Materials and Methods

This was an institutional review board–approved, prospective, randomized trial performed at the University of South Alabama Children’s and Women’s Hospital between the dates of August 2012 and November 2013.

When endeavoring a study of neonatal outcomes, it would be ideal to use long-term outcomes of morbidity and mortality as primary variables; however, the sample size required to power these analyses is a difficult task in a prospective randomized control trial; therefore, previous studies have set a precedent to use hematocrit as a surrogate marker of therapy success. In addition, previous studies have set a precedent of hypothesizing at least a 10% increase in hematocrit when either delayed cord clamping or cord stripping was performed over an immediate cord clamping.

In designing our study, we were attempting to speculate an additive increase in hematocrit when cord stripping was done in conjunction with delayed cord clamping. In an attempt to choose an increase in hematocrit that would be clinically significant but still reasonably attainable, we deduced that a 5% relative difference between our control and test arms would be considered a valuable increase. Therefore, a power analysis with the G*power application was performed for a goal of obtaining a 5% relative increase in hematocrit. In this calculation, we used a predicted average hematocrit of 50%, which was simply chosen by examining the typical hematocrits of neonates admitted to the neonatal intensive care unit (NICU). With an alpha of 0.05, a power of 80%, and a predicted SD of 3.5%, it was determined that a minimum of 32 patients were to be recruited in each arm.

Informed consent was obtained from obstetric patients at risk for preterm delivery, with randomization occurring just prior to delivery. Randomization was performed with opaque envelopes contained on the labor and delivery unit containing cards with instruction on either delayed cord clamping alone or delayed cord clamping plus cord stripping. An equal number of envelopes were created for each arm and were scrambled by a third-party registered nurse.

Using a protocol designed by Mercer et al, delayed cord clamping instructed holding the neonate below the level of the placenta, which was done below the perineum in a vaginal delivery or to the maternal side in a cesarean delivery. The 30-second delay was verbally stated in 5 second increments by the neonatal nurse practitioner present at the delivery. After the cord clamp, the neonate was immediately transferred to the warmer and care was assumed by the awaiting pediatric team.

The cord stripping protocol was designed to mimic a previous protocol by Rabe et al in which, in addition to the above 30 second delay, the full length of the visible cord, which is estimated to be one third to two thirds of the full cord length, is manually stripped between 2 fingers by the surgeon or assistant toward the neonate. This stripping was done 4 times during the above-described delay with instructions to allow 4-5 seconds between strippings to allow the cord to refill completely.

Protocol also dictated that uterotonic agents were not to be used until after cord clamping, except in cases in which pitocin was already being administered to achieve vaginal delivery. In those patients pitocin administration was allowed to continue at the existing rate.

Singleton deliveries from both cesarean deliveries and vaginal deliveries with estimated gestational ages between 22 0/7 weeks and 31 6/7 weeks were included. Patients at periviable gestational ages received counseling and were included only if they desired full interventions on behalf of the fetus both prior to and after delivery. Patients were excluded if the fetus had known anomalies or there was a suspected placental abruption. The primary outcome was initial hematocrit, which was obtained as soon as reasonably possible within the first 30 minutes of life from either venous or arterial blood draws.

The protocol allowed arterial blood draws if an arterial line was available because this was deemed to be in the best interest of the neonate. Venous draws were initiated if an arterial line was not yet established. Capillary hematocrits were not obtained because these can differ from venous and arterial hematocrit too widely. The secondary outcome variables were the length of time on the ventilator, days to discharge, neonatal mortality, peak bilirubin, number of phototherapy days, and neonatal complication rates.

The ideal randomized control trial has double blinding. We obviously could not blind the surgeon to the therapy; however, because randomization occurred just prior to delivery, all care leading up to delivery, including the decision to deliver and delivery timing, was done prior to the providers being aware of randomization.

NICU protocol requires a team of neonatal providers to be present at delivery when possible. This team includes either a neonatologist or a neonatal nurse practitioner. The neonatal team was not told which patients were participating in the study, and the randomization arm was not documented on the infants’ charts. This was done in an effort to avoid alteration in subsequent management and achieve blinding of the care team.

The care provided to the neonate after delivery was at the discretion of the attending neonatologist. A study by Hosono et al created a protocol for postnatal management, which required serial blood counts with specific guidelines for transfusions. In contrast, Mercer et al allowed the clinical management of the infant to be at the discretion of the neonatologist in their study.

