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Keywords:

  • congenital diaphragmatic hernia;
  • Doppler;
  • intrapulmonary artery;
  • neonatal morbidity;
  • O/E lung-to-head ratio

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Objective

To explore the potential value of intrapulmonary artery Doppler velocimetry in predicting neonatal morbidity in fetuses with left-sided congenital diaphragmatic hernia (CDH) treated with fetoscopic tracheal occlusion (FETO).

Methods

Observed/expected lung-to-head ratio (O/E-LHR), and intrapulmonary Doppler pulsatility index and peak early-diastolic reversed flow were evaluated within 24 h before FETO in a consecutive cohort of 51 fetuses with left-sided CDH at between 24 and 33 weeks' gestation. Lung Doppler parameters were converted into Z-scores and defined as abnormal if the pulsatility index had a Z-score of > 1.0 or the peak early-diastolic reversed flow had a Z-score of > 3.5. The association of O/E-LHR and Doppler velocimetry with neonatal outcome was assessed using multiple linear or logistic regression analysis adjusted for gestational age at birth.

Results

Among the 26 fetuses that survived, 18 (69.2%) had normal and eight (30.8%) had abnormal Doppler values. O/E-LHR was not associated with neonatal morbidity in surviving fetuses. Compared with the group with normal Doppler parameters, cases with abnormal intrapulmonary Doppler were associated with a significant increase in the duration of mechanical ventilation (average increase of 21.2 (95% CI, 9.99–32.5) days; P < 0.01), conventional ventilation (15.2 (95% CI, 7.43–23.0) days; P < 0.01), high-frequency ventilation (6.34 (95% CI, 0.69–11.99) days; P < 0.05), nitric oxide therapy (5.73 (95% CI, 0.60–10.9) days; P < 0.05), oxygen support (36.5 (95% CI, 16.3–56.7) days; P < 0.01), parenteral nutrition (19.1 (95% CI, 7.53–30.7) days; P < 0.01) and stay in neonatal intensive care unit (42.7 (95% CI, 22.9–62.6) days; P < 0.001), and with significantly higher rates of high-frequency ventilation (87.5 vs 44.4%;P < 0.05), oxygen requirement at 28 days of age (75.0 vs 11.1%; P < 0.01), gastroesophageal reflux (62.5 vs 22.2%; P < 0.05) and tube feeding at discharge (37.5 vs 5.56%; P < 0.05).

Conclusion

As previously reported, O/E-LHR did not predict neonatal morbidity. In contrast, intrapulmonary artery Doppler evaluation was predictive of neonatal morbidity in CDH fetuses treated with FETO.Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Isolated left congenital diaphragmatic hernia (CDH) is associated with a high risk of neonatal mortality and morbidity, mainly owing to pulmonary hypoplasia and/or hypertension[1-3]. In an attempt to improve postnatal survival and lower morbidity, therapy with fetoscopic tracheal occlusion (FETO) is offered in cases with estimated chances of poor neonatal survival, demonstrating an increment of around 25% in survival rate[4]. In spite of an overall improvement in outcomes, FETO is associated with huge variability in the pulmonary response after tracheal occlusion and in the degree of postnatal morbidity and mortality[5]. The identification of clinical predictors to refine individualized prognoses is on the agenda of many research groups and would be of great help in making clinical and patient decisions.

In terms of perinatal mortality, the best predictor of response to fetal therapy is lung area on the side contralateral to the hernia (measured as the lung area-to-head circumference ratio and expressed as a ratio between observed and expected-for-gestational-age value, O/E-LHR)[6, 7]. In addition, evaluation of the intrapulmonary circulation has been suggested as a promising predictor of neonatal prognosis in CDH[8-12]. Thus, recent studies suggest that abnormalities in lung Doppler velocimetry discriminate between cases with moderate to high survival rates and those with extremely low chances of survival after FETO[13].

Aside from mortality, information on the risks of serious postnatal morbidity might be of interest to patients when considering the option of prenatal therapy. While O/E-LHR has been shown to be a good predictor of neonatal morbidity among survivors managed expectantly[14], in a recent study it failed to predict morbidity in fetuses treated with FETO[15]. With respect to intrapulmonary Doppler, there are no studies evaluating its value as a predictor of morbidity after FETO.

