Serial amnioinfusions as a regenerative therapy for pulmonary hypoplasia in fetuses with intrauterine renal failure: rationale, techniques, and ethical considerations.

Serial Amnioinfusion as Regenerative Therapy for Pulmonary Hypoplasia in Fetuses With Intrauterine Renal Failure or Severe Renal Anomalies: Systematic Review and Future Perspectives.

Background. Fetuses with congenital diaphragmatic hernia (CDH) are at risk of death from pulmonary hypoplasia at birth.Objective. To determine the value of prenatal imaging parameters for predicting lethal pulmonary hypoplasia in fetuses with CDH.Search strategy. Relevant papers were identified by searching MEDLINE (1966–2008), EMBASE (1988–2008) and the Cochrane Library (2008 issue 3).Selection criteria. Selected studies examined diagnostic tests for the prenatal prediction of lethal pulmonary hypoplasia in fetuses with CDH. The primary outcome measure was perinatal survival.Results. Twenty-one studies fulfilled the entry criteria, of which six examined entirely unique heterogeneous parameters and the remaining 15 examined lung–head ratios (LHR) and/or the presence of liver in the fetal thorax. The strongest association was that of LHR ≥ 0.6 compared to <0.6 (OR: 17.02; 95% CI: 2.10–137.89), although more clinically relevant was that of LHR >1.0 (OR: 5.07; 95% CI: 2.94–8.74). The finding of liver in the fetal chest was a poor prognostic feature (survival OR: 0.32; 95% CI: 0.21–0.49).Conclusion. In CDH, LHR and the presence of liver in the fetal thorax may be a useful predictive indicator of perinatal survival. Future usage of developing techniques needs careful evaluation prior to usage to guide therapy.

The objective of our study was to evaluate the potential of the sonographic fetal lung volume-body weight ratio to predict neonatal deaths and pulmonary hypoplasia in fetuses with isolated congenital diaphragmatic hernia (CDH). Between January 2002 and December 2004, 40 fetuses with isolated CDH and 450 control subjects were prospectively evaluated in two centers. Fetal lung volumes were estimated on 3D sonography using the rotational technique and fetal weight on 2D sonography using the Hadlock equation. The ratio of sonographic fetal lung volume to body weight was calculated in each case and was correlated with neonatal deaths using the Mann-Whitney U test. Accuracies of the ratio in predicting neonatal deaths and pathologic diagnosis of pulmonary hypoplasia were also evaluated. The ratio of sonographic fetal lung volume to body weight is constant throughout gestation, with a mean value of 0.025. The ratio was significantly lower in neonates that died (median, 0.009; range, 0.004-0.021) than in those that survived (median, 0.011; range, 0.008-0.020) (p = 0.018). Pulmonary hypoplasia was suspected prenatally in 34 of 40 (85.0%) fetuses with CDH, in all cases of death (100%), and in seven of nine (77.8%) neonates that survived. At autopsy, pulmonary hypoplasia was diagnosed in 19 cases (86.4%). Accuracies of the ratio in predicting neonatal deaths and pulmonary hypoplasia were 64.5% (20/31) and 86.4% (19/22), respectively. The sonographic fetal lung volume-body weight ratio can be used more accurately to diagnose pulmonary hypoplasia than to predict neonatal deaths in fetuses with isolated CDH. Further studies are necessary to show the prevalence of pulmonary hypoplasia in fetuses with isolated CDH and its importance for predicting neonatal deaths.

The effects of prenatal intraamniotic surfactant or dexamethasone administration on lung development are comparable to changes induced by tracheal ligation in an animal model of congenital diaphragmatic hernia

Prediction of pulmonary hypoplasia in mid‐trimester preterm prelabor rupture of membranes: research or clinical practice?

Plain Language SummaryFetal renal failure in early pregnancy from congenital anomalies and/or absent kidneys leads to a complete lack of amniotic fluid, which critically impairs fetal lung development. Historically, this condition has been universally fatal. However, the technique of serial infusions of fluid into the amniotic cavity (amnioinfusions) to maintain fluid volumes in these pregnancies has the potential to allow for survival with subsequent management of neonatal end-stage renal disease and is being studied by the Renal Anhydramnios Fetal Therapy (RAFT) clinical trial. There are some risks involved with serial amnioinfusions, including preterm prelabor rupture of membranes, separation of the placental and amniotic membranes (chorioamniotic separation), infection, placental abruption, and preterm labor. This study investigated the performance of two different approaches for serial amnioinfusions through an analysis of amnioinfusions performed during one institution’s external pilot and feasibility phases of the RAFT trial. Procedural details, complications, and obstetric outcomes were compared between the two groups. The strategy of frequent, smaller volume, serial amnioinfusions was found to maintain amniotic fluid for a longer duration compared to less frequent, larger volume infusions. Obstetric complications were not increased when more amnioinfusions at smaller volumes were performed and allowed delivery to occur at a gestational age favorable for medical management of end-stage renal disease.

