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Pulmonary hypoplasia associated with congenital heart diseases: a fetal study.

Ruchonnet-Metrailler I, Bessieres B, Bonnet D, Vibhushan S, Delacourt C - PLoS ONE (2014)

Bottom Line: Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age.CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH.

View Article: PubMed Central - PubMed

Affiliation: AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France.

ABSTRACT

Background: Abnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).

Objective: To determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment.

Methods: Between January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry.

Results: Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio <0.015 before 28 weeks, and <0.012 after 28 weeks, PH was detected in 15 of the 119 fetuses analyzed (13%). It was significantly associated with CHD with right outflow obstruction, independently of chromosomal abnormalities and associated extracardiac abnormalities (p<0.03). Right outflow obstruction was detected in 60% of the fetuses with CHD and PH, but in only 32% of those with CHD but no PH. In fetuses with right outflow obstruction, no difference was observed between those with PH and those without PH, in terms of the ratio of pulmonary artery diameter to aortic diameter, lung CD31 expression, or lung VEGF expression.

Conclusion: CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.

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CD31 immunohistochemistry.Original magnification×10, and ×40 magnification of the area identified by a rectangle. CD31 (brown) and counterstaining with hematoxylin. Fetuses with PH (A, C, E) were compared with fetuses of a similar gestational age without PH (B, D, F). A: Fetus with right ventricular hypoplasia and a septal defect, 18 weeks, LW/BW = 0.010; B: Fetus with pulmonary atresia and a septal defect, 16 weeks, LW/BW = 0.024; C: Fetus with tetralogy of Fallot, 22 weeks, LW/BW = 0.005; D: Fetus with an atrioventricular septal defect, 17 weeks, LW/BW = 0.027; E: Fetus with pulmonary atresia and tricuspid atresia, 36 weeks, LW/BW = 0.009; F: Fetus with tetralogy of Fallot, 33 weeks, LW/BW = 0.029.
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pone-0093557-g003: CD31 immunohistochemistry.Original magnification×10, and ×40 magnification of the area identified by a rectangle. CD31 (brown) and counterstaining with hematoxylin. Fetuses with PH (A, C, E) were compared with fetuses of a similar gestational age without PH (B, D, F). A: Fetus with right ventricular hypoplasia and a septal defect, 18 weeks, LW/BW = 0.010; B: Fetus with pulmonary atresia and a septal defect, 16 weeks, LW/BW = 0.024; C: Fetus with tetralogy of Fallot, 22 weeks, LW/BW = 0.005; D: Fetus with an atrioventricular septal defect, 17 weeks, LW/BW = 0.027; E: Fetus with pulmonary atresia and tricuspid atresia, 36 weeks, LW/BW = 0.009; F: Fetus with tetralogy of Fallot, 33 weeks, LW/BW = 0.029.

Mentions: We investigated whether the significant association between right outflow obstruction and PH was related to abnormalities of the pulmonary vascular bed. The diameters of the ascending aorta (Ao) and main pulmonary artery (PA) were available for 80 fetuses with CHDs, including 35 cases of CHD and right outflow obstruction. As expected, the PA/Ao ratio was significantly lower in the group of fetuses with CHD and right outflow obstruction, attesting for reduced PA diameters (Figure 2, p<0.0001). However, there was no correlation with PH in this subgroup. The median value of this ratio (IQR) was 0.50 (0.43–0.65) in fetuses with right outflow obstruction and PH (n = 9), versus 0.40 (0.37–0.50) in those without PH (n = 26). Similarly, we found no correlation between PA/Ao ratio and LW/BW value, expressed as a percentage of the predicted value (r = 0.06, p>0.7). We investigated the peripheral pulmonary vasculature in fetuses with right outflow obstruction by immunohistochemistry and CD31 labeling (Figure 3). PH was not associated with a low level of lung CD31 labeling. The median values of CD31-expressing cell density obtained by the point-counting method were 0.21 (0.19–0.26) for fetuses without PH, and 0.26 (0.18–0.38) for those with PH. We also analyzed expression of the key angiogenic factor VEGF (Figure 4). In the fetuses with the lowest gestational ages, VEGF was present in the branching airway epithelium and mesenchymal cells (Fig. 4 A–B). In the oldest fetuses (greatest gestational age), VEGF labeling was scattered, but was observed particularly in the distal epithelium and mesenchyme (Fig. 4 E–F). No reliable quantification was possible. No obvious difference in the pattern of VEGF expression was noted between fetuses with and without PHPH.


