提示: 手机请竖屏浏览!

胎儿左侧重度膈疝手术的随机试验
Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia


Jan A. Deprest ... 妇产科和儿科 • 2021.07.08
NEJM 动画解读

胎儿左侧重度膈疝手术

摘要


背景

观察性研究表明,在孤立性先天性左侧膈疝导致重度肺发育不全的婴儿中,胎儿镜下气管腔内阻塞术(FETO)与生存率提高相关,但目前缺乏随机试验数据。

 

方法

此项开放标签试验在具备FETO和其他类型产前胎儿手术经验的治疗中心开展,我们以1∶1的比例将单胎妊娠,且胎儿患孤立性先天性左侧重度膈疝的孕妇随机分组,两组分别在妊娠27~29周接受FETO治疗或期待治疗。两种治疗后均应用标准化出生后治疗方案。主要结局是婴儿存活至离开新生儿重症监护病房(NICU)。我们应用了成组序贯设计,对优效性进行5次预设的期中分析,最大样本量为116名孕妇。

 

结果

完成第3次期中分析后,本试验因观察到疗效而提前终止。在包括80名孕妇的意向治疗分析中,FETO组40%的婴儿(16/40)存活至离开NICU,而期待治疗组为15%(6/40)(相对危险度,2.67;95%置信区间[CI],1.22~6.11;双侧P=0.009)。存活至6月龄的婴儿比例与存活至离开NICU的婴儿比例相同(相对危险度,2.67;95% CI,1.22~6.11)。FETO组孕妇的未足月胎膜早破(47% vs. 11%;相对危险度,4.51;95% CI,1.83~11.9)和早产(75% vs. 29%;相对危险度,2.59;95% CI,1.59~4.52)发生率高于期待治疗组孕妇。1例新生儿死亡发生于因胎儿镜下取出球囊导致胎盘撕裂而紧急分娩后,1例新生儿死亡的原因是取出球囊失败。在增加11名参与者(我们在试验终止后获得了这些参与者的数据)的一项分析中,FETO组婴儿存活至离开NICU的比例为36%,期待治疗组的比例为14%(相对危险度,2.65;95% CI,1.21~6.09)。

 

结论

在患孤立性先天性左侧重度膈疝的胎儿中,在婴儿存活至离开NICU方面,在妊娠27~29周行FETO与期待治疗相比有显著益处,而且这一益处在婴儿6月龄时仍持续。FETO增加了未足月胎膜早破和早产的风险(由欧洲委员会[European Commission]等资助,TOTAL在ClinicalTrials.gov注册号为NCT01240057)。





作者信息

Jan A. Deprest, M.D., Ph.D., Kypros H. Nicolaides, M.D., Alexandra Benachi, M.D., Ph.D., Eduard Gratacos, M.D., Ph.D., Greg Ryan, M.D., Nicola Persico, M.D., Ph.D., Haruhiko Sago, M.D., Ph.D., Anthony Johnson, M.D., Mirosław Wielgoś, M.D., Ph.D., Christoph Berg, M.D., Ph.D., Ben Van Calster, Ph.D., and Francesca M. Russo, M.D., Ph.D. for the TOTAL Trial for Severe Hypoplasia Investigators*
From the Department of Obstetrics and Gynecology, KU Leuven (J.A.D., F.M.R.) and Academic Department of Development and Regeneration, Biomedical Sciences, University Hospitals KU Leuven, Leuven, Belgium (J.A.D., B.V.C., F.M.R.); King’s College Hospital (K.H.N.) and the Institute for Women’s Health, University College London Hospital (J.A.D.) — both in London; Hospital Antoine–Béclère, Université Paris–Saclay, Clamart, France (A.B.); Hospital Clinic and Sant Joan de Déu, Barcelona (E.G.); Mount Sinai Hospital, Toronto (G.R.); Hospital Maggiore Policlinico, Milan (N.P.); the National Center for Child Health and Development, Tokyo (H.S.); Children’s Memorial Hermann Hospital, Houston (A.J.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and University Hospital Bonn, Bonn, Germany (C.B.). Address reprint requests to Dr. Deprest at the Academic Department of Obstetrics and Gynecology, University Hospitals KU Leuven, and Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium, or at jan.deprest@uzleuven.be. *The TOTAL Trial for Severe Hypoplasia Investigators are listed in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv Exp Med Biol 2010;686:349-364.

2. Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia: epidemiology and outcome. Clin Perinatol 1996;23:671-688.

3. Ameis D, Khoshgoo N, Keijzer R. Abnormal lung development in congenital diaphragmatic hernia. Semin Pediatr Surg 2017;26:123-128.

4. Harting MT, Lally KP. The Congenital Diaphragmatic Hernia Study Group registry update. Semin Fetal Neonatal Med 2014;19:370-375.

5. American Academy of Pediatrics Section on Surgery, American Academy of Pediatrics Committee on Fetus and Newborn, Lally KP, Engle W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics 2008;121:627-632.