To gain insight into the role of the insulin-like growth factors (IGFs) in regulating lung development, we have used in situ hybridization histochemistry (ISHH) to examine the ontogeny and sites of expression of IGF-I and IGF-II, IGF binding proteins (IGFBP-1 to IGFBP-6), and IGF cell surface receptors in fetal rat lung from 15 to 21 days of gestation. Both IGF-I and IGF-II mRNAs were expressed throughout the developmental period studied with little change in apparent abundance. IGF-I mRNA localized to mesenchymal cells, especially those surrounding airway epithelium, while IGF-II mRNA, which was somewhat more abundant, localized predominantly to epithelia. The type 1 IGF receptor, the receptor that likely mediates the actions of both IGFs, was expressed widely in virtually all cells, whereas the expression of the type 2 IGF receptor, thought to be involved in IGF internalization and degradation, was confined to the mesenchyme and medial layers of intrapulmonary vessels. As with the IGFs, there was little apparent change in the abundance of IGF receptor mRNAs through fetal development, and the type 2 IGF receptor mRNA was more abundant. The expression of IGFBPs changed significantly during lung development. IGFBP-2, -3, -4, and -5 were expressed from day 15 of gestation, but their sites of expression and ontogeny differed. IGFBP-2 mRNA expression was abundant and constant throughout gestation and was confined to proximal and distal airway epithelia. IGFBP-3 and IGFBP-5 also were expressed by proximal airway epithelia, but also exhibited significant expression in interstitial mesenchyme and in mesenchyme surrounding vessels. The abundance of both increased as gestation progressed (IGFBP-5 greater than IGFBP-3). IGFBP-4 mRNA was confined to interstitial mesenchyme and its abundance peaked at days 16 to 19 of gestation. We found no evidence for expression of either IGFBP-1 or IGFBP-6. We conclude that the expression of IGF-I, IGF-II, and the type 1 IGF receptor throughout gestation in the lung supports a role for the IGFs in lung growth and development. The complex pattern of IGFBP expression (differing sites and ontogeny of expression) suggests that the IGFBPs modulate IGF actions at specific target sites. Furthermore, because there is little change in the expression of IGFs or IGF receptor mRNAs during fetal lung development, regulation of IGFBP expression may be essential to the control of IGF actions during lung development.

The role of Trop2 in fetal lung development

MRI and three dimensional ultrasonography in the assessment of pulmonary hypoplasia in fetuses with urinary tract anomalies

To review the most used tests for diagnosis of pulmonary hypoplasia, and their pertinence in different pathological conditions. The two-dimensional biometric parameters are not accurate enough to be applied in clinical practice, except for the lung-to-head ratio (LHR): the observed/expected LHR remains the best predictor of pulmonary hypoplasia in fetuses with congenital diaphragmatic hernia. The introduction of three-dimensional ultrasound tecniques has allowed to directly measure lung volume. Three-dimensional-derived nomograms seem reliable for the prediction of both normal and pathological pulmonary volumes. MRI is attracting increasing attention. The studies recently published on this method are highly heterogeneous; universally accepted standardized values for the prediction of pulmonary hypoplasia are, hence, not available. Finally, some authors proposed Doppler ultrasound velocimetry to detect changes in pulmonary vascularization that correlate to pulmonary hypoplasia. However, a well-defined test to predict pulmonary hypoplasia has not emerged so far. The prediction of the lethal type of pulmonary hypoplasia is pivotal to improve counseling and neonatal assistance. There is not a single test that can, at least for now, predict postnatal lung function. For different underlying pathologies, different combinations of clinical, ultrasound, and MRI parameters seem to better assess the risk of pulmonary hypoplasia.

