PLACENTAL TRANSFUSION

Move slowly – Prolonged placental transfusion stabilizes preterm newborns

Puran Falaturi

(Photo: iStock.com/MedicalArtInc)

The optimal moment for clamping the umbilical cord is a recurrent subject of discussion. Early clamping allows for immediate transfer of the infant to the neonatologist. Later clamping, however, results in a prolonged placental transfusion which improves peripartum circulation and so can have other positive outcomes for the newborn (1) (2). This is true for full-term as well as for preterm neonates. For premature infants, however, interventions that can have an additional stabilizing effect are far more urgent.

Examples of improved outcomes that can result from prolonged placental transfusion include a lower incidence of intraventricular hemorrhages (IVH), a higher birth weight, better hemoglobin concentration and larger iron reserves up to six months after birth. As a result of the large volume and the higher hemoglobin (Hb) values, infants with later umbilical clamping require fewer erythrocyte transfusions (2, 3, 4, 5). Hyperbilirubinemia that requires phototherapy and hypothermia were described as negative concomitant phenomena in several studies (1, 2), but were not confirmed in all studies.

Reviews and meta-analyses

Several reviews with meta-analyses have been published on this subject. Some of these focus on preterm and extremely preterm newborns. Rabe et al. (1) updated a Cochrane Review in 2012 on the comparison of early and late clamping in premature infants. The authors searched the study registry of the Cochrane Pregnancy and Childbirth Group through June 2012. The age of the included neonates was between 24 and 36 weeks gestational age. The review included randomized controlled studies that compared early and delayed clamping and other procedures for prolonged placental transfusion. Fifteen studies (738 infants) could be included.

The results of the Cochrane Review showed a maximum period until clamping of 180 seconds. Delayed clamping was associated in seven studies with 392 infants with significantly fewer blood transfusions (risk ratio (RR) 0.61). In ten studies with a total of 539 infants, there were significantly fewer sonographically confirmed intraventricular hemorrhages independent of the degree of severity (RR 0.59). Five studies with a total of 241 children found a lower risk of necrotizing enterocolitis (NEC with delayed clamping (RR 0.62). However, the bilirubin peak in infants with delayed clamping was significantly higher than in the controls (seven studies, 320 children, mean difference 15.01 mmol/L). Most of the other outcomes including mortality rate, serious intraventricular hemorrhages and PVL did not show any clear differences. There were no significant differences between the groups in the mean Bayley II Score at the corrected age of seven months (58 children). None of the studies reported about outcomes for the mothers.

Ghavam et al. (4) showed in a 2014 review that delayed clamping and postpartum cord milking in extremely low birth weight (ELBW) infants under 30 weeks (<1000g) had many short-term benefits. They analyzed literature up to December 2012. Ten of 19 identified studies were included (n = 199). Neurological development disorders in the sense of a disability were not significantly increased at an age of 18 and 24 months. But there were short-term benefits such as better blood pressure and hemoglobin values and with this a reduced need for blood transfusions.  In addition, the researchers found a trend towards fewer intraventricular hemorrhages and less late onset sepsis.

Current clinical studies confirm benefits

In both reviews, the researchers concluded that further clinical studies should be conducted in future. A quite recent publication has come from neonatologists in the USA in 2016 (the Bolstridge study) (5). This publication compares two cohorts with infants who were born prior to gestational week 37 (level 3 hospital, 52 beds). Only very low birth weight (VLBW) infants were included in the analysis. Cohort 1 consisted of 136 children who were born prior to the recommendation for delayed clamping and were more or less immediately clamped (exception 0.7 percent). The observation period extended from 1 July 2012 to 30 June 2013. Cohort 2 included 142 infants born in the period from 1 July 2013 to 30 June 2014 after the implementation of the recommendation for delayed clamping. This occurred independent of umbilical cord management since all of the newborns were also participating in the quality improvement program, and so the data for all the births was included. In total, 72 percent of the children in Cohort 2 had delayed cord clamping.

