Abstract
OBJECTIVE. To investigate whether it was possible to promote placental blood transfer to infants at preterm delivery by (1) delaying cord clamping, (2) holding the infant below the placenta, and (3) administering an oxytocic agent to the mother, we measured the infants' blood volumes.
DESIGN. Randomized study.
METHODS. Forty-six preterm infants (gestational age: 24[0/7] to 32[6/7] weeks) were assigned randomly to either placental blood transfer promotion (delayed cord clamping [DCC] group, ie, ≥30 seconds from moment of delivery) or early cord clamping (ECC) with conventional management (ECC group). Eleven of 23 and 9 of 23 infants assigned randomly to DCC and ECC, respectively, were delivered through the vaginal route. The study was conducted at a tertiary perinatal center, the Queen Mother's Hospital (Glasgow, United Kingdom).
RESULTS. The infants' mean blood volume in the DCC group (74.4 mL/kg) was significantly greater than that in the ECC group (62.7 mL/kg; 95% confidence interval for advantage: 5.8–17.5). The blood volume was significantly increased by DCC for infants delivered vaginally. The infants in the DCC group delivered through cesarean section had greater blood volumes (mean: 70.4 mL/kg; range: 45–83 mL/kg), compared with the ECC group (mean: 64.0 mL/kg; range: 48–77 mL/kg), but this was not significant. Additional analyses confirmed the effect of DCC (at least 30 seconds) to increase average blood volumes across the full range of gestational ages studied.
CONCLUSIONS. The blood volume was, on average, increased in the DCC group after at least a 30-second delay for both vaginal and cesarean deliveries. However, on average, euvolemia was not attained with the third stage management methods outlined above.
Immediate clamping of the umbilical cord for animals (foals, infant rabbits/bunnies, and puppies) causes an approximately 30% to 50% reduction in the newborn animals' blood volume, compared with the prenatal fetoplacental blood volume,1 as well as a pulmonary syndrome resembling respiratory distress syndrome (RDS).2 Augmenting the placental transfusion and increasing the newborn infant's blood volume by delaying cord clamping has been well documented for term infants.3–7 At 30 weeks of gestation, approximately one half of the fetoplacental blood volume of ∼110 mL/kg remains outside the newborn infant's circulation if the umbilical cord is clamped immediately.8 Reports on placental transfusion and measured newborn infants' blood volumes are very limited for preterm infants.4 Despite the historical controversy, generally the umbilical cord is now clamped immediately, especially after preterm delivery, for fear of delaying resuscitation9 or causing hypothermia.
Some workers found that delayed cord clamping (DCC) might reduce the severity of RDS,10–14 although not all investigators confirmed this.15,16 Early cord clamping (ECC) at preterm delivery results in hypovolemia,8 and placental transfusion may reduce the need for donor blood transfusion.11,17,18 DCC resulted in higher blood pressure and improved blood glucose homeostasis for preterm infants soon after birth,19 and DCC may also reduce intraventricular hemorrhage among preterm infants.20,21 DCC may help to reduce early-infancy anemia among term infants.22,23 There is concern that excessive placental transfusion could result in polycythemia, hypervolemia,24 and hyperbilirubinemia.4 However, randomized studies of DCC for preterm infants at <33 weeks of gestation found that it is a safe procedure.11,17–19 The promotion of placental transfusion at cesarean section deliveries is difficult25–27 because of uterine atony, which prevents the “placental squeeze.”
Euvolemia is the desired objective of DCC. We report the effect of DCC on the infants' measured blood volumes for groups of preterm infants (24[0/7] to 32[6/7] weeks of gestation) delivered vaginally or through cesarean section. These infants were a subgroup of a larger study, a randomized, controlled trial comparing DCC and ECC management at preterm delivery.