Pulmonary hypoplasia associated with congenital heart diseases: a fetal study.

Ruchonnet-Metrailler I, Bessieres B, Bonnet D, Vibhushan S, Delacourt C - PLoS ONE (2014)

CD31 immunohistochemistry.Original magnification×10, and ×40 magnification of the area identified by a rectangle. CD31 (brown) and counterstaining with hematoxylin. Fetuses with PH (A, C, E) were compared with fetuses of a similar gestational age without PH (B, D, F). A: Fetus with right ventricular hypoplasia and a septal defect, 18 weeks, LW/BW = 0.010; B: Fetus with pulmonary atresia and a septal defect, 16 weeks, LW/BW = 0.024; C: Fetus with tetralogy of Fallot, 22 weeks, LW/BW = 0.005; D: Fetus with an atrioventricular septal defect, 17 weeks, LW/BW = 0.027; E: Fetus with pulmonary atresia and tricuspid atresia, 36 weeks, LW/BW = 0.009; F: Fetus with tetralogy of Fallot, 33 weeks, LW/BW = 0.029.
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pone-0093557-g003: CD31 immunohistochemistry.Original magnification×10, and ×40 magnification of the area identified by a rectangle. CD31 (brown) and counterstaining with hematoxylin. Fetuses with PH (A, C, E) were compared with fetuses of a similar gestational age without PH (B, D, F). A: Fetus with right ventricular hypoplasia and a septal defect, 18 weeks, LW/BW = 0.010; B: Fetus with pulmonary atresia and a septal defect, 16 weeks, LW/BW = 0.024; C: Fetus with tetralogy of Fallot, 22 weeks, LW/BW = 0.005; D: Fetus with an atrioventricular septal defect, 17 weeks, LW/BW = 0.027; E: Fetus with pulmonary atresia and tricuspid atresia, 36 weeks, LW/BW = 0.009; F: Fetus with tetralogy of Fallot, 33 weeks, LW/BW = 0.029.
Mentions: We investigated whether the significant association between right outflow obstruction and PH was related to abnormalities of the pulmonary vascular bed. The diameters of the ascending aorta (Ao) and main pulmonary artery (PA) were available for 80 fetuses with CHDs, including 35 cases of CHD and right outflow obstruction. As expected, the PA/Ao ratio was significantly lower in the group of fetuses with CHD and right outflow obstruction, attesting for reduced PA diameters (Figure 2, p<0.0001). However, there was no correlation with PH in this subgroup. The median value of this ratio (IQR) was 0.50 (0.43–0.65) in fetuses with right outflow obstruction and PH (n = 9), versus 0.40 (0.37–0.50) in those without PH (n = 26). Similarly, we found no correlation between PA/Ao ratio and LW/BW value, expressed as a percentage of the predicted value (r = 0.06, p>0.7). We investigated the peripheral pulmonary vasculature in fetuses with right outflow obstruction by immunohistochemistry and CD31 labeling (Figure 3). PH was not associated with a low level of lung CD31 labeling. The median values of CD31-expressing cell density obtained by the point-counting method were 0.21 (0.19–0.26) for fetuses without PH, and 0.26 (0.18–0.38) for those with PH. We also analyzed expression of the key angiogenic factor VEGF (Figure 4). In the fetuses with the lowest gestational ages, VEGF was present in the branching airway epithelium and mesenchymal cells (Fig. 4 A–B). In the oldest fetuses (greatest gestational age), VEGF labeling was scattered, but was observed particularly in the distal epithelium and mesenchyme (Fig. 4 E–F). No reliable quantification was possible. No obvious difference in the pattern of VEGF expression was noted between fetuses with and without PHPH.

Bottom Line: Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age.CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH.

View Article: PubMed Central - PubMed

Affiliation: AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, Paris, France.

ABSTRACT

Background: Abnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).

Objective: To determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment.

Methods: Between January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry.

Results: Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio <0.015 before 28 weeks, and <0.012 after 28 weeks, PH was detected in 15 of the 119 fetuses analyzed (13%). It was significantly associated with CHD with right outflow obstruction, independently of chromosomal abnormalities and associated extracardiac abnormalities (p<0.03). Right outflow obstruction was detected in 60% of the fetuses with CHD and PH, but in only 32% of those with CHD but no PH. In fetuses with right outflow obstruction, no difference was observed between those with PH and those without PH, in terms of the ratio of pulmonary artery diameter to aortic diameter, lung CD31 expression, or lung VEGF expression.

Conclusion: CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.

Show MeSH
Related in: MedlinePlus