Introduction

Congenital diaphragmatic hernia (CDH), despite the introduction of such postnatal interventions as high-frequency oscillation (HFO) and inhaled nitric oxide (iNO), still has a high mortality with survival rates of between 60 and 70 % [19, 20], although certain centres have reported greater than 90 % survival [4, 8]. As a consequence, antenatal interventions including foetal endoscopic tracheal occlusion (FETO) have been undertaken in foetuses with the worst prognosis. Meta-analysis of three randomised controlled trials (RCTs) demonstrated a significantly higher survival rate following FETO, but a significantly greater rate of premature delivery [17]. We [1] previously highlighted that mortality was greater in foetuses who underwent FETO and delivered prior to 35 weeks of gestation. FETO, as above, is performed in those with the worst prognosis. We, therefore, hypothesised that CDH infants who had undergone FETO compared to those who had not would have similar survival rates but suffer greater morbidity. An aim of this study was to test that hypothesis.

Various predictors of mortality or requirement for extracorporeal membrane oxygenation (ECMO) in infants with CDH have been reported. These include being born with very low birth weight, an absent or low 5-min Apgar score [3], the oxygenation index in the first 24 h [16, 18], the SNAP-II score and highest arterial carbon dioxide level (PaCO2) in the first 24 h, although the latter was not significant after multivariate adjustment [5]. Most studies, however, have not included infants who had been treated with FETO. Hence, we additionally wished to see which factors were associated with survival regardless of antenatal intervention.

Materials and methods

A retrospective review was undertaken of the case notes of infants with CDH without serious congenital or chromosomal abnormalities born at King’s College Hospital (KCH) NHS Foundation Trust between 2009 and 2014. This audit was approved by the King’s College Hospital NHS Foundation Trust Clinical Audit Support System and, as it was not a research project, did not require informed parental consent. KCH is a tertiary referral centre for CDH infants who might benefit from FETO; hence, our population includes CDH foetuses with the worst prognosis. Foetuses were eligible for FETO if they had a left CDH and lung to head ratio (LHR) ≤ 1.0 or a right-sided CDH with the liver in the chest. FETO occurred between 23 and 32 weeks of gestation depending on when the mothers were referred to the Fetal Assessment Centre at KCH. From 2013, if parental consent was given, CDH infants were entered into the tracheal occlusion to accelerate lung growth (TOTAL) trial which is a randomised trial (RCT) of FETO versus expected management during pregnancy in foetuses with left-sided isolated CDH. There were six infants recruited into the TOTAL trial in the time period of this study, their results have been excluded from our analyses.

FETO was performed by placing a thin-walled flexible Teflon cannula loaded with a custom-designed pyramidal trocar into the amniotic cavity through the abdominal and uterine walls and directed towards the foetal mouth. The trocar was then withdrawn and fetoscopic instruments, including an endoscope inserted. The endoscope was introduced into the foetal mouth, pharynx and epiglottis and advanced through the focal cords to identify the carina, and the catheter was positioned to deliver the balloon just above it. The procedure was usually performed under local anaesthesia [6]. Foetuses who did not undergo FETO had the same antenatal and postnatal management as the FETO group. Antenatal steroids were given to the FETO group at the time of balloon insertion if it was thought there was an increased risk of premature labour. In the non-FETO group, antenatal steroids were given if there was threatened premature labour before 34 weeks of gestation. The criteria to determine mode of delivery was the same in both groups, that is based on maternal and foetal health problems. Repair of the hernia was performed only when the infant’s respiratory and cardiovascular status had stabilise, that is, they no longer required high-frequency oscillation (HFO) or inhaled nitric oxide (iNO) (see below) and no inotropes other than low-dose dopamine. Infants all received neuromuscular blocking agents during ventilation. They were initially started on time-cycled, pressure-limited ventilation but transferred to HFO if they were difficult to ventilate/oxygenate. Infants were only considered for extracorporeal membrane oxygenation under unusual circumstances [9] and, in this series, no infant was referred for ECMO. Infants were started on iNO if they required more than 50 % supplementary oxygen and had at least a 10 % difference in the pre- and post-ductal oxygen saturations as per the unit’s protocol. Inotropes were commenced (dopamine first, then dobutamine added and then if necessary adrenaline) to achieve suprasystemic blood pressure in infants with evidence of pulmonary hypertension (diagnosed by differential pre/postductal saturations and/or echocardiography).

