Fetal Surgery for Severe Left Diaphragmatic Hernia

February 14, 2022

MANUSCRIPT CITATION

Deprest JA, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, Sago H, Johnson A, Wielgoś M, Berg C, Van Calster B, Russo FM; TOTAL Trial for Severe Hypoplasia Investigators. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. N Engl J Med 2021; 385:107-118. DOI: 10.1056/NEJMoa2027030. PMID: 34106556.

REVIEWED BY

Beth Godden
Neonatal Registrar
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia

Amy Keir
Consultant Neonatologist
Department of Neonatal Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia
Healthy Mothers, Babies and Children Theme, South Australian Health and Medical Institute, North Adelaide, South Australia
Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia

TYPE OF INVESTIGATION

Treatment

QUESTION

In fetuses with severe pulmonary hypoplasia due to isolated left-sided congenital diaphragmatic hernia (P), does fetoscopic endoluminal tracheal occlusion (FETO) (I) compared with expectant care (C) improve postnatal survival (O)?

METHODS

  • Design: Multicentre, parallel-group, superiority randomised control trial.
  • Randomisation: Women were randomly assigned, in a 1:1 ratio, to FETO or expectant care group, without stratification factors. Block randomisation was used for equal distribution per group at every analysis.
  • Allocation: Performed by a fetal medicine specialist using a purposely developed secure website.
  • Blinding: This was an open-label trial and was not blinded to participants or investigators.
  • Follow-up period: 6 months of age.
  • Setting: 10 FETO centres and 26 neonatal centres in Belgium, United Kingdom, France, Spain, Canada, Italy, Japan, United States, Germany, Netherlands, Switzerland, and Poland.
  • Patients: 80 participants with 40 in each group.
    • Inclusion criteria:
      • Maternal age ≥18 years
      • Singleton pregnancy
      • Gestational age at randomisation of less than 29+6
      • Left-sided congenital diaphragmatic hernia with no other major structural or chromosomal defects
      • Severe pulmonary hypoplasia, defined as <25% observed-to-expected lung-to-head ratio, irrespective of liver position
    • Exclusion criteria:
      • Maternal conditions that would make fetal surgery risky
      • Technical limitations precluding fetal surgery
      • Elevated risk of preterm birth
      • Psychological, socioeconomic, or other factors that might prevent adherence to protocol
  • Intervention: Fetoscopic endoluminal tracheal occlusion (FETO) versus expectant prenatal care. Fetoscopic placement of tracheal balloon was performed between 27+0 to 29+6 weeks gestation. Reversal of occlusion, either by fetoscopy or ultrasound-guided balloon puncture, was scheduled at 34+0 to 34+6 weeks gestation or was performed emergently in the case of imminent preterm birth. Both groups received standardised postnatal care according to international consensus guidelines.
  • Outcomes:
    • Primary outcome:
      • Survival to discharge from the neonatal intensive care unit (NICU)
    • Secondary outcomes:
      • Operative complications
      • Pregnancy complications
        • Preterm birth
      • Fetal survival
      • Survival to 6 months of age
      • Neonatal complications
  • Analysis: A group-sequential design and five interim analyses were used to allow for early stopping for superiority. The primary outcome was analysed using the z test for unpaired proportions according to the intention-to-treat principle. A secondary analysis was performed according to the per-protocol principle. Post hoc analyses were performed later to include participants who had undergone randomisation but for whom outcome data were not yet available at the time of the third interim analysis when the trial was stopped early for superiority.
  • Sample size: The sample size calculation was based on previous studies and assumed that survival to discharge from NICU would be 50% in the FETO group and 25% in the expectant care group. A total of 116 participants (58 in each group) would be required if the trial was not stopped early.
  • Patient follow-up: No patients were lost to follow up. One patient in the FETO group was excluded from the per-protocol analysis due to a genetic diagnosis leading to palliation. Two participants in the expectant care group were excluded from the per-protocol analysis due to the decision to terminate the pregnancy.

MAIN RESULTS

  • Primary outcome: The outcome of survival to discharge from NICU was significantly higher in the FETO group. Sixteen of the 40 infants (40%) in the FETO group and 6 of 40 infants (15%) in the expectant care group survived to discharge from NICU (relative risk 2.67; confidence interval 1.22 to 6.11; p=0.009). There were no significant differences in baseline characteristics between groups. The median quotient of the observed-to-expected lung-to-head ratio was the same in both groups (21%).
  • Secondary outcomes: Survival to 6 months of age was identical to survival to discharge from NICU. There were significantly higher preterm, prelabour rupture of membranes (PPROM) and preterm birth rates in the FETO group compared with the expectant care group. PPROM occurred in 19 of 40 women (47%) in the FETO group and 4 of 38 women (11%) in the expectant care group (relative risk 4.51; confidence interval 1.83 to 11.9). Preterm birth occurred in 30 of 40 women (75%) in the FETO group compared to 11 of 38 women (29%) in the expectant care group (relative risk 2.59; confidence interval 1.59 to 4.52). Two terminations of pregnancy in the expectant care group were excluded in this outcome. The median gestational age at delivery was 34 weeks 4 days in the FETO group and 38 weeks 3 days in the expectant care group. Despite the difference in gestation, there were no obvious differences in the rates of adverse neonatal outcomes related to prematurity; however, the trial was not powered for this secondary outcome. Notably, participants in the FETO group received steroids before balloon removal to assist with lung maturation.
  • Adverse events: There were two deaths in the FETO group related to the intervention. One case was secondary to a placental laceration from fetoscopic balloon removal. The other case was due to preterm birth at a local unit with no experience in FETO, where an attempt at postnatal balloon puncture was unsuccessful.
  • Additional results: Results for 71 eligible cases who were not randomised were also available. Of these cases, one was lost to follow up, and 28 underwent termination of pregnancy. Twenty-five cases had FETO outside the study protocol, and 17 had expectant management. Two in the FETO group and one in the expectant care group were lost to follow up. 9 of 23 infants (39%) in the FETO group and 5 of 16 infants (31%) in the expectant care group survived to discharge from NICU. The observed-to-expected lung-to-head ratio was slightly higher in the expectant care group (23%) compared to the FETO group (21%).

