Investigations of the association between neonatal blood volume and placental transfusion date back to the middle of the 20th century. Several studies1–7 investigated the effects of gravity, of drugs that support uterine contraction, different cord clamping times ranging from 5 to 180 seconds, and milking the cord toward the neonate on blood volume or red cell mass among preterm neonates.
However, the comparative risks and benefits of early compared with delayed cord clamping in the preterm neonate continue to be a subject of much debate and the optimal timing of clamping of the umbilical cord remains largely unresolved. Attempts to transfuse the neonate from the placenta at the time of delivery may conflict with the need for resuscitation and may be associated with risk of hypothermia, polycythemia, and hyperbilirubinemia. In addition, delaying clamping of the umbilical cord may increase the chance of postpartum hemorrhage or interfere with collection of cord blood.5 Conversely, reported advantages of delayed cord clamping include reduced risk of respiratory distress,1 decreased need for blood transfusions, reduced need for respiratory support, and decreased incidence of intraventricular hemorrhage and iron deficiency anemia.2–4 Furthermore, delayed clamping may result in transfusion of blood enriched in stem cells and immunoglobulins.
In contrast to term neonates, preterm neonates have a low red cell mass, especially when combined with some degree of birth asphyxia, and are also more prone to develop respiratory distress syndrome.1 In addition, the issue of reduced need for blood transfusion is particularly important in preterm neonates born below 32 completed weeks of gestation, of whom between 60 and 80% receive blood transfusions during the first weeks of life.6 Available studies on this subject among the preterm neonates are few in number, underpowered, and consistently selective in the outcome variables evaluated. The objective of this study is to determine the short-term effects of delayed clamping of the umbilical cord in preterm neonates in a comprehensive manner.
MATERIALS AND METHODS
We conducted a randomized controlled trial comparing immediate with delayed cord clamping among preterm neonates born between 24 weeks 0 days and 34 weeks 0 days of gestation at the University of Oklahoma Medical Center between January 2008 and May 2011. The study was approved by the institutional review board of the University of Oklahoma Health Sciences Center and was registered with Registry of clinical Trials (ClinicalTrials.gov Identifier: NCT00579839).
Physicians and research nurses approached candidates for the trial and obtained formal written consent from those who elected to participate before randomization into the study and after full disclosure of the nature, potential benefits, and risks of participating in the trial. Allocation sequence was generated by simple randomization using a computer. The allocation sequence was concealed by using sequentially numbered, opaque, sealed envelopes kept in a central location on labor and delivery.
All women with singleton pregnancies presenting with preterm labor, preterm premature rupture of membranes, or at risk of been delivered prematurely were screened for eligibility using the specific inclusion and exclusion criteria. We included singleton pregnancies, between 24 weeks 0 days and 34 weeks 0 days of gestation who were deemed to be at risk of being delivered prematurely. We excluded pregnant women carrying fetuses with known major fetal structural or chromosomal abnormalities, multiple gestations, diabetes, intrauterine growth restriction, or nonreassuring fetal heart tracings. The intent of immediate cord clamping was to clamp the umbilical cord within 5 seconds of delivery and then intention in the delayed cord clamping group was to clamp of the cord after 30 seconds after birth (median 32 seconds, range 31–35 seconds). Three to four passes of milking of the umbilical cord toward the neonate was allowed in all neonates in the delayed cord clamp group. Oxytocin infusion was not initiated during the period of cord clamping and was started only after delivery of the placenta. In addition, neonates were not held below the level of the introitus in vaginal delivery or operating table in cases of cesarean delivery. Stopwatches were used to strictly adhere to the timing. For the neonates in the delayed cord clamping group, their care included provision of warmth using a warming mattress, bulb suction, and stimulation as appropriate. Further management in the delivery room and in the neonatal intensive care unit was the discretion of the responsible staff neonatologists and in line with usual clinical practice.
The primary study outcome was the need for blood transfusion as determined by neonatologists who in general initiated red blood cell transfusion when the hemoglobin was below 10 g/dL (hematocrit 30%) or anemia was symptomatic. The main secondary outcomes were initial hemoglobin and hematocrit and the rate of intraventricular hemorrhage. Hematocrit and hemoglobin were determined on venous blood drawn within the first 4 hours of life. Each preterm neonate had transfontanellar cranial ultrasound scans within the first 3 days of life and on day 7. Neurosonograms were evaluated by skilled radiologists not aware of the assigned group with regard to cord clamping. Intraventricular hemorrhage was graded as described by Papile et al.8 Periventricular leukomalacia was diagnosed by the presence of persistent echogenicity or echolucent areas in the periventricular region on sagittal and coronal views. Other secondary outcomes included requirement for resuscitation, Apgar scores at 5 minutes and 10 minutes, hypothermia during first hour of life, death, respiratory distress syndrome (assessed by clinical signs, oxygen requirement, respiratory support, chest radiograph) during first 36 hours of life, use of exogenous surfactant, days of ventilation, days of oxygen dependency, oxygen dependency at 28 days after birth, oxygen dependency at equivalent of 36 completed weeks of gestational age, chronic lung disease (Northway stage 2, 3, or 4), number and volume of blood transfusions, volume (colloid, sodium chloride 0.9%, blood transfusion) administration for hypotension during the first 24 hours of life, inotropic support for hypotension during the first 24 hours of life, and treatment for patent ductus arteriosus.9
We also evaluated rate of anemia of prematurity (defined as hemoglobin less than 10 g/dL or hematocrit less than 30%), treatment for hyperbilirubinemia with phototherapy, treatment for hyperbilirubinemia with blood exchange transfusion, intraventricular hemorrhage grades 3 and 4, periventricular leukomalacia, and necrotizing enterocolitis. Maternal outcome evaluated included postpartum hemorrhage, retained placenta, uterine inversion, and maternal mortality.