In the present study we evaluated the ability of O/E-LHR and of intrapulmonary artery Doppler velocimetry to predict neonatal morbidity in survivors in a consecutive cohort of fetuses with left-sided CDH treated with FETO.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Subjects

A prospective cohort of singleton fetuses with confirmed isolated left CDH selected for intrauterine therapy with FETO at the Hospital Clinic, Barcelona, Spain was included in the study. Entry criteria for fetal surgery were CDH cases with O/E-LHR below 45% and intrathoracic liver herniation. None of the cases included in this study took part in any clinical trials. Exclusion criteria were presence of other congenital malformations, chromosomal abnormalities and neonatal mortality during follow-up. The protocol was approved by the hospital ethics committee and patients provided written informed consent (IRB 2009/5463).

Ultrasound and Doppler measurements

All ultrasound, including Doppler, examinations were performed within 24 h before FETO by one of two experienced examiners (R.C.M or O.M.A) using a Siemens Sonoline Antares ultrasound machine (Siemens Medical Systems, Malvern, PA, USA) with a 6–2-MHz linear curved-array transducer.

The lung contralateral to the side of the hernia was evaluated in a cross-sectional view of the fetal thorax at the level of the four-chamber view of the heart. Lung size was estimated using the two major perpendicular diameters of the lung, as previously described by Metkus et al.[16]. The expected LHR was calculated using normal reference ranges according to gestational age (GA) as:

E-LHR = –3.4802 + (0.3995×GA) – (0.0048×GA2)[17].

The observed value was compared with that expected for gestational age in order to calculate the O/E-LHR, expressed as a percentage.

Using color directional spectral Doppler, the proximal branch of the intrapulmonary artery in the lung contralateral to the side of the hernia was located. Spectral Doppler was applied and the characteristic pulmonary blood flow waveform was identified, as previously described by Laudy et al.[18, 19]. The Doppler sample volume (2 mm) was located close to the emerging most proximal branch of the intrapulmonary artery (Figure 1), with an angle of insonation as close to 0° as possible. A high-pass wall filter of 70 Hz was used to record slow-flow movements and to avoid sound artifacts. Doppler recordings including three similar good-quality waveforms were used for analysis. All studies were performed in the absence of fetal corporal or respiratory movements and, if required, with voluntary maternal suspended breathing. Mechanical and thermal indices were maintained below 1. Waveform analysis included pulsatility index and peak early-diastolic reversed flow. All values were converted into Z-scores according to previously reported normal ranges[10] and defined as abnormal if the pulsatility index Z-score was > 1.0 or the peak early-diastolic reversed flow Z-score was > 3.5[13].

image

Figure 1. Spectral Doppler images from the proximal branch of the intrapulmonary artery in cases with: (a) normal intrapulmonary impedance (pulsatility index, 3.65) and (b) abnormal intrapulmonary impedance (pulsatility index, 6.78). Note reduction in degree of flow during diastole and increased peak early-diastolic reversed flow (arrows), which was 10 cm/s in (a) and 32 cm/s in (b).

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Fetoscopic endoluminal tracheal occlusion

FETO was performed under combined spinal-epidural anesthesia and fetal analgesia as previously described[20, 21]. Briefly, a 1.2-mm endoscope within a 3.0-mm sheath (Karl Stortz, Tüttlingen, Germany) was introduced into the trachea to position a detachable balloon between the carina and the vocal cords. Ultrasound examination to confirm the endotracheal presence of the inflated balloon and to monitor lung growth by means of the O/E-LHR value was performed every week. Whenever preterm delivery was anticipated, a course of corticosteroids (betamethasone) was administrated and active tocolysis was attempted, unless contraindicated. The balloon was removed either prenatally, by fetoscopy or ultrasound-guided puncture, or by tracheoscopy at the time of delivery by ex-utero intrapartum technique[22].

Neonatal management

Postnatal therapy included a range of options from ventilator support to endotracheal intubation and mechanical ventilation, use of high-frequency ventilation (HFV), inhaled nitric oxide (INO) for refractory pulmonary hypertension, extracorporeal membrane oxygenation (ECMO) and surgical repair. The neonatologists were blinded to the prenatal Doppler status.

The following outcome measures were examined: duration of mechanical ventilation, conventional ventilation and oxygen requirement, use of ECMO, HFV and INO, need for supplementary oxygen for at least 28 days after birth, age at full enteral feeding, presence of gastroesophageal reflux, length of hospitalization in the neonatal intensive care unit and need for oxygen therapy or tube feeding at discharge. All survivors were followed until the age of 3 months.

Statistical analysis

Student's t-test and the Pearson chi-square test were used to compare quantitative and qualitative data, respectively. The value of the spectral Doppler parameters and O/E-LHR in predicting neonatal morbidity was evaluated by multiple linear or logistic regression analysis adjusted for gestational age at birth. Statistical calculations were performed using the Statistical Package for the Social Sciences software (SPSS 18.0, SPSS Inc., Chicago, IL, USA).

