Objective
Despite significant proposed benefits, delayed umbilical cord clamping (DCC) is not practiced widely in preterm infants largely because of the question of feasibility of the procedure and uncertainty regarding the magnitude of the reported benefits, especially intraventricular hemorrhage (IVH) vs the adverse consequences of delaying the neonatal resuscitation. The objective of this study was to determine whether implementation of the protocol-driven DCC process in our institution would reduce the incidence of IVH in very preterm infants without adverse consequences.
Study Design
We implemented a quality improvement process for DCC the started in August 2013 in infants born at ≤32 weeks’ gestational age. Eligible infants were left attached to the placenta for 45 seconds after birth. Neonatal process and outcome data were collected until discharge. We compared infants who received DCC who were born between August 2013 and August 2014 with a historic cohort of infants who were born between August 2012 and August 2013, who were eligible to receive DCC, but whose cord was clamped immediately after birth, because they were born before the protocol implementation.
Results
DCC was performed on all the 60 eligible infants; 88 infants were identified as historic control subjects. Gestational age, birthweight, and other demographic variables were similar between both groups. There were no differences in Apgar scores or admission temperature, but significantly fewer infants in the DCC cohort were intubated in delivery room, had respiratory distress syndrome, or received red blood cell transfusions in the first week of life compared with the historic cohort. A significant reduction was noted in the incidence of IVH in the DCC cohort compared with the historic control group (18.3% vs 35.2%). After adjustment for gestational age, an association was found between the incidence of IVH and DCC with IVH was significantly lower in the DCC cohort compared with the historic cohort; an odds ratio of 0.36 (95% confidence interval, 0.15–0.84; P < .05). There were no significant differences in deaths and other major morbidities.
Conclusion
DCC, as performed in our institution, was associated with significant reduction in IVH and early red blood cell transfusions. DCC in very preterm infants appears to be safe, feasible, and effective with no adverse consequences.
There is growing evidence that enhanced placental transfusion by delaying umbilical cord clamping (DCC) in very preterm infants may improve hemodynamic stability after birth and decrease the incidence of major neonatal morbidities, such as intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that supported DCC in preterm infants, with the possibility for a nearly 50% reduction in IVH. However, the practice of DCC in preterm infants has not been adopted widely, mainly because of the concern of a delay in initiating resuscitation in this vulnerable population. Furthermore, there is uncertainty regarding the magnitude of published benefits in very preterm infants because previous trials were limited by small sample sizes, wide variability in the technique, and inconsistent reporting of factors that may have contributed to clinical outcomes.
We recently implemented a DCC quality improvement (QI) process in very preterm infants at a large delivery hospital. The objective of this cohort study was to evaluate the clinical consequences of a protocol-driven DCC implementation in singleton infants who were born at ≤32 weeks’ gestation. We hypothesized that DCC would not compromise initial resuscitation and would be associated with a significant decrease in early red blood cell transfusions and IVH compared with a historic cohort.
Materials and Methods
On average, our level III Neonatal Intensive Care Unit cares for approximately 200 very preterm inborn infants every year. The previous routine clinical practice was to clamp the umbilical cord immediately after the birth. The DCC QI process was implemented starting August 2013. All infants born at ≤32 weeks’ gestation were eligible for DCC, unless they met the following exclusion criteria: severe maternal illness that prompted immediate delivery, placental causes (abruption or previa) or fetal causes (multiple gestation, major congenital anomalies, severe growth restriction, or hydrops fetalis). After birth, the infant was left unstimulated, attached at or slightly below the level of placenta for 45 seconds. The cord was then clamped and cut, and the neonatal team initiated resuscitation efforts. Apgar timing was initiated at the time of birth when the infant was delivered completely.
With approval by the institutional review board, prospective and retrospective data were extracted from maternal and neonatal electronic medical records. The prospective study period was 1 year, from Aug.19, 2013, to Aug. 18, 2014. The study period for the historic cohort was also 1 year, from Aug. 19, 2012, to Aug. 18, 2013. Collected data included maternal demographics, obstetric complications, any antenatal steroid and magnesium use, and other labor and delivery variables. Neonatal data included gestational age, birthweight, sex, postdelivery data variables such as Apgar scores, resuscitation data, and the infant’s temperature upon admission to the neonatal intensive care unit. Other clinical variables included treatment with phototherapy, ( intensive phototherapy defined as irradiance in the blue-green spectrum of at least 30 μW/cm 2 per nm), red blood cell transfusions, and inotropic and corticosteroid therapy within 1 week of life. Additional outcome variables included incidence of respiratory distress syndrome (RDS), surfactant therapy, therapy for patent ductus arteriosus, and incidence of culture positive sepsis. We also recorded major outcomes such as death, bronchopulmonary dysplasia (BPD), NEC Bell’s stage ≥2, retinopathy of prematurity (ROP), and IVH. Diagnosis of BPD was made at 36 weeks postmenstrual age if there was any oxygen requirement. Any operative interventions for NEC or ROP were also documented. IVH was graded 1-4 based on the criteria developed by Papile et al who defined grades 3 and 4 as severe IVH. White matter injury such as periventricular leukomalacia and porencephaly also were documented.
