Results

Of 36 term neonates with Down’s syndrome consecutively born between 1989 and 1998, one with direct Coombs’ positive ABO isoimmunisation, and one with both G-6-PD deficiency and maternal diabetes, were excluded from the survey. Therefore, a total of 34 Down’s syndrome neonates were reviewed. The mean (SD) gestational age of these neonates was 39 (1) weeks, and birthweight 2956 (367) g. The male:female ratio was 12:22. Seventeen were being breastfed. Nineteen of the 34 (55.9%) Down’s syndrome neonates developed a peak serum total bilirubin > 256 μmol/l during the first week of life. The mean maximal serum total bilirubin of the hyperbilirubinaemic neonates was 284 (20) μmol/l, although institution of phototherapy in 18 of these probably modified the peak serum bilirubin values. Serum total bilirubin values in the one infant who did not receive phototherapy peaked at 256 μmol/l. Age at the maximal noted serum total bilirubin in the hyperbilirubinaemic Down’s syndrome neonates was 77 (21) hours. Gestational age and birthweight of the subgroup of Down’s syndrome neonates who developed hyperbilirubinaemia were not significantly different from the entire cohort (38.9 (1.0) weeks and 2900 (374 g), respectively). Only one neonate in this subgroup had a gestational age <38 weeks. Fifty three per cent of the hyperbilirubinaemic babies were breastfeeding.

Clinical details for the subset of consecutively born Down’s syndrome neonates in whom COHb determinations were performed, and 32 controls, are summarised in table 1. Twenty Down’s syndrome neonates were studied, but as the COHbc value of one of these neonates was exceptionally high (3.75%, equivalent to mean ± 10 SD), with a simultaneously drawn serum total bilirubin value of 171 μmol/l), this baby was regarded as an outlier and excluded from the analysis. The Down’s syndrome subset therefore includes 19 neonates. Table 1 shows that the risk of neonates of this Down’s syndrome subset developing hyperbilirubinaemia was significantly increased compared with controls. All 10 Down’s syndrome neonates and six of the seven controls who became hyperbilirubinaemic received phototherapy.

Results of the third day studies (serum total bilirubin, tHb, and COHbc) are detailed in table 2. Both COHbc (fig 1) values and serum total bilirubin values were significantly higher in the Down’s syndrome neonates than in the controls. However, despite higher COHbc values, not all of the Down’s syndrome neonates developed hyperbilirubinaemia. Furthermore, Down’s syndrome neonates with maximal serum total bilirubin values >256 μmol/l did not necessarily have higher COHbc values than those who did not become hyperbilirubinaemic (0.87 ± 0.26% and 0.95 ± 0.23%, respectively, NS). In contrast, higher COHbc values were found in those control neonates who developed hyperbilirubinaemia than those who did not (0.74 ± 0.15% vs 0.60 ± 0.16%, respectively, p<0.05).

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Figure 1

Day 3 mean (SD) COHBc values in Down’s syndrome (n=19) and control neonates (n = 32) showing values for total population studied, values for those who became hyperbilirubinaemic, and values for those who did not develop hyperbilirubinaemia.

COHbc values above the median were not a prerequisite for the development of hyperbilirubinaemia in either group: of the Down’s syndrome neonates, four of the nine who developed hyperbilirubinaemia had COHbc values below the median value of 0.89%, while two of the seven hyperbilirubinaemic control neonates had COHbc values below the median value of 0.60% for that group. The increased rate of haemolysis had no effect on the tHb values.

Clinical confounding variables known to delay bilirubin conjugation and excretion were analysed. Birthweight and gestational age were not significantly different when Down’s syndrome neonates who developed serum bilirubin values ⩾256 μmol/l were compared with those whose values did not exceed this value (2877± 384 gvs 2942 ±197 g, and 38.8 ± 1.6 weeksvs 38.6 ± 0.9 weeks, respectively). Only one neonate (in the hyperbilirubinaemic group) had a gestational age below 38 weeks. Six of 10 (60%) of the hyperbilirubinaemic groupvs three of nine (33%) of the non-hyperbilirubinaemic babies were being breastfed (NS). No infant had a weight loss greater than 10% of birthweight documented in the first three days of life.

Discussion

An association between Down’s syndrome and prolonged and sometimes severe neonatal jaundice was noted by Zuelzer and Brown6 and Panizon.7 However, subsequent clinical studies and reviews have not related in any detail to the phenomenon of Down’s syndrome associated neonatal jaundice.8 The more than 55% incidence of neonatal jaundice in our Down’s syndrome cohort reaffirms that neonatal jaundice is common in that condition, and occurs with a frequency not encountered in normal neonatal population groups.9 For comparison, the incidence of hyperbilirubinaemia, using the same definition as was used in this study, in a cohort of G-6-PD normal neonates recently reported from the same nursery as these Down’s syndrome neonates, was 9.2%.10 The higher incidence in the small group used as controls for COHbc determinations may have been an artefact due to the low number of babies included in this subset.