CONCLUSION

In fetuses with severe pulmonary hypoplasia due to isolated left-sided congenital diaphragmatic hernia, prenatal intervention with FETO resulted in significantly higher survival rates to discharge from NICU than expectant care. This improvement in survival was sustained at 6 months of age. However, there was a significant increase in preterm, prelabour rupture of membranes and preterm birth in the FETO group, with 4.5 times the risk of PPROM and 2.6 times the risk of preterm birth in the FETO group compared with the expectant care group.

COMMENTARY

Previous observational and small single centre randomised trials have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated left-sided congenital diaphragmatic hernia. The Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial, including the Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia (1) and the Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia (2), was designed to test this hypothesis.

The Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia (1) was an open-label, multicentre, parallel-group, superiority trial conducted in 10 FETO centres and 26 neonatal centres from February 2011 to March 2020. The trial was stopped early for efficacy after the third interim analysis and included 80 participants. The primary outcome, survival to discharge from NICU, was significantly higher in the FETO group compared to the expectant care group (40% vs 15%, relative risk 2.67; confidence interval 1.22 to 6.11; p=0.009) but was associated with a significantly increased risk of preterm, prelabour rupture of membranes (47% vs 11%; relative risk 4.51; confidence interval 1.83 to 11.9) and preterm birth (75% vs 29%; relative risk 2.59; confidence interval 1.59 to 4.52).

Limitations to the study include the lack of longer-term outcomes and insufficient power to assess the effect of preterm birth associated with FETO on neonatal conditions such as bronchopulmonary dysplasia. The results should only be applied to centres that are experienced in the use of FETO and cannot be generalised to centres with minimal experience in fetoscopy or without the resources to perform emergency balloon removal safely. The procedure may not be successful and can potentially cause both maternal and fetal complications. Spontaneous balloon deflation occurred in five cases and may be due to the device being “off-label” with the intended use for endovascular occlusion.

The survival rate in the expectant care group was 15% which is lower than other studies have previously reported (3). In the 71 cases that were eligible but not randomised, the survival rate in those who underwent expectant care was 31%. Considering this, the survival benefit shown in this study with the use of FETO may not be as significant if the survival rate in the expectant care group was not so low.

This trial was stopped early for efficacy after the third interim analysis as per the pre-specified stopping rules. It is well demonstrated that the early stopping of clinical trials is associated with larger treatment effect sizes than seen in randomised control trials not stopped early. This impact has been shown to be independent of the presence of statistical stopping rules and is greatest in smaller studies (4). Therefore, the significant increase in survival with the use of FETO seen in this trial may have been overestimated considering the potential bias of stopping early.

The Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia (2) was designed to compare FETO with expectant prenatal care in cases of moderate isolated left-sided congenital diaphragmatic hernia. FETO was performed later in this cohort, at 30 to 32 weeks gestation, to reduce the risk of premature birth. Sixty-two of the 98 infants (63%) in the FETO group and 49 of 98 (50%) in the expectant care group survived until discharge from NICU, which was not a statistically significant result (relative risk 1.23; confidence interval 0.99 to 1.63; two-sided p=0.06). This trial demonstrated no significant benefit of FETO in those fetuses with moderate pulmonary hypoplasia. FETO was associated with a similar increase in the risk of PPROM and preterm birth as with severe hypoplasia.

The results of the TOTAL trial have shown an improvement in survival with the use of FETO in infants with severe pulmonary hypoplasia due to isolated left-sided congenital diaphragmatic hernia, without a similar significant benefit seen in cases of moderate pulmonary hypoplasia. The use of FETO is associated with a significantly increased risk of PPROM and preterm birth and the potential risk of procedure-related adverse outcomes. Data regarding longer-term outcomes and prematurity related complications is lacking. Further studies are needed before this intervention should be routinely recommended.

REFERENCES

  1. Deprest JA, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, et al. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. New England Journal of Medicine. 2021;385(2):107-18.
  2. Deprest JA, Benachi A, Gratacos E, Nicolaides KH, Berg C, Persico N, et al. Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia. 2021;385(2):119-29.
  3. Deprest JA, Flemmer AW, Gratacos E, Nicolaides K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Seminars in fetal & neonatal medicine. 2009;14(1):8-13.
  4. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. Jama. 2010;303(12):1180-7.
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