Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates.

Systematic review and meta-analysis of randomized trials in neonates receiving parenteral nutrition, predominantly preterm, very low birth weight, or extremely low birth weight infants. The review assessed short-term growth, nitrogen balance, plasma cysteine measures, and clinical outcomes across multiple small trials and one large multicountry trial.

Randomized trials evaluated short-term parenteral supplementation of neonatal PN with cysteine or cystine, most commonly as cysteine hydrochloride at about 0.46 to 1.0 mmol/kg/day for 6 days or similar brief courses. One large trial evaluated N-acetyl-L-cysteine at 16 to 32 mg/kg/day (0.10 to 0.20 mmol/kg/day) for 6 days added to cysteine-containing PN. Comparators were cysteine-free or standard PN, with placebo in the N-acetylcysteine trial.

Routine cysteine supplementation of cysteine-free PN improved nitrogen balance and plasma cysteine measures, but it did not clearly improve growth. In Zlotkin 1981, weight gain was MD -4.1 g/kg/day (95% CI -9.7 to 1.5), length gain was MD 0 cm/6 days, and nitrogen retention increased WMD 31.8 mg/kg/day (95% CI 8.2 to 55.4). The large extremely low birth weight N-acetylcysteine trial did not show clinical benefit: first-week weight gain MD 0.25 g/kg/day, death by 36 weeks RR 1.23, and no reduction in ROP, NEC, IVH, or PVL; plasma cysteine at end of therapy was slightly lower with N-acetylcysteine (MD -2.5 micromoles/100 ml). Overall, the review did not support routine N-acetylcysteine use in extremely low birth weight infants, and uncertainty remained about adverse effects such as metabolic acidosis.

Most contributing trials were small and short in duration, with heterogeneous formulations, doses, and comparators. Clinical outcomes and long-term safety data were limited, so much of the evidence relied on surrogate biochemical endpoints rather than durable infant outcomes. The largest trial addressed N-acetylcysteine in a specific extremely low birth weight population, limiting generalizability to other neonatal PN settings.