The methods used for determination of COHb have been perfected at Stanford University and assays of both CO and tHb have been shown to be extremely sensitive and accurate.2 11 12 Blood samples remain stable for up to several months when stored or transported at 4°C.2 Due to its low detection limit (0.005% COHb) and its insensitivity to substances known to cause interference in spectrophotometric methods, the gas chromatography system is regarded as the reference method for accurate COHb determination.13Although other non-haem sources of CO contribute to the endogenous CO pool, the predominant source of CO derives from haem catabolism, 80–90% of which is derived from haemoglobin.1 14 Berket al 15 have shown that the quantitative contribution to total endogenous CO production from sources other than haem catabolism is small. Therefore, accurately determined COHb values, corrected for inspired CO, offer a reliable index of the rate of haem catabolism, and by inference, bilirubin production. For comparison, we have provided COHbc values for other haemolytic conditions, taken from neonates studied in the same nursery as the current study: G-6-PD deficient neonates who developed hyperbilirubinaemia had a mean third day COHbc value of 0.80 ± 0.19%,16 while direct Coombs’ test positive ABO isoimmunised neonates ranged from 0.9 + 0.3% in the milder cases, to 1.8 ± 0.7% in the more severe cases.17

Serum total bilirubin values at any one time depend on a balance between the rates of bilirubin production and bilirubin elimination. The pathogenesis of neonatal hyperbilirubinaemia is clearly multifactorial, influencing both bilirubin production and elimination. The high COHbc values documented in the current Down’s syndrome cohort reflected an overall increased rate of haem catabolism and therefore bilirubin production. However, despite this increase in haem breakdown, not all Down’s syndrome neonates developed hyperbilirubinaemia. Furthermore, in neither the study nor control groups were increased COHbc values a prerequisite for the development of hyperbilirubinaemia. While there is a tendency to attribute neonatal hyperbilirubinaemia to increased bilirubin production, bilirubin elimination, which was not accounted for in the current study, can vary enormously among patients. This process involves uptake of bilirubin from the serum into hepatocytes, conjugation with glucuronic acid to form direct bilirubin, and excretion via the bile into the intestine. None of these processes is easily evaluated by non-invasive clinical means. Clinical variables known to affect bilirubin metabolism, such as gestational age, breastfeeding, and excessive weight loss, were examined, but were not significantly different when hyperbilirubinaemic and non-hyperbilirubinaemic Down’s syndrome babies were compared. Decreased bilirubin conjugation may have played a greater part in the production of the hyperbilirubinaemia in Down’s syndrome neonates compared with controls, similar to that recently demonstrated in G-6-PD deficiency.10

The reason for the increased bilirubin production is unknown. The defect in bone marrow regulation in Down’s syndrome extends to many cellular elements, and varied haematological abnormalities, affecting erythrocyte, granulocyte, and platelet cell lines, have been documented and comprehensively summarised.18 19 Polycythaemia, very common in Down’s syndrome neonates,7 20 and a likely cause of increased haem breakdown, was surprisingly not demonstrated, and cannot be implied, in the present series. Wilsonet al 21 showed that neonates with Down’s syndrome had lower haemoglobin F concentrations at birth, which decreased more rapidly with age, and higher haemoglobin A2 concentrations, tending to increase more rapidly after birth, than normal controls. There is some evidence of decreased erythrocyte life span and premature ageing of erythrocytes, with increased removal from the circulation, in adults with Down’s syndrome.22 23 As the gene for superoxide dismutase has been located to chromosome 21, the additional genetic material for this enzyme results in an excess of Cu/Zn superoxide dismutase in Down’s syndrome24 which may also be responsible for premature tissue aging. De Haan et al 25 reported an altered superoxide dismutase 1 to glutathione peroxidase ratio in Down’s syndrome tissue, and suggested that this imbalance may contribute to the accumulation of H₂O₂, with the resultant formation of tissue damaging hydroxyl radicals. Any of the above mentioned factors may contribute to the exaggerated haemolysis and increased bilirubin production evident in our COHbc studies. Taking into account the many haematological and biochemical abnormalities already associated with Down’s syndrome, we speculate that these neonates may also have ineffective erythropoiesis, resulting in increased haem turnover.