Investigations of the association between neonatal

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1 Original Research Compared With Cord in the Preterm Neonate A Randomized Controlled Trial Andrew Elimian, MD, Jean Goodman, MD, Marilyn Escobedo, MD, Lydia Nightingale, MD, Eric Knudtson, MD, and Marvin Williams, DO OBJECTIVE: The comparative risks and benefits of early compared with delayed cord clamping in the preterm neonate remain unclear. Our objective was to evaluate the short-term effects of delayed clamping of the umbilical cord in preterm neonates. METHODS: We conducted a randomized controlled trial comparing immediate with delayed cord clamping among preterm neonates born between 24 and 34 weeks of gestation. The primary study outcome was the need for blood transfusion. To detect a 33% reduction in this outcome (from 65 to 43.5%) with a two-tailed a of 0.5 and b of 0.8 required 178 patients equally divided into two groups. RESULTS: A total of 200 women were randomized, 99 to the delayed and 101 to the immediate clamp group. The groups were similar with respect to baseline characteristics. The mean gestational age at delivery was weeks in the delayed compared with weeks in the immediate clamp group (P5.64). 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 (P5.8). The rates of various neonatal outcomes including From the Departments of Obstetrics and Gynecology and Pediatrics, University of Oklahoma Health Sciences Center, Williams Pavilion, Oklahoma City, Oklahoma. Presented at the 33rd Annual Meeting of the Society for Maternal-Fetal Medicine, February 11 16, 2013, San Francisco, California. Corresponding author: Andrew Elimian, MD, New York Medical College, Westchester Medical Center, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, 19 Bradhurst Avenue, Suite 2700, Hawthorne, NY 10532; Andrew_Elimian@nymc.edu. Financial Disclosure The authors did not report any potential conflicts of interest by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: /14 respiratory distress syndrome, periventricular leukomalacia, necrotizing enterocolitis, anemia of prematurity, and neonatal morality did not differ significantly between the groups. However, the mean initial hemoglobin ( compared with g/dl, P5.001) and hematocrit ( compared with , P5.001) was significantly higher in the delayed group. In the delayed clamp group, 11.1% (11/99) of neonates had intraventricular hemorrhage compared with 19.8% (20/101) in the immediate clamp group (P5.09). CONCLUSION: cord clamping for 30 seconds did not decrease the need for blood transfusion among preterm neonates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT (Obstet Gynecol 2014;124:1075 9) DOI: /AOG LEVEL OF EVIDENCE: I Investigations of the association between neonatal blood volume and placental transfusion date back to the middle of the 20th century. Several studies 1 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 VOL. 124, NO. 6, DECEMBER 2014 OBSTETRICS & GYNECOLOGY 1075

2 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 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: NCT ). 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 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 1076 Elimian et al Cord in the Preterm Neonate OBSTETRICS & GYNECOLOGY

3 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 twotailed 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 x 2 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. RESULTS A total of 200 women were randomized: 99 to the delayed cord clamp (median 32 seconds, range 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 (P5.8; Table 2). The mean initial hemoglobin ( compared with g/dl, P5.001) and hematocrit ( compared with , P5.001) 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 (P5.09). 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 (P5.055). 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 (P5.11). There were no statistically significant differences in various neonatal characteristics at birth (Table 3). Enrollment Assessed for eligibiity (n=520) Randomized (n=200) Excluded (n=320) Did not meet gestational age inclusion criteria at delivery: 294 Declined to participate: 11 Met exclusion criteria: 15 Allocation Allocated to delayed cord clamp (n=99) Received allocated intervention: 99 Allocated to immediate cord clamp (n=101) Received allocated intervention: 101 Fig. 1. Study profile. Follow-up Excluded (n=0) Lost to follow-up: 0 Discontinued intervention: 0 Excluded (n=0) Lost to follow-up: 0 Discontinued intervention: 0 Elimian. Cord in the Preterm Neonate. Obstet Gynecol Analysis Analyzed (n=99) Analyzed (n=101) VOL. 124, NO. 6, DECEMBER 2014 Elimian et al Cord in the Preterm Neonate 1077