6. Raval MV, Wang X, Reynolds M, Fischer AC. Costs of congenital diaphragmatic hernia repair in the United States — extracorporeal membrane oxygenation foots the bill. J Pediatr Surg 2011;46:617-624.

7. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-152.

8. Jani J, Nicolaides KH, Keller RL, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol 2007;30:67-71.

9. Done E, Debeer A, Gucciardo L, et al. Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracheal occlusion era: a single-center study. Fetal Diagn Ther 2015;37:24-32.

10. Jani JC, Benachi A, Nicolaides KH, et al. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol 2009;33:64-69.

11. Doné E, Gratacos E, Nicolaides KH, et al. Predictors of neonatal morbidity in fetuses with severe isolated congenital diaphragmatic hernia undergoing fetoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2013;42:77-83.

12. Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993;28:1433-1440.

13. Khan PA, Cloutier M, Piedboeuf B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am J Med Genet C Semin Med Genet 2007;145C:125-138.

14. Evrard VA, Verbeken EA, Vandenberghe K, Lerut T, Flageole H, Deprest JA. Endoscopic in utero tracheal plugging in the fetal lamb to treat congenital diaphragmatic hernia. J Am Assoc Gynecol Laparosc 1996;3:Suppl:S11-S11.

15. Benachi A, Dommergues M, Delezoide AL, Bourbon J, Dumez Y, Brunnelle F. Tracheal obstruction in experimental diaphragmatic hernia: an endoscopic approach in the fetal lamb. Prenat Diagn 1997;17:629-634.

16. Davey M, Shegu S, Danzer E, et al. Pulmonary arteriole muscularization in lambs with diaphragmatic hernia after combined tracheal occlusion/glucocorticoid therapy. Am J Obstet Gynecol 2007;197(4):381.e1-381.e7.

17. Flageole H, Evrard VA, Piedboeuf B, Laberge JM, Lerut TE, Deprest JA. The plug-unplug sequence: an important step to achieve type II pneumocyte maturation in the fetal lamb model. J Pediatr Surg 1998;33:299-303.

18. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000;183:1059-1066.

19. Deprest J, Gratacos E, Nicolaides KH. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24:121-126.

20. Jani JC, Nicolaides KH, Gratacós E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009;34:304-310.

21. Reiss I, Schaible T, van den Hout L, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354-364.

22. Snoek KG, Reiss IKM, Greenough A, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus — 2015 update. Neonatology 2016;110:66-74.

23. Deprest JA, Benachi A, Gratacos E, et al. Randomized trial of fetal surgery for moderate left diaphragmatic hernia. N Engl J Med 2021;385:119-129.

24. Dekoninck P, Gratacos E, Van Mieghem T, et al. Results of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia and the set up of the randomized controlled TOTAL trial. Early Hum Dev 2011;87:619-624.

25. Engels AC, DeKoninck P, van der Merwe JL, et al. Does website-based information add any value in counseling mothers expecting a baby with severe congenital diaphragmatic hernia? Prenat Diagn 2013;33:1027-1032.

26. Van der Veeken L, Russo FM, De Catte L, et al. Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia. Gynecol Surg 2018;15:9-9.

27. Jiménez JA, Eixarch E, DeKoninck P, et al. Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia. Am J Obstet Gynecol 2017;217(1):78.e1-78.e11.

28. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869-c869.

29. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-556.

30. Dimairo M, Pallmann P, Wason J, et al. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ 2020;369:m115-m115.

31. Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916-1924.

32. Peralta CFA, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2005;26:718-724.

33. Ruano R, Yoshisaki CT, da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2012;39:20-27.

34. Jani JC, Nicolaides KH. Fetal surgery for severe congenital diaphragmatic hernia? Ultrasound Obstet Gynecol 2012;39:7-9.

35. Al-Maary J, Eastwood MP, Russo FM, Deprest JA, Keijzer R. Fetal tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of survival. Ann Surg 2016;264:929-933.

36. Grivell RM, Andersen C, Dodd JM. Prenatal interventions for congenital diaphragmatic hernia for improving outcomes. Cochrane Database Syst Rev 2015;11:CD008925-CD008925.

37. Araujo Júnior E, Tonni G, Martins WP, Ruano R. Procedure-related complications and survival following fetoscopic endotracheal occlusion (FETO) for severe congenital diaphragmatic hernia: systematic review and meta-analysis in the FETO era. Eur J Pediatr Surg 2017;27:297-305.

38. Alfaraj MA, Shah PS, Bohn D, et al. Congenital diaphragmatic hernia: lung-to-head ratio and lung volume for prediction of outcome. Am J Obstet Gynecol 2011;205(1):43.e1-43.e8.

39. Snoek KG, Capolupo I, van Rosmalen J, et al. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (the VICI-trial). Ann Surg 2016;263:867-874.

40. Gregoir C, Engels AC, Gomez O, et al. Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia. Hum Reprod 2016;31:2024-2030.

41. Sacco A, Van der Veeken L, Bagshaw E, et al. Maternal complications following open and fetoscopic fetal surgery: a systematic review and meta-analysis. Prenat Diagn 2019;39:251-268.

服务条款 | 隐私政策 | 联系我们