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

A total of 51 fetuses fulfilled the entry criteria. In all cases FETO was successfully performed and the overall mortality rate was 49.0% (25/51), leaving a final study population of 26 survivors. Table 1 shows the maternal and neonatal clinical characteristics of the study population. Among survivors, only one case required ECMO; 15 (57.7%) required HFV, eight (30.8%) required oxygen support at 28 days of age, nine (34.6%) showed gastroesophageal reflux and four (15.4%)needed tube feeding at discharge. The O/E-LHR values before FETO ranged from 17.7 to 40.5%. In addition, Doppler values before therapy were normal in 18 (69.2%) and abnormal in eight (30.8%) fetuses.

Table 1. Maternal and neonatal clinical characteristics of the study group of fetuses with left-sided congenital diaphragmatic hernia (CDH)
CharacteristicSurvivors (n = 26)Non-survivors (n = 25)P
  • Data given as mean (range) or n (%).

  • *

    Fifteen cases died before surgical correction. FETO, fetal endoscopic tracheal occlusion; GA, gestational age; N/A, not applicable; O/E, observed/expected; PPROM, preterm premature rupture of membranes.

GA at first scan (weeks)25.4 (19.4–30.3)24.3 (18.3–28.4)0.18
Maternal age (years)29.4 (18.0–39.8)29.5 (17.5–39.6)0.96
Primiparity12 (46.2)9 (36.0)0.46
Non-Caucasian ethnicity6 (23.1)3 (12.0)0.30
O/E lung-to-head ratio28.0 (17.7–40.5)27.0 (14.3–44.9)0.59
GA at FETO (weeks)29.4 (26.4–33.3)29.1 (26.0–32.9)0.61
Length of occlusion (days)28.2 (9–49)29.3 (9–69)0.78
GA at occlusion removal (weeks)33.4 (30.3–35.4)33.4 (28.6–36.4)0.99
PPROM10 (38.5)14 (56.0)0.21
GA at PPROM (weeks)33.7 (29.9–36.3)31.9 (28.3–35.0)0.08
Postnatal balloon removal1 (3.8)5 (20.0)0.07
Cesarean section6 (23.1)11 (44.0)0.11
GA at delivery (weeks)36.8 (32.7–40.4)35.2 (28.6–40.3)0.06
Birth weight (g)2584 (1680–4010)2280 (1100–3100)0.09
5-min Apgar score < 72 (7.7)9 (36.0)0.01
Neonatal age at CDH repair (days)2.0 (1–8)15.1 (1–63)< 0.01
Need for patch at surgical correction22/26 (64.6)8/10* (80.0)0.74
Extracorporeal membrane oxygenation1 (3.8)6 (24.0)0.04
Inhaled nitric oxide used12 (46.2)22 (88.0)< 0.01
High-frequency ventilation15 (57.7)23 (92.0)< 0.01
Neonatal age at extubation (days)16.6 (2–63)35.8 (2–64)0.03
Conventional ventilation (days)11.2 (1–38)5.5 (1–64)0.14
Oxygen therapy at 28 days8 (30.8)N/A
Gastroesophageal reflux9 (34.6)N/A
Time in neonatal intensive care unit (days)42.8 (12–120)18.1 (1–84)< 0.01
Tube feeding at discharge4 (15.4)N/A

While gestational age at birth was only significantly associated with the duration of conventional ventilation (P = 0.040) and oxygen support (P = 0.038), regression analysis adjusted for gestational age at birth showed no significant association between O/E-LHR and any of the analyzed outcomes, including days of mechanical ventilation (P = 0.28), conventional ventilation (P = 0.29), HFV (P = 0.96), INO therapy (P = 0.26), oxygen support (P = 0.06), parenteral nutrition (P = 0.83), length of stay in neonatal intensive care unit (P = 0.20), frequency of gastroesophageal reflux (P = 0.61), oxygen requirement at age 28 days (P = 0.86) or tube feeding at discharge (P = 0.49).

Table 2 shows the neonatal clinical characteristics of CDH cases with normal and abnormal intrapulmonary artery Doppler parameters. Cases with abnormal lung Doppler required significantly higher duration of mechanical ventilation, conventional ventilation, HFV, oxygen support, parenteral nutrition and longer stay in the neonatal intensive care unit. After adjustment for gestational age at birth, linear regression analysis showed that the group with abnormal intrapulmonary Doppler findings was significantly associated with an increase in the duration of: mechanical ventilation (average increase of 21.2 (95% CI, 9.99–32.5) days; P = 0.001), conventional ventilation (15.2 (95% CI, 7.43–23.0) days; P = 0.001), HFV (6.34 (95% CI, 0.69–11.99) days; P = 0.04), nitric oxide therapy (5.73 (95% CI, 0.60–10.9) days; P = 0.03), oxygen support (36.5 (95% CI, 16.3–56.7) days; P = 0.001), parenteral nutrition (19.1 (95% CI, 7.53–30.7) days; P = 0.002) and stay in neonatal intensive care unit (42.7 (95% CI, 22.9–62.6) days; P < 0.001) when compared with the group with normal intrapulmonary Doppler values.

