Two studies from the Tracheal Occlusion to Accelerate Lung Growth (TOTAL) researchers have demonstrated when fetoscopic endoluminal tracheal occlusion (FETO) is beneficial for fetal hypoplasia, and when it is not.
The bottom line? FETO offers significant survival benefits when performed earlier (at 27-29 weeks), and in cases of severe—rather than moderate—pulmonary hypoplasia caused by congenital diaphragmatic hernia. Results from the two TOTAL studies—one in fetuses with moderate hypoplasia, and the second in those with severe hypoplasia—are published in The New England Journal of Medicine.
“The prevalence of congenital diaphragmatic hernia is approximately 1 in 4,000 births, and in 85% of cases, the defect is on the left side,” wrote lead author of both studies, Jan A. Deprest, MD, PhD, of University Hospitals KU Leuven, Belgium, and fellow investigators.
“In congenital diaphragmatic hernia, intrathoracic herniation of the abdominal viscera impairs normal airway and pulmonary vascular development. Consequently, the condition is associated with a high risk of neonatal death due to respiratory failure and pulmonary hypertension. Infants who survive may have serious health complications, including gastrointestinal and respiratory problems, orthopedic deformations and neurodevelopmental delay,” they added.
Thus, they conducted both trials—The TOTAL Trial for Moderate Hypoplasia and the TOTAL Trial for Severe Hypoplasia.
According to results from the TOTAL Trial for Moderate Hypoplasia, when performed at 30 to 32 weeks of gestation and compared with expectant care, FETO in fetuses with moderate congenital diaphragmatic left-sided hernia offered no significant benefits in increasing survival to discharge or the need for oxygen supplementation at 6 months. In addition, FETO in this population also increased the risks of preterm, prelabor membrane rupture in mothers, as well as preterm birth.
However, according to results from a second trial—the TOTAL Trial for Severe Hypoplasia— FETO brought about significant benefits compared with expectant care when performed at 27-29 weeks in fetuses with isolated, severe, left-sided congenital diaphragmatic hernia in survival to discharge, which was sustained to 6 months of age. The efficacy results were so compelling that this trial was stopped early after the third interim analysis.
In the TOTAL Trial for Moderate Hypoplasia, researchers randomized 196 women carrying singleton fetuses with a moderate isolated congenital left-sided diaphragmatic hernia to FETO at 30-32 weeks’ gestation or expectant care, both followed by standard postnatal care. The primary study outcome was infant survival to discharge from a NICU and survival without oxygen supplementation at 6 months.
In the intention-to-treat analysis, 63% of infants treated with FETO survived to discharge, compared with 50% in the expectant care group (RR: 1.27; 95% CI: 0.99-1.63; two-sided P=0.06). At 6 months of age, 54% versus 44% of infants, respectively, were alive without oxygen supplementation (RR: 1.23; 95% CI: 0.93-1.65).
Women in the FETO group, however, had a higher incidence of preterm, prelabor membrane rupture compared with those in the expectant care group (44% vs 12%, respectively; RR: 3.79; 95% CI: 2.13-6.91), as well as a higher incidence of preterm birth (64% vs 22%; RR: 2.86; 95% CI: 1.94-4.34). Researchers found no other associations between FETO and other serious maternal complications.
Two spontaneous fetal deaths occurred, one in each group, and these had no obvious cause. One neonatal death occurred as well and was associated with balloon removal.
In the second study, the TOTAL Trial for Severe Hypoplasia, researchers included 80 women in an intention-to-treat analysis and found that 40% of infants in the FETO group survived to discharge, compared with only 15% of those in the expectant care group (RR: 2.67; 95% CI: 1.22-6.11; two-sided P=0.009). Identical results were seen in survival to 6 months of age.
Again, women in the FETO group had a higher incidence of preterm, prelabor membrane rupture compared with those in the expectant care group (47% vs 11%; RR: 4.51; 95% CI: 1.83-11.9), as well as a higher incidence of preterm birth (75% vs 29%; RR: 2.59; 95% CI: 1.59-4.52).
One neonatal death occurred after emergency delivery due to placental laceration caused by fetoscopic balloon removal, and one occurred due to failed balloon removal.
Deprest and colleagues also did an analysis of 11 additional women after the trail was ended, and found a 36% survival to discharge in infants in the FETO group, and 14% in those in the expectant care group (RR: 2.65; 95% CI: 1.21-6.09).
“In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27-29 weeks of gestation resulted in a significant benefit over expectant are with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth,” concluded Deprest and colleagues.
Both trails have several limitations, including the lack of data beyond the 6-month time point, the small size of cohorts in both studies, and the lack of prospective genetic screening, wrote F. Sessions Cole, MD, of the Washington University School of Medicine and St. Louis Children’s Hospital, both in St. Louis, in an accompanying editorial. In addition, technical questions (diagnostic and surgical), as well as questions regarding technique, are raised in both studies, both diagnostically and surgically.
Nevertheless, these results will ultimately help inform clinicians and parents.
“If parents choose FETO, they should seek an experienced center, ideally one that is involved in collaborative research to reduce risks associated with FETO and to track short-term and long-term maternal, fetal, and infant outcomes. The lack of a significant survival benefit with FETO in fetuses with moderate pulmonary hypoplasia should prompt providers to encourage participation in additional randomized trials of FETO efficacy and outcomes and to avoid offering FETO outside such trials,” Cole wrote.
“The current reports serve as a critical basis for future studies to improve outcomes in pregnancies complicated by fetal congenital diaphragmatic hernia and in infants,” he concluded.
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In fetuses with isolated moderate congenital diaphragmatic hernia on the left side, FETO did not significantly increase survival of infants to NICU discharge or reduce the need for oxygen supplementation.
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In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO significantly increased survival to hospital discharge, which was sustained until 6 months of age, but increased risks of preterm prelabor membrane rupture and preterm birth.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
These studies were supported by grants from the European Commission, KU Leuven, Wellcome Trust, and the Engineering and Physical Sciences Research Council of the U.K, and the Unité de Recherche Clinique Paris Assistance Publique-Hôpitaux de Paris Center, Université de Paris Necker-Cochin, and from Assistance Publique-Hôpitaux de Paris.
Deprest has received grants from the European Commission during the conduct of this study and is a patron/member of patient organizations supporting families who have a member with Congenital Diaphragmatic Hernia, and is a member of the European Reference Network for CDH.
Cole has received person fees from and is a consultant for Centene Corporation, outside the submitted work.
Cat ID: 138
Topic ID: 85,138,730,191,41,138,192,195,925,159
