Fatal Vernix Caseosa Aspiration Associated With Persistent Pulmonary Hypertension of the Newborn

Introduction

Neonatal aspiration syndrome is a respiratory disease associated with fetal hypoxia. The most common cause is meconium aspiration syndrome (MAS) related to fetus-aspirated meconium-stained amniotic fluid (MSAF).^1,2 In addition to MSAF, vernix caseosa has been rarely associated with neonatal aspiration syndrome.^3,4 Our case herein is the third reported case of vernix caseosa aspiration confirmed by histopathological examination of the lung in the literature and the first associated with initial PPHN.

Case Report

A 39-week-gestation male neonate was born via cesarean section due to a breech presentation and fetal distress from a healthy 32-year-old mother under good antenatal care, with a birth weight of 2680 g, and Apgar scores of 2 and 2 at 1 and 5 minutes, respectively. The amniotic fluid was neither meconium stained nor showing a vernix caseosa appearance, and an unusual amount of vernix covering his skin was not observed. He was intubated immediately after birth due to grunting and central cyanosis and transferred to the neonatal intensive care unit. During intubation, vernix caseosa was not observed either in the oral cavity or endotracheal tube. Conventional mechanical ventilation was started, and the results of an initial arterial blood gas taken at 1 h of age were partial pressure of carbon dioxide (PaCO₂) of 112 mmHg, partial pressure of oxygen (PaO₂) of 70 mmHg, pH of 6.9, and base excess of −16 mmol/L. Therapeutic hypothermia with core temperature control of 34℃ was initiated, and phenobarbital was started to control subclinical convulsions due to abnormal electroencephalography. Chest radiography revealed reticulonodular infiltration in both lungs (Figure 1). Ampicillin and gentamicin were started for presumed sepsis after the work-ups. At 1 h of age, his clinical condition had deteriorated to severe refractory hypoxia without preductal and postductal pulse oximetry (SpO₂) difference (74%, and 71%, respectively). His respiratory support was changed to high-frequency oscillatory ventilation (HFOV). Serial arterial blood gas readings during these HFOV settings were PaCO₂ of 64 mmHg, PaO₂ of 35 mmHg, pH of 7.1, and base excess of −10 mmol/L. An echocardiogram done at 4 h of age confirmed the diagnosis of PPHN by showing moderate tricuspid regurgitation (pressure gradient 47 mmHg), bidirectional flow though a large foramen ovale and patent ductus arteriosus, without evidence of cyanotic heart disease. One hour following the PPHN diagnosis, he was started on inhaled nitric oxide (iNO) at an initial dose of 20 PPM. In accordance with the treatment protocol of our institution for severe PPHN with hypoxic refractory treatment, with oral administration of sildenafil, intravenous iloprost and intravenous milrinone, was initiated. Hemodynamic stability was maintained using dopamine, dobutamine, and epinephrine. Adequate sedation was achieved with fentanyl and midazolam. Unfortunately, he died at 26 h after birth due to severe PPHN.

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Figure 1.

An initial chest radiograph showing bilateral diffuse ground-glass opacity related to vernix caseosa aspiration. A postmortem biopsy was performed on tissue from the upper area of the right lower lobe of the lung (*).

After written informed consent from the boy’s parents was obtained, a postmortem lung biopsy was performed on a tissue sample from the upper area of the right lower lobe of the lung weighing 3 g and measuring 2.5 × 1.8 × 1 cm (Figure 1). Whitish material with smooth pleural surface was found (Figure 2(A)), and the later histopathological study of the lung found diffuse alveolar hemorrhage with a large amount of layered squames and keratin obstructing the segmental bronchi (Figure 2(B)) and alveoli (Figure 2(C)). There was evidence of smooth muscle hyperplasia in the intra-acinar pulmonary arteries (Figure 2(D)). No evidence of meconium was detected by mucin or Hall’s bilirubin staining, indicating an absence of mucus and bile in the lung tissue, respectively.

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Figure 2.

A, Lung tissue from the necropsy shows dilated bronchi (*) filled with a thick coating of vernix caseosa (arrow). B, The segmental bronchi (*) are plugged by layered squames with diffuse alveolar hemorrhage. H&E × 40. C, Airspaces in the alveoli are filled with impacted squames (*). H&E × 400. D, There is evidence of smooth muscle hyperplasia (arrow) in the intra-acinar pulmonary arteries (more than 30 µm external diameter). H&E × 100.

Discussion

Vernix caseosa is a white creamy substance covering the skin of the human fetus and newborn, consisting of an admixture of sebaceous glandular secretions, lanugo hair, and desquamated squamous cells, which is produced during the third trimester of gestation.^5,6 A large amount of vernix caseosa is occasionally present in the amniotic fluid and is probably aspirated in utero when a fetus gasps in response to fetal hypoxia.

