Hemodynamic Changes with Umbilical Cord Milking in Nonvigorous Newborns: A Randomized Cluster Cross-over Trial.

OBJECTIVE: To assess the hemodynamic safety and efficacy of umbilical cord milking (UCM) compared with early cord clamping (ECC) in nonvigorous newborn infants enrolled in a large multicenter randomized cluster-crossover trial. STUDY DESIGN: Two hundred twenty-seven nonvigorous term or near-term infants who were enrolled in the parent UCM vs ECC trial consented for this substudy. An echocardiogram was performed at 12 ± 6 hours of age by ultrasound technicians blinded to randomization. The primary outcome was left ventricular output (LVO). Prespecified secondary outcomes included measured superior vena cava (SVC) flow, right ventricular output (RVO), peak systolic strain, and peak systolic velocity by tissue Doppler examination of the RV lateral wall and the interventricular septum. RESULTS: Nonvigorous infants receiving UCM had increased hemodynamic echocardiographic parameters as measured by higher LVO (225 ± 64 vs 187 ± 52 mL/kg/min; P < .001), RVO (284 ± 88 vs 222 ± 96 mL/kg/min; P < .001), and SVC flow (100 ± 36 vs 86 ± 40 mL/kg/min; P < .001) compared with the ECC group. Peak systolic strain was lower (-17 ± 3 vs -22 ± 3%; P < .001), but there was no difference in peak tissue Doppler flow (0.06 m/s [IQR, 0.05-0.07 m/s] vs 0.06 m/s [IQR, 0.05-0.08 m/s]). CONCLUSIONS: UCM increased cardiac output (as measured by LVO) compared with ECC in nonvigorous newborns. Overall increases in measures of cerebral and pulmonary blood flow (as measured by SVC and RVO flow, respectively) may explain improved outcomes associated with UCM (less cardiorespiratory support at birth and fewer cases of moderate-to-severe hypoxic ischemic encephalopathy) among nonvigorous newborn infants.

Bilirubin Levels in Neonates ≥35 Weeks of Gestation Receiving Delayed Cord Clamping for an Extended Time-An Observational Study.

OBJECTIVE: To describe bilirubin levels in neonates ≥350/7 gestational weeks, receiving delayed cord clamping (CC), in relation to the updated Bhutani nomogram. STUDY DESIGN: This was a retrospective, observational study based on data from medical records and local data sheets. Singleton neonates, born vaginally at a gestational age ≥350/7, and with a registered time to CC and at least one registered bilirubin, were included. We excluded neonates with positive direct antiglobulin test or hemolytic disorders. Adjusted analyses were performed using ANOVA and linear or logistic regression. RESULTS: We analyzed 558 neonates, mean gestational age (SD) 39.9 (1.3) weeks. CC was performed at a median (IQR) time of 6 (5-8) minutes. The dataset contained 1330 bilirubin measurements. Median (IQR) age at bilirubin measurement was 37 (22-54) hours. Bilirubin percentiles in neonates with CC time ≥2 minutes were similar, or lower, compared with the Bhutani nomogram between 12 and 72 hours, but with greater 95th percentile at later hours of age. Phototherapy was initiated in 13 (2.3 %) of the neonates. We found no association between time to CC and hyperbilirubinemia (ß = -0.05, P = .07). Need for phototherapy was marginally greater in neonates with shorter time to CC. CONCLUSIONS: Bilirubin levels were not correlated to time to CC. Our findings indicate that CC beyond 2 minutes can be performed without additional monitoring for jaundice.

Effect of Breathing Support in Very Preterm Infants Not Breathing During Deferred Cord Clamping: A Randomized Controlled Trial (The ABC Study).