Data retrieved from the medical records included birth weight, gestational age at birth, the LHR at diagnosis and the last LHR before delivery. The maximum oxygen saturation in the delivery suite and the number in each group who had an oxygen saturation > 90 % in the delivery suite were also recorded. Oxygen saturation in the delivery suite was recorded from the right arm (i.e., preductal), and the inspired oxygen concentration increased as necessary to try and achieve an oxygen saturation of at least 90 %. Post-natally, the nurses recorded hourly on observation charts the type and amount of respiratory support and other treatments (such as inotropes and inhaled nitric oxide (iNO)) the infant received. All infants had indwelling arterial lines from which blood gases were sampled and the results recorded on the observation charts. From those records, the lowest (i.e., best) oxygenation index in the first 24 h after birth was calculated. In addition, the highest carbon dioxide (PaCO2) level in the first 24 h was noted. The durations of mechanical ventilation, supplementary oxygen and inotropic support were determined, as were the times to full enteral and full oral feeding. The type of hernia repair and the length of hospital stay were also documented.

Statistical analysis

The data were tested for normality using the Kolmogorov-Smirnov test and found to be not normally distributed. Differences between those who did and did not have FETO, therefore, were assessed for statistical significance using the Mann-Whitney U test or Chi-square test as appropriate. Analysis of outcomes was conducted unadjusted and after adjustment for gestational age, birth weight and antenatal steroids using logistic and linear regression analysis. Differences between infants who did and did not survive were assessed for statistical significance using the Mann-Whitney U and chi-squared tests as appropriate. The ability of variables to predict survival was assessed by using receiver operating characteristic curve (ROC) and calculating the area under the curve (AUROC). The analysis was performed using SPSS version 22.0 (SPSS, Inc., Chicago, IL).

Results

The results of 78 infants (including 43 who had undergone FETO) were analysed. Two of the 43 foetuses who underwent FETO had no change in their LHR post-FETO. Overall, five infants died in the labour suite (in the FETO group) as they could not be resuscitated. Nineteen infants in the FETO group and 13 in the non FETO group did not achieve cardiopulmonary stability and, therefore, did not undergo surgery (p = 0.67). Compared to non-FETO infants, the FETO infants had a lower median gestational age, birth weight and lung-to-head ratio at referral and were more likely to have been exposed to antenatal steroids and have had a patch repair (Table 1). The lung to head ratio prior to birth, however, did not differ significantly between the two groups, neither did the survival rate (p = 0.30). The mean duration of mechanical ventilation of the FETO infants was significantly longer than that of the non-FETO infants even after adjusting for gestational age, birth weight and antenatal steroid exposure (p = 0.007) (Table 2). Similarly, the duration of supplementary oxygen and the length of stay of the FETO infants were also significantly longer than that of the non-FETO infants (Table 2). The median times to full enteral feeds and full oral feeds of the FETO infants were significantly longer than those of the non-FETO infants. There was no statistically significant difference between the groups with regard to the duration of inotropic support. There were no significant differences between the two groups with regard to the lowest oxygenation index or the highest carbon dioxide level in the first 24 h.

Table 1 Patient characteristics according to treatment group
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Table 2 Infant outcomes according to treatment group
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Overall, lower gestational age, maternal age, and Apgar score at 5 min were associated with a significantly higher mortality risk (Table 3). A higher best oxygenation index and a highest carbon dioxide level in first 24 h were also associated with a significantly increased risk of mortality (Table 3). The strongest relationships with survival were observed with the oxygenation index in the first 24 h (AUROC = 0.876) and the carbon dioxide level in the first 24 h (AUROC = 0.772).

