Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial.

BACKGROUND: Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits. OBJECTIVE: We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation. STUDY DESIGN: This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSION: Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

Role of L-carnitine in apnea of prematurity: a randomized, controlled trial.

OBJECTIVE: Carnitine is thought to be a conditionally essential biological cofactor for premature infants. A preliminary study suggested that carnitine could significantly reduce apnea of prematurity. The objective of this study was to evaluate critically the role of carnitine in idiopathic apnea of prematurity and to determine whether the use of carnitine would facilitate discontinuation of mechanical ventilatory support, shorten the duration of ventilatory support, and reduce the amount of time that such infants are exposed to both mechanical ventilation and oxygen. We also wanted to determine the effects of supplemental carnitine on weight gain, time to regain birth weight, time to achieve full enteral feedings, and length of hospital stay. METHODS: A prospective, randomized, blinded trial was conducted on 44 preterm infants who were from the same neonatal intensive care unit and who were < or =32 weeks' gestational age with a postnatal age <48 hours and a birth weight <1500 g and required total parenteral nutrition (TPN). Infants were randomized to receive carnitine supplementation or placebo without crossover. Carnitine-supplemented infants received 30 mg/kg/d carnitine in their TPN until the they were tolerating 120 mL/kg/d enteral feedings, and then they received 30 mg/kg/d oral carnitine. The placebo group received TPN without supplemental carnitine; when they tolerated 120 mL/kg/d enteral feedings, they received an oral placebo. The 2 groups continued on their respective supplemental carnitine or placebo until 34 weeks' adjusted age, at which time the study period was completed. Twelve-hour cardiorespiratorygrams to record heart rate, respiratory impedance, and oxygen saturation, and a nasal thermistor to detect expiratory airflow were performed every 4 days on 3 occasions and at 30 and 34 weeks' adjusted age. Plasma carnitine levels were measured at day 14. RESULTS: There were no significant differences between the 2 groups in the occurrence of apnea as detected by cardiorespiratorygram or nursing observation. There were no significant differences between the groups in regard to total days on ventilator, days of nasal continuous positive airway pressure, time to regain birth weight, time to reach enteral feedings of 120 mL/kg/d, discharge weight, adjusted age at discharge, need for oxygen at 28 days' and 36 weeks' adjusted age, or length of stay. The plasma carnitine level was a median of 15.5 micromol/L (range: 7.6-30.5) for the placebo infants compared with a median of 195.3 micromol/L (range: 71.7-343.6) for the carnitine infants. CONCLUSIONS: In this blinded, randomized, placebo-controlled study, we found that infants who received supplemental carnitine did not demonstrate any reduction in apnea of prematurity, ventilator or nasal continuous positive airway pressure days, or the need for supplemental oxygen therapy. Although carnitine may be of significant nutritional benefit for very low birth weight infants, our study does not support its use to reduce apnea of prematurity or decrease dependence on mechanical ventilation.