OBJECTIVE: To determine if providing respiratory support to very preterm infants who fail to breathe regularly during deferred cord clamping (DCC) decreased red cell transfusion. STUDY DESIGN: Infants less than 31 weeks of gestation undergoing DCC who were apneic or not breathing regularly at 15 seconds underwent stratified randomization. Pale, limp, and nonresponsive infants were excluded. The standard group received gentle stimulation in a neutral position for 50 seconds; the intervention group received intermittent positive pressure ventilation via face mask and T piece from 20 to 50 seconds of age with a fractional inspired oxygen of 0.3. The primary outcome was the proportion transfused, with a secondary composite outcome of death, severe intraventricular hemorrhage, or chronic lung disease. RESULTS: Of 311 assessed infants, 113 met the inclusion criteria and were studied; 57 received the intervention and 56 standard treatment. Patient characteristics were similar. Overall, 105 infants (93%) received the intended 50 seconds DCC (54 in the intervention group and 51 in the standard group). Rates of transfusion were similar (28% vs 30% in the intervention vs control groups), as were rates of the composite outcome (46% vs 38% in the intervention vs the control arms; P = .45). CONCLUSIONS: Providing breathing support during 50 seconds of DCC in this single-center cohort seemed to be safe and feasible, but did not decrease the transfusion rates or improve outcomes. TRIAL REGISTRATION: http://www.anzctr.org.au/ACTRN12615001026516.aspx.

Evidence-based labor management: third stage of labor (part 5).

During the third stage of labor, oxytocin and tranexamic acid, oxytocin and misoprostol, oxytocin and methylergometrine, or carbetocin is recommended for the prevention of postpartum hemorrhage after vaginal delivery. Intravenous oxytocin (10 IU) immediately after delivery of the neonate (after either anterior shoulder or whole-body delivery) and before delivery of the placenta is recommended. If oxytocin and tranexamic acid combination is chosen, intravenous tranexamic acid (1 g) in addition to intravenous oxytocin (10 IU) immediately after delivery of the neonate and before placental delivery is recommended. If oxytocin and misoprostol combination is chosen, sublingual misoprostol (400 µg) in addition to intravenous oxytocin (10 IU) immediately after delivery of the neonate is recommended. If there is no intravenous access or if in low-resource settings, sublingual misoprostol (400 µg) and intramuscular oxytocin (10 IU) are recommended. If oxytocin and methylergometrine combination is chosen, intramuscular methylergometrine (0.2 mg) and intravenous oxytocin (10 IU) immediately after delivery of the neonate are recommended. Single-dose intravenous or intramuscular carbetocin (100 µg) immediately after delivery of the neonate is recommended. Controlled cord traction and delayed cord clamping for approximately 60 seconds is recommended. There is insufficient evidence to support or refute umbilical cord milking, uterine massage, or nipple stimulation for the prevention of postpartum hemorrhage. Repair of first- and second-degree lacerations with continuous synthetic suture technique is recommended. No repair of first-degree lacerations if hemostatic and normal cosmesis can be considered. Repair of third-degree lacerations with end-to-end or overlap continuous synthetic suture technique is recommended. Repair of fourth-degree lacerations with delayed absorbable 4-0 or 3-0 polyglactin or chromic suture in a running fashion is recommended. The use of single-dose second-generation cephalosporin at the time of third- or fourth-degree laceration repairs can be considered. Skin-to-skin contact after delivery is recommended. There is insufficient evidence to support or refute routine cord blood gas sampling after delivery. Public cord blood banking is recommended.

FIGO good practice recommendations on delayed umbilical cord clamping.

Delayed cord clamping in the first minute in preterm infants born before 34 weeks of gestation improves neonatal hematologic measures and may reduce mortality without increasing any other morbidity. In term-born babies, it also seems to improve both the short- and long-term outcomes and shows favorable scores in fine motor and social domains. However, there is insufficient evidence to show what duration of delay is best. The current evidence supports not clamping the cord before 30 seconds for preterm births. Future trials could compare different lengths of delay. Until then, a period of 30 seconds to 3 minutes seems justified for term-born babies.

Impact of Deferred Cord Clamping on Mortality and Severe Neurologic Injury in Twins Born at <30 Weeks of Gestation.