All statistical analysis was performed with SAS Enterprise Guide software (version 5.1; SAS Institute Inc, Cary, NC). Demographic and outcome variables were compared between the DCC cohort and historic control groups with the use of the Student t test for continuous variables, and χ 2 or Fisher exact test for categoric variables. We also calculated odds ratios (with 95% confidence interval) for comparisons after adjustment for gestation. Death and other major outcomes were also reported after stratification for gestational age. A probability value < .05 was considered to be the threshold of statistical significance.
Results
During the prospective study period, after implementation of DCC protocol, 157 infants were born at ≤32 weeks’ gestation. After excluding multiple gestation infants, 96 singleton infants were included in analysis. DCC was performed on all of the 60 eligible infants per prespecified protocol (DCC cohort). During the retrospective study period, 158 infants were born at ≤32 weeks’ gestation, of which 127 were singletons. Among them, 88 infants would have been eligible to receive DCC (historic cohort). All of these infants received immediate umbilical cord clamping after birth. The Figure shows the distribution of both cohorts, including exclusion criteria.
There were no significant differences in maternal characteristics ( Table 1 ). Artificial reproductive therapy and cesarean delivery numbers were not different between the groups. Similarly, there were no differences in other maternal variables such as chorioamnionitis, gestational hypertension or diabetes mellitus, preeclampsia, or poly- or oligohydramnios. Overall antenatal steroid administration and maternal magnesium exposure were similar between the groups. However, there was a significantly higher incidence of rupture of membranes at >18 hours before birth in the historic cohort (17.1% vs 5%).
| Variable | Cohort | P value | |
|---|---|---|---|
| Historic (n = 88) | Delaying umbilical cord clamping (n = 60) | ||
| Maternal age, y a | 28.9 ± 7.2 | 27.6 ± 6.2 | .27 |
| Maternal race, n (%) | .7 | ||
| White | 27 (30) | 19 (32) | |
| Black | 43 (49) | 25 (42) | |
| Hispanic | 18 (21) | 16 (26) | |
| Other | 0 | 0 | |
| Artificial reproductive technique, n (%) | 1 (1.1) | 1 (1.7) | .77 |
| Antenatal steroids, n (%) | 84 (95.4) | 56 (93.3) | .96 |
| Maternal magnesium, n (%) | 82 (93.1) | 56 (93.3) | .95 |
| Cesarean delivery, n (%) | 58 (65.9) | 39 (65) | .92 |
| Chorioamnionitis, n (%) | 9 (10.2) | 9 (15) | .51 |
| Pregnancy-induced hypertension/preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome, n (%) | 29 (32.9) | 17 (28.3) | .63 |
| Poly-/oligohydramnios | 5 (5.7) | 1 (1.7) | .4 |
| Prolonged rupture of membranes >18 hours | 15 (17.1) | 3 (5) | .04 |
| Gestation, wk a | 27.9 ± 2.8 | 27.9 ± 2.4 | .86 |
| Birthweight, g a | 1155.1 ± 399 | 1173.5 ± 362 | .78 |
| Male, n (%) | 47 (53.4) | 32 (53.3) | .99 |
| Apgar score, n b | |||
| 1 minute | 5 (1-9) | 6 (1-9) | .2 |
| 5 minutes | 7 (1-9) | 8 (3-10) | .19 |
| Admission temperature, degrees F a | 97.6 ± 1.6 | 98.2 ± 1 | .47 |
| Events in the delivery room, n (%) | |||
| Intubation | 46 (62.2) | 11 (18.3) | < .0001 |
| Chest compressions | 1 (1.1) | 2 (3.3) | .56 |
| Epinephrine | 2 (2.3) | 0 | .52 |
| Packed red blood cells | 1 (1.1) | 0 | 1.00 |
There were no significant differences in baseline neonatal characteristics between the groups ( Table 1 ). Mean gestational age was 27.9 ± 2.8 weeks in the historic cohort compared with 27.9 ± 2.4 weeks in the DCC cohort; mean birthweight was 1155 ± 399 g in the historic cohort compared with 1173 ± 362 g in the DCC cohort. Male infants represented 53% in both groups. There were no significant differences in 1- and 5-minute Apgar scores or admission temperature. However, significantly fewer infants in the DCC cohort were intubated in the delivery room compared with the historic cohort (18.3% vs 62.2%).