Table 2. Fetal and neonatal clinical characteristics for congenital diaphragmatic hernia (CDH) survivors with normal and abnormal intrapulmonary artery Doppler velocimetry
CharacteristicNormal lung Doppler (n = 18)Abnormal lung Doppler (n = 8)P*
  • Results are expressed as mean ± SD or n (%).

  • *

    Student's t-test. FETO, fetal endoscopic tracheal occlusion; GA, gestational age; PPROM, preterm premature rupture of membranes.

GA at ultrasound (weeks)25.3 ± 3.125.6 ± 2.90.80
GA at FETO (weeks)29.2 ± 1.629.7 ± 2.10.54
Length of occlusion (days)29.1 ± 10.626.3 ± 9.90.53
GA at occlusion removal (weeks)33.4 ± 1.533.4 ± 1.80.93
PPROM5 (27.8)5 (62.5)0.09
GA at PPROM (weeks)34.4 ± 2.632.9 ± 1.20.28
GA at delivery (weeks)37.3 ± 2.435.5 ± 2.00.07
Birthweight (g)2630 ± 7382480 ± 4330.60
5-min Apgar score < 71 (5.6)1 (12.5)0.54
Neonatal age at CDH repair (days)1.7 ± 1.12.6 ± 2.40.20
Need for patch15 (83.3)7 (87.5)0.79
Oxygen support (days)19.7 ± 14.945.9 ± 33.70.01
Mechanical ventilation (days)11.4 ± 6.627.6 ± 19.2< 0.01
High-frequency ventilation (days)3.39 ± 4.98.63 ± 7.40.04
Conventional ventilation (days)7.53 ± 4.519.0 ± 13.6< 0.01
Inhaled nitric oxide (days)2.44 ± 4.95.88 ± 7.10.16
Parenteral nutrition (days)17.1 ± 7.133.9 ± 17.8< 0.01
Time in neonatal intensive care unit (days)31.2 ± 13.367.5 ± 32.4< 0.01

Figure 2 shows the frequency of adverse neonatal outcomes for CDH cases classified according to the presence or absence of abnormal intrapulmonary artery Doppler velocimetry. CDH fetuses with abnormal lung Doppler velocimetry had a significantly higher rate of HFV (87.5 vs 44.4%; P = 0.040), oxygen requirement at 28 days of age (75.0 vs 11.1%; P = 0.009), gastroesophageal reflux (62.5 vs 22.2%; P = 0.038) and tube feeding at discharge (37.5 vs 5.56%; P = 0.045) than those with normal intrapulmonary Doppler.

image

Figure 2. Frequency of adverse neonatal outcome for congenital diaphragmatic hernia survivors with normal (image) and abnormal (image) intrapulmonary artery Doppler velocimetry. *P < 0.05, adjusted for gestational age at birth by multiple logistic regression analysis.

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DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Clinical experience has demonstrated that there is wide individual variability in the response to FETO in human fetuses[4]. A subgroup of survivors still presents serious neonatal morbidity[5], mainly in the form of pulmonary but also with gastrointestinal complications. This study provides evidence that intrapulmonary artery Doppler velocimetry is an independent predictor of neonatal prognosis, discriminating a subgroup of CDH fetuses with liver herniation treated with FETO that is associated with decreased survival and increased neonatal morbidity.

The findings of the study in relation to the predictive value of O/E-LHR in fetuses treated with FETO are in agreement with a previous study in which O/E-LHR did not show any correlation with the likelihood of neonatal morbidity[15]. On the contrary, among CDH cases managed expectantly, Jani et al.[14] reported a significant negative correlation between O/E-LHR with days of assisted ventilation needed and the need for supplemental oxygen at 28 days. The discrepancy between reports with treated and untreated cases could be explained by differences in the population characteristics with respect to average O/E-LHR values. Thus, the study on expectantly managed cases included higher O/E-LHR values, ranging from 15 to 83%. Concerning the value of Doppler velocimetry, this is the first study on the prediction of morbidity, and therefore we cannot compare the findings with previous studies. However, Doppler velocimetry has previously been shown to add valuable information when used in combination with O/E-LHR for predicting mortality in fetuses treated with FETO[13]. In a recent study we demonstrated that, in fetuses with O/E-LHR below 26%, a combination of O/E-LHR with intrapulmonary Doppler helped to stratify the probability of survival. Among the small series of survivors, Doppler velocimetry did not appear to add any benefit in cases with O/E-LHR above 26%, since this subgroup was already associated with a mean survival rate of over 90% after FETO[13].