OBJECTIVE: To determine whether deferred cord clamping (DCC) compared with early cord clamping (ECC) was associated with reduction in death and/or severe neurologic injury among twins born at <30 weeks of gestation. STUDY DESIGN: We performed a retrospective cohort study including all liveborn twins of <30 weeks admitted to a tertiary-level neonatal intensive care unit (NICU) in Canada between 2015 and 2018 using the Canadian Neonatal/Preterm Birth Network database. We compared DCC ≥30 seconds vs ECC <30 seconds. Our primary outcome was a composite of death and/or severe neurologic injury (severe intraventricular hemorrhage grade III/IV and/or periventricular leukomalacia). Secondary outcomes included neonatal morbidity and health care utilization outcomes. We calculated aORs and ß coefficients for categorical and continuous variables, along with 95% CI. Models were fitted with generalized estimated equations accounting for twin correlation. RESULTS: We included 1597 twins (DCC, 624 [39.1%]; ECC, 973 [60.9%]). Death/severe neurologic injury occurred in 17.8% (n = 111) of twins who received DCC and in 21.7% (n = 211) of those who received ECC. The rate of death/severe neurologic injury did not differ significantly between the DCC and ECC groups (aOR 1.07; 95% CI, 0.78-1.47). DCC was associated with reduced blood transfusions (adjusted ß coefficient, -0.49; 95% CI, -0.86 to -0.12) and NICU length of stay (adjusted ß coefficient, -4.17; 95% CI, -8.15 to -0.19). CONCLUSIONS: The primary composite outcome of death and/or severe neurologic injury did not differ between twins born at <30 weeks of gestation who received DCC and those who received ECC, but DCC was associated with some benefits.

A Comparison of Strategies for Managing the Umbilical Cord at Birth in Preterm Infants.

OBJECTIVE: To evaluate the rates of practice, and the associations between different cord management strategies at birth (delayed cord clamping [DCC], umbilical cord milking [UCM], and early cord clamping [ECC]) and mortality or major morbidity, rates of blood transfusion, and peak serum bilirubin in a large national cohort of very preterm infants. STUDY DESIGN: We retrospectively studied preterm infants <33 weeks of gestation admitted to the Canadian Neonatal Network between January 2015 and December 2017. Patients who received ECC (<30 seconds), UCM, or DCC (≥30 seconds) were compared. Multiple generalized linear/quantile logistic regression models were used. RESULTS: Of 12 749 admitted infants, 9729 were included; 4916 (50.5%) received ECC, 394 (4.1%) UCM, and 4419 (45.4%) DCC. After adjustment for potential confounders identified between groups in univariate analyses, the odds of mortality or major morbidity were higher in the ECC group when compared with UCM group (aOR, 1.18; 95% CI, 1.03-1.35). Mortality and intraventricular hemorrhage were associated with ECC as compared with DCC (aOR, 1.6 [95% CI, 1.22-2.1] and aOR, 1.29 [95% CI, 1.19-1.41], respectively). The odds of severe intraventricular hemorrhage were higher with UCM compared with DCC (aOR, 1.38; 95% CI, 1.05-1.81). Rates of blood transfusion were higher with ECC compared with UCM and DCC (aOR, 1.67 [95% CI, 1.31-2.14] and aOR, 1.68 [95% CI, 1.35-2.09], respectively), although peak serum bilirubin levels were not significantly different. CONCLUSIONS: Both DCC and UCM were associated with better short-term outcomes than ECC; however, the odds of severe intraventricular hemorrhage were higher with UCM compared with DCC.

Stem Cell Composition of Umbilical Cord Blood Following Milking Compared with Delayed Clamping of the Cord Appears Better Suited for Promoting Hematopoiesis.

In comparing placental transfusion strategies, blood obtained from an umbilical cord that has been "milked" vs one in which clamping was simply delayed contains mesenchymal stromal cells in addition to solely hematopoietic stem cells, a composition more favorable for hematopoiesis, as suggested by its superior rescue of lethally irradiated bone marrow-depleted mice.

Postpartum use of oxytocin and volume of placental transfusion: a randomised controlled trial.

OBJECTIVE: To assess whether oxytocin administered before clamping the umbilical cord modifies the volume of placental transfusion. DESIGN: Randomised controlled trial. METHODS: Mothers of term infants born vigorous by vaginal delivery with informed consent provided in early labour were randomly assigned to oxytocin (10 IU) given intravenously within 15 s of birth (group 1) or after clamping the umbilical cord 3 min after delivery (group 2). Soon after birth, all infants were weighed using a 1 g precision scale and subsequently placed on the mother's abdomen or chest. At 3 min, in both groups, the cord was clamped and cut, and the weight was again obtained. The primary outcome (volume of placental transfusion) was estimated by the difference in weights. RESULTS: 144 patients were included. There were no differences in the primary outcome: infants in group 1 (n=70) gained a mean weight of 85.9 g (SD 48.3), and in group 2 (n=74) 86.7 g (SD 49.6) (p=0.92). No differences were found in secondary outcomes, including newborns' haematocrit and bilirubin concentrations and severe maternal postpartum haemorrhage. On the advice of the Data and Safety Monitoring Committee, the trial was stopped due to futility at 25% of the planned sample size. CONCLUSIONS: When umbilical cord clamping is delayed for 3 min, term newborn infants born vigorous receive a clinically significant placental transfusion which is not modified by the administration of intravenous oxytocin immediately after birth. TRIAL REGISTRATION NUMBER: NCT02618499.