Neonatal aspiration due to vernix caseosa has been previously reported only twice in the English literature. The first was a 1985 report by Ohlsson et al., ³ diagnosed by a substance identified as vernix caseosa seen in a suction tube placed in the trachea prior to the first breath of life. Immediate endotracheal and oral suction was applied to prevent the vernix caseosa moving into the deep respiratory airways. The newborn was given only oxygen therapy, physiotherapy with postural drainage, and regular suction of the nasopharynx. The treatment was successful, and the infant was discharged from hospital at 11 days of age. The other report was that of Nishijima et al. ⁴ in 2005 from Japan. The initial diagnosis in this case was made at birth when vernix caseosa was found in the oral cavity, following which suctioning and endotracheal intubation were immediately performed. The endotracheal tube was changed 7 times due to obvious vernix caseosa obstruction, and clinical desaturation was detected. The infant was only treated by mechanical ventilation and surfactant administration, but they were unable to save him and he died at 2 h of age. Although vernix caseosa aspiration syndrome was initially diagnosed immediately at delivery, histopathological examination of the lung was ordered to confirm the diagnosis, which reported vernix caseosa and layered keratins in the bronchi and bronchioli, similar to the results of our case (Figure 2(B)). In this Japanese case, antenatal ultrasonography before delivery had noted a diffused pattern of high-level echoes, but we believe that this finding cannot definitively be connected with the later vernix caseosa aspiration syndrome. In fact, the main constituents of amniotic fluid are water and electrolytes together with proteins, carbohydrates, lipids and phospholipids, urea, and vernix caseosa. ⁷ Both of these earlier cases found a substantial amount of vernix caseosa scattered in the amniotic fluid. Thus, we suggest as a diagnostic guideline that if a neonate develops respiratory distress immediately following birth, and with a chest radiograph positive likely to be MAS with notable vernix caseosa in the amniotic fluid, vernix caseosa aspiration syndrome should be considered in the differential diagnosis.

It is challenging to speculate concerning the exact etiology of vernix caseosa aspiration in our case. The infant’s birth weight was in the 6th percentile as determined by the Fenton growth chart, ⁸ which indicates that the fetus was not well, probably due to chronic placental insufficiency resulting in fetal stress, hypoxia, and acidosis. The gasping respiratory efforts that accompanied these distressing situations likely contributed to the entry of amniotic fluid containing squames, vernix caseosa, mucus, lanugo, blood, or meconium. The pulmonary abnormalities in MAS are related primarily to acute airway obstruction, decreased lung tissue, pulmonary surfactant inactivation, parenchymal lung damage due to meconium-related chemical effects, inflammatory responses, or apoptosis. ⁹ Although a definitive pathogenesis of vernix caseosa aspiration syndrome has not been proposed, we believe, based on similar clinical causes and chest radiography findings, that the development of this condition is probably similar to the development of MAS. Additionally, histopathological examination of the lung of our patient confirmed that complete mechanical obstruction was also present in the bronchus and bronchioles. About one-fourth of infants with MAS have development of PPHN which presents as a failure of systemic oxygenation because of marked pulmonary arterial hypertension secondary to an elevated pulmonary vascular resistance, altered pulmonary vasoreactivity due to smooth muscle hyperplasia at the pulmonary bed, or elevated endothelin-1 level.^10–13 Usually, MAS with right to left shunting contributes to the development of PPHN due to maladaptation with increased muscularization of pulmonary vasculature; in our case, we had evidence of thickening media of the small intraacinar pulmonary arteries indicating smooth muscle hyperplasia. Thus, it is likely that the arterial changes begin in utero. ¹⁴ Unfortunately, in this case a full standard autopsy was not performed due to the parents refusing to permit one, which is their right in Thailand, but because of this, we could not assess any medial thickening changes of the preacinar pulmonary arteries at the central origin of the lungs, or other possible abnormalities such as heart disease, pulmonary vasculature anomalies, or brain disease.

The prevalence of PPHN in developing countries remains high, approximately 2.8 per 1000 live births, compared to 1.9 per 1000 live births in developed countries.^15,16 The most common etiology of PPHN is still MAS, a condition which has different treatment approaches. ¹⁵ The main management for PPHN is inducing pulmonary vasodilatation, and in our case, we used several pulmonary vasodilators, notably iNO, intravenous milrinone, oral sildenafil, and intravenous iloprost, but the patient did not respond to any of these treatments. In recent years since we have been keeping records, almost one-third of infants with PPHN in our institute have died although we have modern treatments, such as HFOV or iNO. ¹⁷ We did not use the promising recent treatment for PPHN of extracorporeal membrane oxygenation, as this is not yet available in our institution. We believe that the most likely explanation for the death in our case is that vernix caseosa became diffusely dispersed over the respiratory airway resulting in ventilation and oxygenation failure. In terms of other treatments, surfactant therapy has also been reported as a successful treatment of secondary surfactant deficiency as a result of MAS, maternal blood aspiration, or severe pneumonia.^18,19 Celik et al. ²⁰ reported successful treatment in a preterm neonate with maternal blood aspiration syndrome; however, we do not believe secondary surfactant deficiency was a factor in our case.

In conclusion, this current case describes a rare case of vernix caseosa aspiration syndrome in a neonate. The definite diagnosis in such a case needs to be confirmed by the presence of vernix caseosa in the respiratory tract and/or histopathological examination. An autopsy or postmortem lung biopsy should be performed in fatal cases of unknown etiology of PPHN to find the exact cause of disease.