Previous studies have demonstrated that CDH is associated with profound changes in the pulmonary vasculature in the form of a decreased number of arterial branches and increased muscular thickness in the wall of the intrapulmonary vessels[23-25]. Vascular anomalies are thought to be the main reason for the high prevalence of pulmonary hypertension, which in many cases determines the degree of morbidity and mortality, more so than pulmonary insufficiency[24]. However, in human CDH, the degree of vascular changes, and consequently the severity of pulmonary hypertension, may show important individual variation, which seems not to be fully identifiable by lung size and O/E-LHR measurement. The present study showed that intrapulmonary artery Doppler predicted neonatal pulmonary morbidity in survivors after FETO, while O/E-LHR did not. These findings confirm previous studies that fetuses with similar lung sizes, as assessed by O/E-LHR, may present substantial differences in the intrapulmonary impedance as measured by Doppler, and possibly in the degree of primary vascular disease. Doppler studies add to the body of evidence suggesting that the diagnostic category of CDH includes several related diseases with various pathophysiological origins and a mixed component of mechanical lung compression with primary lung anomalies, which are not completely reflected in lung size.

Interestingly, Doppler velocimetry also predicted the prevalence of gastrointestinal complications. Gastroesophageal reflux disease requiring antacid medication is the major contributor to non-pulmonary neonatal morbidity in CDH. It has been reported in up to 40% of cases, of which 50% required antireflux medication at discharge[26, 27]. We hypothesize that the association of lung Doppler velocimetry with the risk of gastrointestinal morbidity could reflect an indirect association between the degree of pulmonary morbidity, which includes prolonged ventilatory support and use of a nasogastric tube, and the development of gastroesophageal reflux disease[26, 28, 29]. Aside from a direct relationship between therapeutic aggressiveness and consequent morbidity, the relationship between lung Doppler and gastroesophageal reflux could represent an example of the theory of gastric CO2 ventilation, which postulates coordination of respiratory and digestive control networks regulating CO2 elimination during respiratory acidosis, and which has been proposed to partially explain the frequent co-expression of pulmonary disease and chronic respiratory acidosis with gastroesophageal reflux disease[30].

From a clinical perspective, the results of this study, if confirmed by others, might be useful for counseling patients. Previous studies on CDH survivors with severe lung hypoplasia have shown a 40% risk of late gastroesophageal reflux disease, 25% risk of sensorineural hearing loss in childhood[31] and 30% risk of adverse neurodevelopment at 6–16 years of age[32]. Since such long-term morbidity is especially increased in cases with severe lung hypoplasia requiring prolonged respiratory support[29, 33, 34], lung Doppler abnormalities could assist in the identification of cases at highest risk and may be of help in making clinical and patient decisions.

This study has several limitations. Firstly, sample size was not sufficiently large to evaluate other associations such as the potential existence of differences in the use of ECMO. Secondly, since there was no control group we cannot establish comparisons with contemporary cases managed expectantly. Thirdly, we acknowledge that insonation of the fetal intrapulmonary vasculature is technically difficult. It requires training to achieve competence and strict criteria for acquisition in order to ensure reproducibility, and therefore its clinical use is not widely applicable. We have recently reported that lung Doppler velocimetry in CDH is reliable after a substantial number of examinations[35]. Once competence has been achieved, Doppler velocimetry can be performed in the proximal branch of the intrapulmonary artery with near zero angle on virtually all occasions and with a good degree of agreement between experienced examiners[10, 36].

In conclusion, the present study suggests a new clinical application of intrapulmonary artery Doppler velocimetry in the identification of survivors at the highest risk of neonatal morbidity. Integration of lung Doppler into clinical prognosis algorithms at the time of considering FETO could contribute to improving clinical management and to refining the design of future clinical trials.

ACKNOWLEDGMENTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The study was supported by grants from the Fondo de Investigación Sanitaria (FIS) of the Ministerio de Sanidad y Consumo with the grant PI 06/0585 and by EuroSTEC LSHB-CT-2006-037409. R.C.M. was supported by Marie Curie Host Fellowships for Early Stage Researchers, FETAL-MED-019707-2 and by the Mexican National Council for Science and Technology (CONACyT).

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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