Red blood cell transfusion need in the first week of life was significantly lower in the DCC cohort compared with the historic cohort (13.3% vs 33%), although the use of pressor support or corticosteroids was not different ( Table 2 ). Phototherapy in first week of life was significantly higher in the DCC cohort, but none of the infants in either groups received intensive phototherapy or exchange transfusion. Incidence of RDS and surfactant administration was significantly lower in the DCC cohort. A significant reduction was noted in the incidence of IVH in the DCC cohort compared with the historic cohort (18.3% vs 35.2%). After adjustment for gestational age, an association was found between the incidence of IVH and DCC, with IVH significantly lower in the DCC cohort compared with the historic cohort with an odds ratio of 0.36 (95% confidence interval, 0.15–0.84; P < .05). Severe IVH or white matter injury was not different between both groups. The distribution of IVH grades by cohort is shown in Table 3 . There was no significant difference in mortality or other major morbidity rates ( Table 2 ). Length of hospital stay was similar between both groups.
| Variable | Cohort, n (%) | Odds ratio adjusted for gestation (95% confidence interval) | |
|---|---|---|---|
| Historic (n = 88) | Delaying umbilical cord clamping (n = 60) | ||
| Pressor need in first week | 15 (17) | 7 (11.7) | 0.69 (0.22–2.19) |
| Steroid need in first week | 2 (2.3) | 3 (5) | 3.77 (0.47–30.27) |
| Packed red blood cell transfusion in first week a | 29 (33) | 8 (13.3) | 0.11 (0.03–0.41) |
| Phototherapy in first week a | 72 (81.8) | 56 (93.3) | 5.25 (1.11–24.85) |
| Respiratory distress syndrome a | 58 (65.9) | 26 (43.3) | 0.18 (0.07–0.50) |
| Surfactant administration a | 30 (34.1) | 3 (5) | 0.04 (0.01–0.19) |
| Patent ductus arteriosus treated | 20 (23.7) | 14 (23.3) | 1.06 (0.40–2.76) |
| Death | 10 (11.4) | 4 (6.7) | 0.78 (0.19–3.25) |
| Intraventricular hemorrhage a (grades 1-4) | 31 (35.2) | 11 (18.3) | 0.36 (0.15–0.84) |
| Severe intraventricular hemorrhage (grades 3,4) | 10 (11.4) | 5 (8.3) | 0.80 (0.23–2.76) |
| Periventricular leukomalacia or porencephaly | 4 (4.5) | 2 (3.3) | 0.78 (0.13–4.74) |
| Bronchopulmonary dysplasia | 17 (19.3) | 10 (16.7) | 0.62 (0.20–1.95) |
| Retinopathy of prematurity | 20 (22.7) | 14 (23.3) | 0.80 (0.28–2.32) |
| Surgical retinopathy of prematurity | 4 (5.1) | 1 (1.7) | 0.29 (0.03–2.96) |
| Necrotizing enterocolitis | 4 (4.5) | 5 (8.3) | 2.46 (0.56–10.88) |
| Surgical necrotizing enterocolitis | 3 (3.4) | 4 (6.7) | 2.31 (0.47–11.46) |
| Culture-positive sepsis | 14 (15.9) | 11 (18.3) | 1.54 (0.56–4.24) |
| Grade of hemorrhage | Cohort, n (%) | |
|---|---|---|
| Historic (n = 88) | Delaying umbilical cord clamping (n = 60) | |
| 1 | 12 (14) | 4 (7) |
| 2 | 9 (10) | 2 (3) |
| 3 | 6 (7) | 2 (3) |
| 4 | 4 (5) | 3 (5) |
Death and other major outcomes were also stratified based on 3 gestation groups: 23-26 6/7 weeks, 27-29 6/7 weeks, and 30-32 weeks ( Table 4 ). DCC cohort in the 23-26 6/7 weeks and 27-29 6/7 weeks’ gestation groups had significantly lower need for early red blood cell transfusion compared with the historic cohort of similar gestation group. The incidences of IVH and BPD were significantly lower in DCC cohort compared with historic cohort of the 23-26 6/7 weeks’ gestation group. There was no significant difference in mortality or other major morbidity rates between similar gestation groups.
