Chao AS, Chung CL, Cheng PJ, Lien R, Soong YK. Thoracoamniotic shunting for treatment of fetal bilateral hydrothorax with hydrops. J Formos Med Assoc 1998;97:646–8.
29. Hamada H, Yasuoka M, Urushigawa K, Watanabe H, Sohda S, Kubo T. Successful treatment of primary fetal hydrothorax with hydrops by pleuroamniotic shunt placement. Arch Gynecol Obstet 2001;265:53–4.
30. Nicolaides KH, Azar GB. Thoraco-amniotic shunting. Fetal Diagn Ther 1990;5:153–64.
31. Picone O, Benachi A, Mandelbrot L, Ruano R, Dumez Y, Dommergues M. Thoracoamniotic shunting for fetal pleural effusions with hydrops. Am J Obstet Gynecol 2004;191:2047–50.
32. Rodeck CH, Fisk NM, Fraser DI, Nicolini U. Long-term in utero drainage of fetal hydrothorax. N Engl J Med 1988;319:1135–8.
33. Kuwabara Y, Sawa R, Otsubo Y, Yoneyama Y, Asakura H, Araki T, et al. Intrauterine therapy for the acutely enlarging fetal cystic hygroma. Fetal Diagn Ther 2004;19:191–4.
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