Table 3 Factors associated with survival
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Discussion

We have demonstrated that CDH infants who underwent FETO had significantly greater morbidity than those who did not undergo FETO, but the mortality did not differ significantly between the two groups. The majority of the FETO infants underwent a patch repair compared to the minority of the non-FETO infants, highlighting that the former infants had a larger diaphragmatic defect which likely contributed to their greater morbidity [11, 14, 15]. A patch repair has been associated with a higher mortality, longer duration of supplementary oxygen and greater need for supplementary oxygen at discharge [2, 14]. The FETO group was born significantly more prematurely; indeed, their median gestational age was 34 weeks compared to 38 weeks in the non-FETO group. More premature delivery in FETO infants has been well documented and is the consequence of complications related to balloon insertion [1, 12]. Gestational age at birth has been reported in FETO infants to be predictive of the durations of ventilation and supplementary oxygen and the age at full enteral feeds [7]. If delivery, however, took place after 34 weeks of gestation, neonatal morbidity of FETO cases was comparable with that of expectantly managed cases [7]. It is thus then not surprising our FETO infants required significantly longer durations of mechanical ventilation and supplementary oxygen and had other evidence of greater morbidity than the non-FETO infants, as they were born at a significantly earlier gestational age. A greater proportion of the FETO infants, however, had been exposed to antenatal steroids, it is likely then their longer durations of mechanical ventilation and supplementary oxygen reflect pulmonary maldevelopment as well as immaturity.

The FETO infants had a significantly lower LHR at referral than the non-FETO infants, and the majority were in the worst prognostic group [13]. The LHR prior to delivery, however, did not differ significantly between the two groups, reflecting the increase in LHR resulting from the FETO procedure. There were no significant differences in the proportions of infants in the two groups who underwent surgical repair, i.e., had attained cardiopulmonary stability, which again reflects their similar LHR prior to delivery. Thus, we speculate FETO increased survival but this was at the expense of increased morbidity, as they were a worse prognostic group at referral than the non-FETO infants.

In CDH patients, inotropic support is often given to treat pulmonary hypertension. We did not find any significant difference in the duration of inotropic support between the two groups, suggesting the severity of pulmonary hypertension did not differ between FETO and non-FETO infants. In one study [10], the prenatal LHR predicted pulmonary hypertension at 1 month, but not in the longer term, and the authors suggested their results indicated remodelling of the pulmonary vasculature over time. None of the infants included in that study had undergone FETO, and our results demonstrate in such patients and in those who had not undergone FETO, it is the LHR at referral prior to delivery which differs significantly according to death or survival.

We assessed a large range of perinatal factors with regard to their ability to predict survival. Several factors gave good discrimination (Table 3). The factors that had most discrimination were the best oxygenation index and highest carbon dioxide level in the first 24 h, gestational age at birth, and the Apgar score at 5 min. The best predictor, however, was the best oxygenation index (OI) with an AUROC of 0.876. In a previous study [16], the best oxygenation index in the first 24 h was shown to be a better predictor of survival than birth weight or gestational age in FETO and non-FETO infants.

This study has strengths and some limitations. We report a consecutive series of CDH infants, other than six infants who were entered into the TOTAL trial. The infants underwent management in a single centre with a standardised protocol. The number of infants delivered in the study period indicates KCH is a “high volume” centre. The data were collected retrospectively, and certain information was missing, for example, the mode of delivery and birth weight of the infants who did not survive to the neonatal unit, but as this only applied to five infants, we do not feel this impacted on our overall results. The study population reported received FETO on the basis of the LHR or the position of the liver; thus, we are not able to compare infants who had a low LHR and did undergo FETO with those that did. As shown in Table 1, all those who had a low LHR underwent FETO.

In conclusion, CDH infants who underwent FETO compared to those who did not had greater morbidity, but not mortality. This likely reflects that they were born significantly more prematurely and further emphasises the need to reduce premature delivery following FETO. In both FETO and non-FETO infants, the best OI in the first hours after birth gave the greatest discrimination with regard to survival.