Data analysis was performed in accordance of the intention-to-treat principle. A sample size of 178 neonates provides more than 80% power to detect a 33% difference in the need for transfusion with packed red blood cells assuming a 65% rate of packed red blood cell transfusion in this gestational age range for a two-tailed test of significance at a critical level of .05. The distributional characteristics of the variables were examined. Differences between groups defined by period before cord clamping were examined using Student's t test for continuous data that were normally distributed, Mann Whitney U test for nonnormally distributed data, and χ2 for categorical variables. Fisher's exact test was used when expected cell frequency was equal to or less than five. A P value of <.05 was considered statistically significant.
A total of 200 women were randomized: 99 to the delayed cord clamp (median 32 seconds, range 31–35 seconds) and 101 to the immediate group (median 2 seconds, range 1–5 seconds) as depicted in the study profile (Fig. 1). The two groups were similar with respect to baseline characteristics including maternal age, height and weight, ethnicity, and selected maternal outcome variables (Table 1).
There was no statistically significant difference between groups with regard to the need for blood transfusion: 25 of 99 (25.3%) in the delayed cord clamp group received one or more blood transfusion compared with 24 of 101 (23.7%) in the immediate clamp group (P=.8; Table 2). The mean initial hemoglobin (17.4±2.5 compared with 16.3±2.3 g/dL, P=.001) and hematocrit (51.3±7.3 compared with 47.4±7.3, P=.001) were significantly higher in the delayed clamp group when compared with the immediate cord clamp group; Table 2). In the delayed cord clamp group, 11.1% (11/99) of neonates had intraventricular hemorrhage compared with 19.8% (20/101) in the immediate clamp group (P=.09). For the subgroup of neonates born at or below 26 weeks of gestation, the rate of intraventricular hemorrhage was 16.7% (2/13) in the delayed clamp group compared with 62.5% (5/8) in the immediate clamp group (P=.055).
The rate of various adverse perinatal outcomes including intraventricular hemorrhage grades 3 and 4, periventricular leukomalacia, necrotizing enterocolitis, and treatment for patent ductus arteriosus did not differ significantly between the groups. In the delayed cord clamp group, 36.4% (36/99) of neonates were diagnosed with anemia of prematurity compared with 47.5% (48/101) in the immediate clamp group (P=.11). There were no statistically significant differences in various neonatal characteristics at birth (Table 3).
Our study found that delaying cord clamping for 30 seconds did not decrease the need for blood transfusion in the preterm neonate. It did increase preterm neonatal hematocrit and hemoglobin without exposing the neonate to hypothermia, polycythemia, and hyperbilirubinemia or affecting the process of resuscitation. The lower rate of intraventricular hemorrhage among neonates in the delayed cord clamp group (11%) compared with neonates in the immediate clamp group (20%) was not statistically significant (P=.09). Some elements of our findings are not in agreement, although others did agree with the conclusions of two recent systematic review of this subject matter. The first is the current Cochrane library review7 on this subject, which states that “Providing additional placental blood to the preterm baby by either delaying cord clamping for 30–120 seconds, rather than early clamping, seems to be associated with less need for transfusion, better circulatory stability, less intraventricular hemorrhage (all grades) and lower risk for necrotizing enterocolitis” while alluding to insufficiency of data for reliable conclusions about the comparative effects on any of the primary outcomes reviewed. The second is a recent meta-analysis and systematic review of the literature10 among neonates born at less than 32 weeks of gestation that suggested “that enhanced placental transfusion (delayed umbilical cord clamping or umbilical cord milking) at birth provides better neonatal outcomes than does early cord clamping, most notably reductions in overall mortality, lower risk of intraventricular hemorrhage, and decreased blood transfusion incidence. The optimal umbilical cord clamping practice among neonates requiring immediate resuscitation remains uncertain.”
The main strength of our trial is the sample size, especially when compared with the overall number of neonates that were available for the referenced meta-analyses. For example, there were 738 neonates from 15 trials in the most recent Cochrane library review. In addition, this meta-analysis also included neonates born up to 36 weeks of gestation. Our trial was restricted to an upper limit of 34 weeks 0 days of gestation, the group most vulnerable to anemia of prematurity and to intraventricular hemorrhage. Furthermore, prior studies were selective in the neonatal outcome variables, unlike our study that evaluated a comprehensive list of maternal and neonatal outcome variables, which were a priori identified.
Our study was limited in its relatively small number of neonates delivered before 28 weeks of gestation and thus did not allow for meaningful subgroup analysis. This issue also applies to all available studies on this subject and is related to the proportion of such births in a single institution over a short period of time. In recognition of this, the American College of Obstetricians and Gynecologists committee opinion of this subject stated that “large clinical trials are needed to investigate the effect of delayed umbilical cord clamping on infants delivered at less than 28 weeks of gestation.”11 In addition, our study was not powered to evaluate differences in rare outcomes such as pneumothorax, chronic lung disease, death, use of colloids, dopamine, dobutamine, isoproterenol, and epinephrine, among others.
Our study also differs from other studies in the duration of time before the cord was clamped in the delayed cord clamp group. We chose the lower limit of the period reported in the literature because of concern for perceived need for resuscitation. It is however plausible that a longer duration of time before clamping may be more beneficial.
In conclusion, this study demonstrated that delaying cord clamping for 30 seconds does not decrease the need for blood transfusion in the preterm neonate. We agree with a previous call for a larger multicenter trial comparing delayed and immediate cord clamping in the preterm population and suggest a longer duration of delay (at least 1 minute) before clamping of the cord in this population.
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