Hydrops fetalis

Postmortem findings in the lungs of two siblings with nonimmune hydrops and lung hypoplasia are presented. In one, a girl, the hypoplasia was severe, with reduced numbers of airway generations and markedly reduced radial alveolar counts. In the other, a boy, the hypoplasia of both airway and alveolar development was mild. The reason for the difference in the growth of the lungs in these two children is unknown. The additional finding of Noonan's syndrome in the male sibling with mild hypoplasia and in the father is of interest.

Immune hydrops was common in the past due to Rh incompatibility, and its association with hypoplasia of the lungs has been reported.[1] Nonimmune hydrops is still frequently seen, and there are many causes and associations.[2-6] This report describes in detail the lungs of two siblings with nonimmune hydrops and hypoplasia of the lungs. These cases have additional interest in the fact that Noonan's syndrome was present in one of the siblings and also in the father (Fig 1).

CASE REPORTS

CASE 1

This female infant was delivered vaginally after 32 weeks of gestation to a 22-year-old gravida 2 para 1 mother. The fetal sonogram showed a hydropic baby with pleural effusions and ascites, but neither oligohydramnios nor polyhydramnios. The birth weight was 2,200 g. The Apgar score was 1 and 2 at one and five minutes. The infant was intubated, and pleural effusions were drained with chest tubes. She had pH of 6.8, [PCO.sub.2] of 100 mm Hg, and [PO.sub.2] of 13 mm Hg. The hemoglobin level was 13.8 g/dl, the hematocrit reading was 40.5 percent, total serum protein level was 2.6 g/dl, and the albumin level was 1.8 g/dl. The mother's blood type was AB, Rh(+); the baby was A, Rh(+). Coombs' test was negative. The infant was edematous, but not dysmorphic, and died at 12 hours of age.

The placenta was normal. At autopsy the infant had marked edema. Her weight was 2,000 g (normal, 1,488 [+ or -] 335 g).[7] There was 25 ml of serous ascites and 11 ml of pleural fluid. The heart weighed 12.4 g (normal, 11 [+ or -] 3.7 g)[7] and was normal. The lungs were hypoplastic. Together the inflated lung volume was 25 ml (normal, 50 ml)[8] and weighed 14 g (normal, 34 [+ or -] 11 g).[7] The ratio of lung weight to body weight was 0.007 (normal, 0.022 [+ or -] 0.002).[9] The pulmonary arteries were injected with a barium gelatin suspension at 73 mm Hg, and the lungs were inflated and fixed with 10 percent formalin at 23 cm [H.sub.2]O[8,10] (Fig 2). The posterior basal segment of the bronchial tree was dissected. There were 17 generations (normal mean, 21; maximum, 25;[11] our control, 22 to 23). The alveolar number was reduced, and the radial alveolar count was 1.4 [+ or -] 0.5 (normal, 3.2 [+ or -] 0.9).[12] Pulmonary arteries on the angiogram were narrower than normals matched for gestational age.[8] (Table 1). There was precocious muscularization of arteries accompanying respiratory bronchioles and increased adventitial collagen around the preacinar arteries. Intra-acinar arteries were of normal size[8] (Table 2). There was also increased collagen around pulmonary veins, which showed mild arterialization. The lymphatics were prominent and dilated. [TABULAR DATA OMITTED]

CASE 2

Twenty-one months later, a male sibling was born at 34 weeks of gestation by cesarean section. The sonogram showed polyhydramnios and a hydropic fetus with pleural effusions. The infant weighed 2,250 g. He had an Apgar score of 3 at one minute and 5 at five minutes. He was intubated, and chest tubes were inserted. His blood type was A, Rh(+). He had a pH of 7.14, [PCO.sub.2] of 86 mm Hg, and [PO.sub.2] of 20 mm Hg. The hemoglobin level was 17.8 g/dl, and the hematocrit reading was 51 percent; the serum total protein level was 3.4 g/dl, and the albumin level was 1.5 g/dl. The infant was markedly edematous with low-set ears, depressed nasal bridge, hypertelorism, micrognathia, and a short neck. The tests were small. He was placed on ECMO on the third day. An open lung biopsy on the seventh day revealed medial hypertrophy of pulmonary arteries with intimal proliferation (grade 2 Health-Edwards classification). No lymphangiectasia was present. After ten days on ECMO, the infant was weaned but died at 12 days of age.

The placenta was normal. Body weight at autopsy was 2,675 g (normal, 1,838 [+ or -] 530 g).[7] The facial characteristics were consistent with Noonan's syndrome. There were no pleural effusions. The heart was enlarged and weighed 23.8 g (normal, 13.4 [+ or -] 3.9 g).[7] There was right ventricular hypertrophy. The lungs together weighed 47.8 g (normal, 40 [+ or -] 13 g).[7] The increased weight was probably due to edema because the ratio of lung weight to body weight was low at 0.018 (normal, 0.022 [+ or -] 0.002).[9] Lung volume was not measured. The pulmonary arteries were injected, and the lungs were inflated. Bronchial generations were counted in the right and left lower lobes. The anterior segment of the right lower lobe had 18 generations (normal mean, 19; maximum, 24).[11] The posterior basal segment of the left lower lobe had 20 generations (normal mean, 21; maximum, 25).[11] Radial alveolar count was low normal at 2.7 [+ or -] 0.67 (normal, 3.2 [+ or -] 0.9).[12] The pulmonary arteries were slightly narrower than normal on the angiogram (Table 1). There was medial hypertrophy of the preacinar and intra-acinar arteries, with increased adventitial collagen. Intra-acinar arteries were of normal size, but there was precocious muscularization of arteries accompanying respiratory bronchioles (Table 2). The veins showed arterialization, with increased adventitial collagen, and the lymphatics were slightly dilated.