Objective: To determine if the fetal peripheral pulmonary artery Doppler evaluation can predict the presence of lethal pulmonary hypoplasia in cases of congenital diaphragmatic hernia. Methods: Distal pulmonary artery Pulsatility Index (PI) was calculated in 13 pregnancies with congenital diaphragmatic hernia between 32 and 36 gestational weeks. Associated malformations were discarded by a normal second trimester ultrasound and a normal echocardiography in all cases except one presenting a coarctation of the aorta, this one was eliminated for the posterior data analysis. Associated chromosomal defects were also discarded by fetal kariotype in all cases. Other variables as the presence of polyhydramnios, the side of the hernia, the presence of stomach or liver herniation, the gestational weeks at diagnosis, the weight at birth and the newborn evolution were also recorded. All these variables were compared between the cases that died postnatally and the one’s that survive. Results: All deaths were attributable to pulmonary hypoplasia. The distal pulmonary artery PI was higher in the group that died than in the survivors (P < 0.01); with a mean of PI value of 2.64 (95% CI 2.51–2.76) in those dying and a mean of 2.05 (95% CI 1.71–2.39) in the survivors. All the other analysed values did not present differences between the two groups. Conclusions: Distal pulmonary artery Doppler PI may be useful in the prediction of lethal pulmonary hypoplasia in fetuses affected with congenital diaphragmatic hernia. These results agree with other author’s works which suggest lower pulmonary artery PI values in fetuses without risk of developing pulmonary hypoplasia, showing a low resistance vascular pulmonary bed.

Observed to expected lung area to head circumference ratio (O/E LHR) as an indicator for pulmonary hypoplasia in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT)

The purpose of the present study was to assess the value of biometric lung measurements for the diagnosis of severe fetal pulmonary hypoplasia by investigating whether a significant correlation between two-dimensional lung biometry measurements and autopsy findings could be established. This was a prospective study carried out between 1995 and 1997. Nomograms for normal fetuses of the anterior-posterior and transverse inner thoracic diameters, which describe the growth and shape of the lung, were used as a basis for diagnosis of pulmonary hypoplasia in fetuses at high risk of developing the condition (the fetuses had bilateral renal agenesis or multicystic kidneys; chronic PROM <25 gestational weeks or hydrothorax). Pregnancy was terminated by abortion or intrauterine death in 29/43 high-risk fetuses and autopsies were performed. Only the 29 fetuses for which there were autopsy findings were included in the study. The best plane for diagnosing pulmonary hypoplasia was the four-chamber view. The diagnostic accuracy for this view as expressed by the sensitivity was 57% for the anterior-posterior diameter and 44% for the transverse diameter; as expressed by the specificity it was 42% for the anterior-posterior diameter and 50% for the transverse diameter. The results for the four-chamber view for the various high-risk conditions were as follows: for fetuses with chronic PROM we obtained sensitivities of 75% and 50% (anterior-posterior and transverse dimensions, respectively) and specificities of 80% and 60% (anterior-posterior and transverse dimensions, respectively). The sensitivities of lung biometry in fetuses with hydrothorax were 1% and 80% for the two diameters, but there was a low specificity. In fetuses with bilateral renal agenesis or multicystic kidneys we obtained sensitivities of 36% and 30% (anterior-posterior and transverse dimensions, respectively) and a specificity of 50% (anterior-posterior dimension). The present results show that two-dimensional lung biometry is not a suitable method for antenatal detection of pulmonary hypoplasia. However, in individual cases with high risk for pulmonary hypoplasia, lung biometry might prove to be an additional diagnostic parameter.

Objective: The aim of this study was to assess the capacity of three-dimensional ultrasound (3DUS) for predicting lethality in fetuses with skeletal dysplasia.Methods: Twenty-four fetuses between 20 and 32 weeks of gestation were assessed. Bilateral lung volume scans were performed three times in each fetus during one ultrasound session. The virtual organ computer-aided analysis method was used to obtain a sequence of six sections of each lung around a fixed axis, and a rotation angle of 30° was adopted. Fetal lung volume measurements were analyzed according to the reference range. After birth, lung hypoplasia was diagnosed considering clinical and radiological criteria.Results: Of all cases of skeletal dysplasia, 18 (75%) were lethal. Among the lethal cases, after postnatal diagnosis, four were osteogenesis imperfecta type II, three were thanatophoric dysplasia and two were campomelic dysplasia. The remaining nine cases remained without a definitive diagnosis. The accuracy of 3DUS in predicting lethality in fetuses with skeletal dysplasia was high, with a sensitivity of 83.3%, specificity of 100%, positive predictive value of 100% and negative predictive value of 66.7%. The kappa index of 0.174 showed a good agreement between the possibility of lethality when the 3DUS volume measurement was altered and real lethality after birth (p < 0.001).Conclusion: This study suggests that the 3DUS lung volume measurement is a good predictor of lethal pulmonary hypoplasia in fetuses with skeletal dysplasia, with high accuracy.

Experience of balloon tracheal occlusion in secondary pulmonary hypoplasia in fetuses with congenital diaphragmatic hernia