METHODS
Study Group
Forty-six preterm infants born at 24[0/7] to 32[6/7] weeks of gestation were assigned randomly to either ECC or DCC management. Twelve infants assigned randomly to ECC and 14 infants assigned randomly to DCC were delivered through cesarean section (Table 1). In the DCC group, the cord was clamped 30 to 90 seconds after delivery of the infant, the infant was held as low as the cord length permitted, and, where necessary, the infant received ventilation with appropriate resuscitation. The time of cord clamping was monitored with a stopwatch by one of the neonatal team members. Mothers of infants assigned randomly to DCC at cesarean section also received intravenously administered oxytocin (Syntocinon, Alliance Pharmaceuticals Ltd, United Kingdom; dose: 5 IU) with delivery of the presenting part. Two infants required assisted ventilation with an endotracheal tube, 7 infants received facemask ventilation, and 14 received facial oxygen therapy before clamping of the cord. In the ECC group, the cord was clamped immediately after delivery of the infant.
Comparison of Blood Volumes Between ECC and DCC Groups
Randomization was performed according to a stratified randomization list, just before delivery. For randomization, gestational age group (24[0/7] to 26[6/7] weeks, 27[0/7] to 29[6/7] weeks, or 30[0/7] to 32[6/7] weeks) and type of delivery (vaginal or cesarean) were taken into account.
Of the 46 singleton deliveries, 23 were assigned randomly to ECC and 23 to DCC (Table 1). However, 3 infants delivered through cesarean section who had been assigned randomly to DCC actually underwent ECC, because of short cord length (1 infant) or the attending neonatologist stipulating the need for immediate cord clamping (2 infants). Infants with known major malformations or hemolytic disease and an infant who had received intrauterine transfusions were excluded. Ethics approval was obtained from the hospital research ethics committee, and infants were recruited after informed parental consent was obtained.
Measurement of Blood Volume
Red blood cell volume was measured by using a technique involving dilution of fetal hemoglobin by transfused adult hemoglobin28 or the biotin-labeled, autologous red blood cell dilution method.29 The fetal hemoglobin dilution technique was used when the infant received a blood transfusion soon after delivery. Red blood cell volume was measured with the biotin labeling method for 40 infants and with the fetal hemoglobin dilution method for 6 infants, of whom 4 infants had ECC (2 cesarean section deliveries) and 2 infants had DCC (1 cesarean section delivery). The stated indications for early blood transfusion were low hemoglobin concentration for 4 infants and low hemoglobin concentration with hypotension for 2 infants. Red blood cell volume was measured at ∼4 hours of age. Blood volume was calculated with the following equation: blood volume = red blood cell volume/hematocrit.
Hematocrit levels were measured from either arterial or venous blood soon after admission to the neonatal unit (within 1 hour after admission). The sampling blood losses from birth to red blood cell volume measurement were added to the measured blood volume to approximate the blood volume at the time of birth.
Statistical Analyses
The statistical analyses involved data description with summary statistics and provision of 2-sample t test values and 95% confidence intervals (CIs) for comparison of treatment groups. The analyses were performed on an “intention-to-treat” basis.
RESULTS
The mean blood volume of infants delivered with DCC (74.4 mL/kg; range: 45–103 mL/kg) was significantly greater than that for the ECC group (62.7 mL/kg; range: 47–77 mL/kg; P < .001). The mean blood volume of infants delivered vaginally with DCC (80.5 mL/kg) was significantly greater than that for the ECC group (61.3 mL/kg; P < .001). The infants delivered through cesarean section with DCC had greater blood volume (mean: 70.4 mL/kg; range: 45–83 mL/kg) than did the ECC group (mean: 64.0 mL/kg; range: 48–77 mL/kg), but this difference was not significant (P = .1) (Table 1).
For the gestational ages of 27[0/7] to 29[6/7] weeks and 30[0/7] to 32[6/7] weeks, infants delivered with DCC had significantly greater blood volumes than did those in the ECC group (P < .001 and P = .01, respectively). The infants in the group with gestational ages of 24[0/7] to 26[6/7] weeks on average had greater blood volume after DCC (mean: 78.0 mL/kg) than after ECC (mean: 57.9 mL/kg), but this was not analyzed statistically because the sample size was small (Table 1).
