The detection of persistent cyanosis in the neonate can be difficult because of the changing physiology in the first several hours following delivery, but it is an important marker for a number of pathologies. Cyanosis, a blue discoloration of the skin, results from an increased concentration of reduced (deoxygenated) hemoglobin, typically about 3 g/dL, in the capillary bed. The amount of reduced hemoglobin is a function of the S-shape of the hemoglobin-dissociation curve, which is in turn influenced by the concentration of hemoglobin, the amount fetal hemoglobin present, abnormalities in the hemoglobin itself, and other physiologic parameters such as temperature, pH, and pCo₂. The actual percent oxygen saturation at which cyanosis becomes clinically evident is widely variable, depending on the factors mentioned above, but on average cyanosis is evident when the oxygen saturation less than low 80s. From a clinical standpoint, cyanosis results from either a reduction of arterial oxygen saturation, an increased extraction of oxygen at the capillary level, or an abnormality in the hemoglobin itself.

Focusing on pathologies that result in a reduced arterial oxygen saturation, the causes are straight-forward; either there is diminished oxygen exchange at the alveolar level or desaturated blood is bypassing the alveolus altogether. Diminished oxygen exchange in the alveolus can result from inadequate ventilation, obstruction to airway flow, or abnormalities in the alveolar wall that result in poor exchange of gases. Examples of the latter include pneumonia, meconium pneumonitis, pulmonary edema, and cystic fibrosis. Abnormalities that result in desaturated blood bypassing the alveolus include an intracardiac right-to-left shunt or an intrapulmonary shunts. Intracardiac shunts may result from either from cyanotic congenital heart disease (CHD) or pulmonary hypertension resulting in a right-to-left shunt at the ductal or intracardiac level. Intrapulmonary shunts can arise from an arteriovenous malformation or fistula, for example. The clinician most frequently is faced with distinguishing whether cyanosis is a result of pulmonary or cardiac disease but should remember that other less causes of cyanosis also exist.

As with any other diagnosis, details of the history may hold important clues as to the cause of cyanosis in the newborn. For instance, knowing whether there was meconium at delivery and the adequacy of airway suctioning in the delivery room can help to raise the suspicion of meconium aspiration syndrome and resulting pulmonary hypertension. Other perinatal history such as time of membrane rupture, presence of maternal fever, and maternal infectious disease history may increase the suspicion for neonatal pneumonia or sepsis. The onset of cyanosis may also be helpful. For instance, at 12 to 24 hours of life in the absence of other symptoms, cyanosis is may result from CHD that becomes evident when the patent ductus closes.