The family history of these two siblings was significant in that the father had Noonan's syndrome and pulmonary valvular stenosis. The first child of these parents was born two years before our first patient and also had Noonan's syndrome and pulmonary stenosis, but no hydrops at birth. Both the father and the first son underwent successful pulmonary valvotomy and are well.

DISCUSSION

The causes or associations of nonimmune hydrops fetalis are numerous. In Turner's and Noonan's syndromes, the suggested pathogenesis of hydrops is abnormal lymphatic system and interference in drainage of chyle.[5,6] Our patient 2 had Noonan's syndrome, but pulmonary lymphangiectasia was not severe and was probably not the cause of hydrops.

The lungs of six hydropic babies who died following Rhesus isoimmunization all showed pulmonary hypoplasia, but the severity varied.[1] Whereas airway growth was affected in all, alveolar differentiation was reduced in only two. It was therefore proposed that isoimmunization somehow affected the development of the lungs in the first 16 weeks of gestation when active airway branching occurs. Our patient 1 had severe pulmonary hypoplasia, with both airway and alveolar number reduction,[9,11,13] causing a marked decrease in total alveolar number. These findings suggest an interference in the growth of the lungs beginning early and continuing throughout gestation. In patient 2, pulmonary hypoplasia was mild, and both airway number and acinar development were minimally affected. The striking differences in the severity of pulmonary hypoplasia in these two infants, both of whom had a similar degree of hydrops as judged by their birth weight, suggests that the pulmonary hypoplasia was probably not produced solely by the physical effect of small intrathoracic space due to pleural effusion and ascites. It is possible that humoral factors such as those proposed in immune hydrops played a role. This concept supports the finding in both patients of precocious muscularization of intra-acinar arteries, a process indicative of maldevelopment in utero, as seen in other entities.[14,15] By contrast, in infants with immune hydrops, there was no precocious muscularization of intra-acinar arteries, even through the pulmonary arteries were small and the numbers reduced commensurate with the reduction in airway number.

The familial occurrence of nonimmune hydrops in our patients is intriguing. In a previous report of three siblings in a family with nonimmune hydrops,[2] it was ascribed to abnormal placentation; however, in our children, the placentas were normal. From our observation, it appears that while hydrops and pulmonary hypoplasia could be etiologically related, the role of Noonan's syndrome in hydrops and pulmonary hypoplasia is less certain; however, the possible association of hydrops and abnormal lung development in families with Noonan's syndrome needs to be considered.

REFERENCES

[1] Chamberlain D, Hislop A, Hey E, Reid L. Pulmonary hypoplasia in babies with severe Rhesus isoimmunization: a quantitative study. J Pathol 1977; 122:43-52

[2] Etches PC, Lemons JA. Nonimmune hydrops fetalis: report of 22 cases including three siblings. Pediatrics 1979; 64:326-32

[3] Hutchison AA, Drew JH, Yu VYH, Williams ML, Fortune DW, Beischer NA, et al. Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol 1982; 59:347-52

[4] Holzgreve W, Curry CJR, Golbus MS, Callen PW, Filly RA, Smith JC, et al. Investigation of nonimmune hydrops fetalis. Am J Obstet Gynecol 1984; 150:805-12

[5] McGillivray BC, Hall JG. Nonimmune hydrops fetalis. Pediatr Rev 1987; 9:197-202

[6] Bawle EV, Black V. Nonimmune hydrops fetalis in Noonan's syndrome. Am J Dis Child 1986; 140:758-60

[7] Schulz DM, Giordano DA, Schulz DH. Weights of organs of fetuses and infants. Arch Pathol 1962; 74:244-50

[8] Hislop A, Reid L. Intra-pulmonary arterial development during fetal life: branching pattern and structure. J Anat 1972; 113:35-48

[9] Reale FR, Esterly JR. Pulmonary hypoplasia: a morphometric study of the lungs of infants with diaphragmatic hernia, anencephaly, and renal malformations. Pediatrics 1973; 51:91-6

[10] Hislop A, Reid L. Pulmonary arterial development during childhood: branching pattern and structure. Thorax 1973; 28: 129-35

[11] Bucher U, Reid L. Development of the intrasegmental bronchial tree: the pattern of branching and development of cartilage at various stages of intrauterine life. Thorax 1961; 16:207-18

[12] Emery JL, Mithal A. The number of alveoli in the terminal respiratory unit of man during later intrauterine life and childhood. Arch Dis Child 1960; 35:544-47

[13] Askenazi SS, Perlman M. Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis. Arch Dis Child 1979; 54:614-18

[14] Haworth SG, Reid LM. Quantitative structural study of pulmonary circulation in the newborn with aortic atresia, stenosis, or coarctation. Thorax 1977; 32:121-28

[15] Murphy JD, Rabinovitch M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 1981; 98:962-67

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