Figure 1 illustrates the blood volumes and actual cord-clamping times. The median cord-clamping times were 90 seconds for the DCC group and 10 seconds for the ECC group. The blood volume increased with the delay in cord clamping, especially for vaginal deliveries. Delaying the cord clamping from 60 seconds to 90 seconds (Fig 1) did not lead to a difference in measured blood volumes. The mean hematocrit level for the DCC group (0.53; SD: 0.9) was not significantly different from that for the ECC group (0.49; SD: 0.8; P = .10; 95% CI for advantage: 1 to 10).
Blood volume and time to cord clamping, according to mode of delivery. The circled observations are those that were randomized to delay clamping but were actually clamped early.
When the analysis for all cases was repeated by using the actual cord-clamping status, rather than the intended/assigned status, the 95% CI for the average gain in blood volume with DCC versus ECC (95% CI: 8.0–19.3) showed only a minimal change, compared with that based on the intention to treat (95% CI: 5.8–17.5). There were no complications for infants or mothers during the placental transfusion procedures. We did not analyze clinical outcomes for this study.
DISCUSSION
By measuring blood volumes, we have demonstrated the possibility of achieving partial placental transfusion for preterm infants at 24 to 32 weeks of gestation. Placental transfusion was achieved by delaying cord clamping, gravity, adequate expansion of the lungs when necessary, and intravenous oxytocin treatment to stimulate uterine contraction after cesarean section delivery. The measured blood volumes ranged from 45 to 103 mL/kg in this study. Our infants were nursed in humidified, double-shield incubators to minimize insensible water loss; cumulative blood sampling losses before red blood cell volume measurements were added to the final blood volume.
Mollison et al30 determined blood volume values of 68 to 100 mL/kg (mean: 84.7 mL/kg) by measuring both red blood cell volumes and plasma volumes (“albumin space”) separately for 28 healthy term infants with varied times of cord clamping. Mean blood volumes of 70.3 ± 2.3 mL/kg (ECC after a 5-second delay) and 83.9 ± 2.7 mL/kg (DCC at ≥1 minute) were determined for term infants with the 125I-labeled serum albumin dilution method.3 Saigal et al4 found mean blood volumes of 79.7 mL/kg (ECC) and 89.6 mL/kg (1-minute DCC) for more-mature preterm infants (28–36 weeks; mean: 33.5 weeks) delivered vaginally. Strauss et al27 measured red blood cell volumes for 35 infants born at <36 weeks of gestation and reported significant increases among neonates who underwent DCC (42.1 ± 7.8 mL/kg), compared with ECC (36.8 ± 6.3 mL/kg). For 2 infants of <30 weeks of gestation, a reinfusion of autologous, processed, placental blood was given to mimic placental transfusion.
There are several possible explanations for the differences between actual blood volume findings in the present study and those reported by Saigal et al.4 The discrepancies could be attributable to methodologic differences in blood volume measurements, differences in mode of delivery, and differences in gestational ages of the infants studied. Saigal et al4 reported blood volumes for infants born through the vaginal route at 28 to 36 weeks of gestation, and the blood volume estimations at 4 hours of age were based on plasma volume measurements with the 125I-labeled human serum albumin dilution method. We studied infants born through both the cesarean section and vaginal routes at 24 to 32 weeks of gestation, and the blood volume was estimated by measuring the red blood cell volume at 4 hours of age. We did not use any correction factor for the venous/arterial hematocrit values, whereas the previous study used a correction factor of 0.87 to obtain total-body hematocrit values for calculation of blood volumes. Calculating the blood volume from the measured plasma volume overestimates the actual blood volume, because the labeled albumin method estimates the albumin space rather than the true plasma volume for sick patients with capillary leaks.31,32
The placental transfusion seems to have been more pronounced in the groups with lower gestational ages (24[0/7] to 26[6/7] weeks and 27[0/7] to 29[6/7] weeks) and after vaginal delivery, although the number of infants in the group born at 24 to 26 weeks of gestation was too small for statistical confidence. Most of the published data on placental transfusion, for both term and preterm infants, are from vaginal deliveries; data on cesarean delivery cases are limited. The safety and feasibility of DCC treatment for preterm infants delivered through cesarean section were demonstrated.18,19,26,27 Strauss et al27 reported no difference in mean measured red blood cell volumes for preterm infants delivered through cesarean section with DCC (37.2 ± 8.2 mL/kg) versus ECC (36.8 ± 7.8 mL/kg). The present study confirmed the possibility not only of delaying cord clamping but also of achieving placental transfusion for infants delivered both vaginally and through cesarean section. All 3 infants who were assigned randomly to DCC but actually received ECC (Fig 1) were delivered through cesarean section. When the data were reanalyzed with exclusion of these 3 infants, the blood volume was significantly greater even for infants delivered through cesarean section (DCC: 72.8 mL/kg; ECC: 63.6 mL/kg; P = .01; 95% CI for advantage: 2.0–16.4).