Clamping the Umbilical Cord in Premature Deliveries (CUPiD): Neuromonitoring in the Immediate Newborn Period in a Randomized, Controlled Trial of Preterm Infants Born at <32 Weeks of Gestation.

OBJECTIVE: To compare cerebral activity and oxygenation in preterm infants (<32 weeks of gestation) randomized to different cord clamping strategies. STUDY DESIGN: Preterm infants born at <32 weeks of gestation were randomized to immediate cord clamping, umbilical cord milking (cord stripped 3 times), or delayed cord clamping for 60 seconds with bedside resuscitation. All infants underwent electroencephalogram (EEG) and cerebral near infrared spectroscopy for the first 72 hours after birth. Neonatal primary outcome measures were quantitative measures of the EEG (17 features) and near infrared spectroscopy over 1-hour time frames at 6 and 12 hours of life. RESULTS: Forty-five infants were recruited during the study period. Twelve infants (27%) were randomized to immediate cord clamping, 19 (42%) to umbilical cord milking, and 14 (31%) to delayed cord clamping with bedside resuscitation. There were no significant differences between groups for measures of EEG activity or cerebral near infrared spectroscopy. Three of the 45 infants (6.7%) were diagnosed with severe IVH (2 in the immediate cord clamping group, 1 in the umbilical cord milking group; P = .35). CONCLUSIONS: There were no differences in cerebral EEG activity and cerebral oxygenation values between cord management strategies at 6 and 12 hours. TRIAL REGISTRATION: ISRCTN92719670.

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008.

Delayed Cord Clamping in Infants with Suspected Intrauterine Growth Restriction.

We evaluated a subset of infants with suspected intrauterine growth restriction or birth weights small for gestational age enrolled in a study of delayed cord clamping for preterm infants. Compared with immediate clamping, delayed cord clamping was associated with no apparent harm and less suspected necrotizing enterocolitis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00818220 and NCT01426698.

Delayed Cord Clamping in Newborns Born at Term at Risk for Resuscitation: A Feasibility Randomized Clinical Trial.

Infants may benefit if resuscitation could be provided with an intact umbilical cord. Infants identified at risk for resuscitation were randomized to 1- or 5-minute cord clamping. The 5-minute group had greater cerebral oxygenation and blood pressure. Studies are needed to determine whether this translates into improved outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02827409.

Neonatal Resuscitation with an Intact Cord: A Randomized Clinical Trial.

OBJECTIVE: To assess whether providing ventilation during delayed cord clamping (V-DCC) increases placental transfusion compared with delayed cord clamping alone (DCC only). STUDY DESIGN: Inborn premature infants (230/7-316/7 weeks' gestational age) were randomized to receive at least 60 seconds of V-DCC (initial continuous positive airway pressure) with addition of positive pressure ventilation if needed) or without assisted ventilation (DCC only). For the DCC-only group, infants were dried and stimulated by gently rubbing the back if apneic. The primary outcome was the peak hematocrit in the first 24 hours of life. Delivery room outcomes were analyzed from video recordings and a data acquisition system. Hemodynamic measurements were performed with the use of functional echocardiography, near-infrared spectroscopy, and electrical cardiometry. RESULTS: There was no difference in the primary outcome of peak hematocrit in the first 24 hours of life. The onset of breathing was similar between both groups (25 ± 20 and 27 ± 28 seconds, P = .627); however, infants receiving DCC received a greater duration of stimulation than V-DCC (41 ± 19 and 20 ± 21 seconds P = .002). There were no differences in delivery room interventions, early hemodynamics (cerebral oxygenation by near-infrared spectroscopy, cardiac output and stroke volume by electrical cardiometry, or superior vena cava flow by of functional echocardiography), or neonatal outcomes. CONCLUSIONS: V-DCC was feasible but did not lead to any measurable clinical improvements immediately after delivery or reduce subsequent neonatal morbidity. Caretakers should consider providing adequate stimulation before cord clamping. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02231411.