4 Table 1. Selected Maternal Characteristics Table 2. Selected Neonatal Outcomes Characteristic Outcome P Age (y) Height (inches) Maternal weight at initiation of prenatal care (lb) Maternal weight at delivery (lb) Ethnicity Caucasian 65 (65.6) 64 (63.4) African American 14 (14.1) 22 (21.8) Hispanic 9 (9.1) 5 (5.0) Other 11 (11.1) 10 (9.9) Clinical diagnosis Preterm labor 33 (33.3) 28 (27.7) Preterm PROM 44 (44.4) 44 (43.6) Preeclampsia 18 (18.2) 23 (22.8) Tobacco use 32 (32.3) 30 (29.7) Alcohol use 2 (2.0) 2 (1.9) Drug abuse 2 (2.0) 2 (1.9) Antenatal steroids 93 (93.9) 98 (97.0) Antibiotics 83 (83.8) 73 (72.3) Chorioamnionitis Histologic 35 (35.4) 32 (32.3) Clinical 16 (16.2) 19 (19.0) Uterine prolapse 0 (0) 0 (0) Retained placenta 1 (1.0) 0 (0) Postpartum hemorrhage 0 (0) 0 (0) PROM, premature rupture of membranes. Data are mean6standard deviation or n (%). DISCUSSION 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 clampgroup(11%)comparedwithneonatesinthe immediate clamp group (20%) was not statistically significant (P5.09). 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 review 7 on this subject, which states that Providing additional placental blood to the preterm baby by either delaying cord clamping for seconds, rather than early clamping, seems to be associated with less need for transfusion, better circulatory stability, less intraventricular hemorrhage (all grades) 1 or more blood 25 (25.3) 24 (23.7).80 transfusions Initial hemoglobin (g) Initial hematocrit Patent ductus arteriosus 15 (15.2) 20 (19.8).46 requiring treatment Anemia of prematurity 36 (36.4) 48 (47.5).11 Phototherapy 55 (55.6) 55 (54.5).89 Intraventricular 11 (11.1) 20 (19.8).09 hemorrhage (any) Intraventricular 3 (3.0) 3 (3.0) 1.0 hemorrhage (grade 3 and 4) Periventricular 1 (1.0) 0 (0).50 leukomalacia Necrotizing enterocolitis 1 (1.0) 3 (3.0).62 Data are n (%) or mean6standard deviation unless otherwise specified. 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 metaanalysis and systematic review of the literature 10 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 metaanalyses. 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 Elimian et al Cord in the Preterm Neonate OBSTETRICS & GYNECOLOGY

5 Table 3. Neonatal Outcomes Outcome Gestational age (wk) Birth weight (g) 1, , Sex Male 52 (52.5) 48 (47.5).57 Female 47 (47.5) 53 (52.5) Resuscitation.67 Routine 48 (48.5) 53 (52.5) Advanced 51 (51.5) 48 (47.5) Apgar score Less than 7 at 1 min 38 (48.7) 40 (51.3).89 Less than 7 at 5 min 27 (55.1) 22 (44.9).41 At 10 min Colloids at 24 h 0 (0) 2 (2.0).50 Sodium chloride 6 (6.1) 9 (8.9).59 at 24 h Dopamine at 24 h 4 (4.0) 5 (5.0) 1.0 Dobutamine at 24 h 3 (3.0) 5 (5.0).72 Isoproterenol at 24 h 0 (0) 2 (2.0).50 Epinephrine at 24 h 1 (1.0) 2 (2.0) 1.0 Mean temperature ( C) Exchange blood 1 (1.0) 1 (1.0) 1.0 transfusion Days on ventilator 0 (0, 13) 0 (0, 10).42 Days on oxygen 0 (0, 63) 0 (0, 68).63 Respiratory distress 44 (44.4) 45 (44.6) 1.0 syndrome Surfactant 41 (41.4) 35 (34.7).38 Pneumothorax 0 (0) 3 (3.0).25 Oxygen at day (23.2) 20 (19.8).61 Oxygen at 36 wk 18 (18.2) 14 (13.9).44 Chronic lung disease 8 (8.1) 6 (5.9).59 Neonatal death 4 (4.0) 5 (5.0) 1.0 Data are mean6standard deviation, n (%), or median (10th, 90th percentile) unless otherwise specified. 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. P 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. REFERENCES 1. Linderkamp O, Versmold HT, Fendel H, Reigel KP, Betke K. Association of neonatal respiratory distress with birth asphyxia and deficiency of red cell mass in premature infants. Eur J Pediatr 1978;129: Hudson IRB, Holland BM, Jones JG, Turner TL, Wardrop CAJ. First day total circulating red cell volume (RCV) predicts outcome in preterm infants. Pediatr Res 1990; 27:209A. 3. Holland BM, Wardrop CAJ. Anaemias of the preterm infant. In: Turner TL, editor. Perinatal haematological problems. Chichester (UK): Wiley; p Kinmond S, Aitchison TC, Holland BM, Jones JG, Turner TL, Wardrop CA. Umbilical cord clamping and preterm infants: a randomized trial. BMJ 1993;306: Saigal S, O Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics 1972;49: Ringer SA, Richardson DK, Sacher RA, Keszler M, Churchill WH. Variations in transfusion practice in neonatal intensive care. Pediatrics 1998;101: Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. The Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD DOI: / CD pub3. 8. Papile LA, Burstein J, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: Rabe H, Reynolds G, Diaz-Rossello J. Early versus delayed umbilical cord clamping in preterm infants. The Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD DOI: / CD pub Backes CH, Rivera BK, Haque U, Bridge JA, Smith CV, Hutchon DJR, et al. Placental transfusion strategies in very preterm neonates: a systematic review and meta-analysis. Obstet Gynecol 2014;124: Timing of umbilical cord clamping after birth. Committee Opinion No American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120: VOL. 124, NO. 6, DECEMBER 2014 Elimian et al Cord in the Preterm Neonate 1079