The blood volume of term infants delivered vaginally varies directly in relation to the time of cord clamping.3 Philip and Teng33 reported that placental transfusion might be enhanced by lung expansion, in addition to DCC and gravity, at term cesarean section. For term infants delivered through cesarean section, blood volume is increased by DCC of up to 40 seconds; delaying beyond 40 seconds may reduce the infant's blood volume because of reversal of blood flow to the placenta.34 We found that delaying cord clamping beyond 60 seconds after cesarean section deliveries achieved only small changes in neonatal blood volumes (Fig 1). This could reflect reversal of blood flow between the placenta and the infant because of uterine atonicity, despite the intravenous administration of oxytocin. All of our infants had their lungs expanded through natural crying or facemask or endotracheal ventilation, as required to facilitate reduction of pulmonary vascular resistance and increase of pulmonary blood flow.33
Placental transfusion may increase term and preterm infants' hematocrit and hemoglobin concentrations measured at 2 to 4 hours of age,7,11,17 but some studies did not confirm this.19,27 There was no significant difference in hematocrit levels between the DCC and ECC groups in our study. The hematocrit levels were measured soon after admission to the neonatal unit (<1 hour of age). We think that our finding could be attributable to the proportionate transfer of red blood cells and plasma from placenta to infant. Nelle et al7 also found no difference in hematocrit levels of cord blood or those immediately after birth between DCC and ECC groups. In a randomized, controlled trial of infants at 24 to 28 weeks of gestation, Oh et al35 noted no significant differences in mean hematocrit levels at 4 hours of age (DCC: 0.44; ECC, 0.40). However, the mean hematocrit values (DCC: 0.54; ECC: 0.50) at ∼1 hour of age in the present study were much higher than those found by Oh et al.35
We and others12,36–39 have shown that red blood cell volumes or blood volumes at birth are relevant to the outcomes for preterm infants. Deficiencies of red blood cell volumes and low blood volumes at birth are associated with severe RDS.12,13,38,39 The potential clinical advantages of euvolemia after placental transfusion have been outlined previously.11,40,41
CONCLUSIONS
Blood volume was, on average, increased by delaying cord clamping for at least 30 seconds in both vaginal and cesarean section deliveries. The placental transfusion was more marked after vaginal deliveries and seemed more apparent for preterm infants with lower gestational ages. The enhancement of blood volume we report here was small; euvolemia might not have been achieved for our infants with DCC. Blood volume is expressed in milliliters per kilogram; for preterm infants, whose body fat proportion is significantly less than that of more-mature infants, “optimal” blood volume is likely to exceed values found for term infants. Other tactics for management of the third stage of labor may need to be examined in attempts to achieve euvolemia
Acknowledgments
We are grateful to our obstetric colleagues, the midwifery staff, and the medical and nursing staff of the neonatal unit at the Queen Mother's Hospital (Glasgow, United Kingdom) for their willing cooperation with this study. We thank S. Sooral for typing the manuscript. We also thank “Well Being,” a research grant from the Royal College of Obstetricians and Gynaecologists, for invaluable financial assistance.
Footnotes
- Accepted February 28, 2005.
- Address correspondence to Narendra Aladangady, MD, MRCPCH (UK), Neonatal Unit, Homerton University Hospital, Homerton Row, London E9 6SR, United Kingdom. E-mail: n.aladangady{at}qmul.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
- Copyright © 2006 by the American Academy of Pediatrics