Efecto del clampeo demorado del cordón umbilical en la ferritina sérica a los seis meses de vida. Estudio clínico controlado aleatorizado / The effect ofearly and delayed umbilical cord clamping onferritin levels in term infants at six months oflife. A randomized, controlled trial

Introducción. El clampeo demorado del cordón umbilical aumentaría el depósito de hierro en lactantes. Para comprobar esta hipótesis medimos la ferritina sérica a los seis meses de vida en niños nacidos a término, participantes en un estudio controlado aleatorizado que evaluó el efecto del tiempo de clampeo del cordón en el hematócrito venoso y la evolución neonatal. Métodos. De 276 neonatos incluidos en el estudio original, 255 (92,4%) fueron seguidos seis meses, 86 tuvieron clampeo temprano, 83 al minuto y 83 al tercer minuto. La variable principal de resultado fue la concentración de ferritina sérica a los seis meses. Resultados. Las características de los grupos de madres y niños fueron similares. La ferritina fue significativamente más alta en los niños con clampeo al tercer minuto (33,2 μg/L) que en los de clampeo temprano (20,9 μg/L) (diferencia de medias geométrica: 1,6; IC 95%: 1,2-2,1). No hubo diferencia significativa entre clampeo al minuto (25,5 μg/L) y clampeo temprano. Tampoco hubo diferencia en los valores medios de hemoglobina, entre los grupos temprano [10,6 g/dl (DE 1,11)], al minuto [10,8 g/dl (DE 0,86)] y tres minutos [10,7 g/dl (DE 0,97)], respectivamente. La prevalencia de anemia ferropénica fue tres veces mayor en niños con clampeo temprano (7%) en comparación con los del tercer minuto (2,4%) (diferencias no significativas; RR: 0,30; IC 95%: 0,10-1,60). Conclusión. En niños nacidos a término, el clampeo del cordón umbilical a los tres minutos del nacimiento aumentó significativamente las concentraciones de ferritina a los seis meses de edad. No hubo diferencias significativas en los niveles de hemoglobina.

Background. Delayed umbilical cord clamping could increase iron stores and prevent iron deficieney in infants. To test this hypothesis we measured serum ferritin and hemoglobin levels at six months of age in term infants who had participated in a randomized controlled trial, assessing the effect of cord clamping timing on neonatal hematocrit values and clinical outcome. Main outcome measure. Serum ferritin level at six months of age. Methods. Out of the 276 mothers and their infants that participated in the initial study, 255 (92.4%) were followed up to six months and included in this study. Of these, 86 had their cords clamped within the first 15 seconds (early clamping), 83 at one minute, and 83 at three minutes. The pediatricians in charge of the evaluations during the follow-up period and personnel in charge of the biochemical tests were blinded to the assignment group. In all but 3 infants the ferritin levels and hemoglobin levels were measured at six months of age. Results. Mothers and infants in the three groups had similar baseline characteristics. Serum ferritin levels were significantly higher in the infants of the three minutes group than in the infants of the early group: 33.2 μg/L vs. 20.9 ug/L(geometric mean ratio: 1.6;95%CI: 1.2 to 2.11) but no difference was observed in one minute group (25.5 μg/L) vs. early group. There were no significant differences inmeanhemoglobin values, 10.6 g/dl (SD 1,1); 10.8 g/dl (SD 0.9) and 10.7 g/dl (SD 1.0) between groups early, one minute, and three minutes, respectively. Although there were no significant differences between groups, the prevalence of iron deficiency anemia (hemoglobin < 10.5 g/dl and ferritin < 9 μg/L) was 3 times more frequent in early clampling group (7.2%) than in three minutes group (2.4%) (RR: 0.30; IC 95%: 0.10-1.60). Conclusions. Delayed umbilical cord clamping at three minutes significantly increases serum ferritin levels in infants at 6 months of age. No significant differences were found between groups in mean hemoglobin levels.