Our protocol reflected the latter, rationalized by the fact that strict transfusion parameters might not be appropriate, given differences in estimated gestational ages, age of life, and complications encountered. In addition, not all infants needed serial blood draws, and we did not want to inflict possible harm with a protocol requiring this.

The comparison of the means and Fisher exact tests were utilized to analyze the data.

Results

During the 15 month period of the study, 70 patients were randomized. Three patients were randomized but on final review did not meet inclusion criteria and were excluded from analysis. For the 32 patients in the control arm, receiving 30 second delayed cord clamping alone, and the 35 in the test arm, receiving 30-second delayed cord clamping plus cord stripping, birthweights and gestational ages were similar ( Table ). The mean birthweights were 1087 g and 1111 g, and the mean gestational ages were 28.3 weeks and 28.5 weeks for the control and test arms, respectively.

The causes of preterm deliveries were primarily hypertensive disorders (42%), preterm labor (28%), and preterm rupture of membranes (27%). Thirty-six percent of deliveries were via the vaginal route and 64% were cesarean deliveries. The 2 routes of delivery occurred at similar rates in each arm, and the average hematocrit did not differ when stratified by mode of delivery ( Table ).

The primary outcome, the initial neonatal hematocrit, was compared between the 2 arms. The control arm, which received delayed cord clamping only, had a mean hematocrit of 47.75%. The test arm, which received delayed cord clamping plus cord stripping, had a mean hematocrit of 47.71%.

These results were stratified by estimated gestational age, separating patients into less than 28 weeks and 28 weeks or longer ( Table ). The neonates less than 28 weeks had a higher hematocrit in the test arm (44.7%) than the control arm (41.2%), but this difference was not statistically significant ( P = .12). Interestingly, the infants greater than 28 weeks had a significantly lower hematocrit in the test arm (49.5%) than those in the control arm (52.9%) ( P = .04).

There were 3 neonatal deaths in our study. All 3 deaths were in the control arm with no deaths in the test arm ( P = .10). The gestational ages of the infant deaths were 24 0/7, 24 1/7, and 26 2/7, and causes of death were documented as extreme prematurity with multisystem organ failure, suspected necrotizing enterocolitis, and prematurity with multisystem organ failure, respectively. Secondary outcome variables that contribute to morbidity associated with prematurity were also examined. There were no significant differences observed in incidences of intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, bronchopulmonary dysplasia, or transient tachypnea of the newborn ( Table ).

We evaluated the length of stay and time spent on the ventilator. The infants that died were excluded from these analyses. The mean length of stay was 71.2 days for the control arm and 67.8 days for the test arm ( P = .66). The mean number of days on the ventilator was 4.86 days for the control arm and 3.06 days for the test arm ( P = .34).

In the study, “Placental transfusions and hyperbilirubinemia in the premature,” Saigal et al specifically addressed the concern of increased red blood cell volume leading to hyperbilirubinemia because of delayed cord clamping. This study highlighted the primary reason delayed cord clamping is not routinely recommended for normal term deliveries.

To rule out a deleterious effect, we analyzed peak bilirubin levels and the number of days requiring phototherapy. The 3 infants that died in the control group were excluded from the analysis for a number of phototherapy days. The results showed the average peak serum bilirubin levels to be 8.38 and 8.27 in the control and test arms, respectively ( P = .86). The average phototherapy days were 2.90 and 2.97, respectively ( P = .88).

In previous studies the number of packed red blood cell transfusions has been analyzed as a surrogate marker for long-term hemoglobin and hematocrit levels. We also analyzed the average number of red blood cell transfusions in each arm. The results showed an average of 1.53 transfusions in the control arm and 0.97 transfusions in the test arm ( P = .33).

Not surprisingly, we observed that the significant majority of the blood transfusions were required in the infants born at less than 28 weeks’ gestation. Rarely did infants born at longer than 28 weeks require blood transfusions; in fact, in the 40 infants delivered at a gestation of 28 weeks or longer, only 4 blood transfusions were needed in total. In contrast, in the 27 infants delivered at less than 28 weeks’ gestation, 79 blood transfusions were needed in total. Of these 79 transfusions, 49 were in the control arm and 30 were in the test arm. Although this trended toward fewer transfusions in the test arm, there was not a statistically significant difference.