Results

The sociodemographic data, mortality and Apgar scores did not differ between the two groups. Significant differences in favor of delayed clamping were found in connection with intubation, chest compressions, erythrocyte transfusion, ventilation, CPAP and late onset sepsis (see Table 1). The researchers found no differences between the two groups regarding the incidence of IVH of any degree, PVL, early onset sepsis, NEC or the necessity of inotropic support during the hospital stay. Important to note is the fact that in contrast to previous study results the potentially negative effects of hypothermia and hyperbilirubinemia requiring phototherapy did not increase.

Interpretation

The authors remark that the apparent causality observed between umbilical cord management and reduced need for intubation and chest compression should be viewed cautiously. At the same time as the study, the hospital was implementing a policy of more restrictive ventilation management to reduce the rate of BPD. This could be a reason for the significantly lower figures. However, the reduced rate in CPAP ventilation cannot be explained by the new ventilation management policy. This could more likely be attributed to the delayed clamping. The statistical power of the study was not sufficient for relatively rare disorders such as NEC and PVL.

Conclusion

Both reviews come to the conclusion that prolonged placental transfusion can improve the short-term outcome of ELBW neonates. Rabe et al. (1) state more precisely that prolonged placental transfusion through delayed clamping (30 to 120 seconds) seems to be accompanied by lower need for transfusion, better cardiovascular stability, less intraventricular hemorrhage (all degrees) and a lower risk of NEC. However, the data basis was not sufficiently reliable for definite recommendations. The data basis regarding neurological development disorders and safety aspects is very thin according to Ghavam et al. (4). For that reason, additional well designed RCTs should be made on this subject. The authors of the Bolstridge study (5) emphasize the relevance of having a multidisciplinary and well-trained team so that the best measures can also be successfully implemented. Negative concomitant phenomena such as hyperbilirubinemia and hypothermia could not be consistently confirmed and need to be reviewed. However, in relation to the benefits of delayed clamping, these negative factors are less significant.

Sources:

1. Rabe H, Diaz-Rossello JL, Duley L, Dowswell T, Cochrane Database Syst Rev, 2012 Aug 15;(8):CD003248. doi: 10.1002/14651858.CD003248.pub3, „Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.“
   http://bit.ly/2hnXqEW
2. Wyllie J, Bruinenberg J, Roehr CC, Rüdiger M, Trevisanuto D, Urlesberger B, European Resuscitation Council (ERC), Notfall Rettungsmed 2015, 18:964–983, DOI 10.1007/s10049-015-0090-0, Online publiziert: 9. November 2015, Die Versorgung und Reanimation des Neugeborenen, Kapitel 7 der Leitlinien zur Reanimation 2015 des European Resuscitation Council
   http://www.guidelines2015.com/
3. McDonald SJ, Middleton P, Dowswell T, Morris PS, Cochrane Review Gruppe:  Pregnancy and Childbirth Group, 11. Juli 2013, The Cochrane Library, First published: 11 July 2013, DOI: 10.1002/14651858.CD004074.pub3View/save citation, „Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes.“
4. Ghavam S, Batra D, Mercer J, Kugelman A, Hosono S, Oh W, Rabe H, Kirpalani H, Transfusion. 2014 Apr;54(4):1192-8, „Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.“
   https://www.ncbi.nlm.nih.gov/pubmed/24843886
5. Bolstridge J, Bell T, Dean B, Mackley A, Moore G, Swift C, Viscount D, Paul DA, Pearlman SA, BMC Pediatr. 2016 Sep 13;16(1):155. doi: 10.1186/s12887-016-0692-9, „A quality improvement initiative for delayed umbilical cord clamping in very low-birthweight infants.“
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022231/
6. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Committee opinion no. 543: Timing of umbilical cord clamping after birth. Obstet Gynecol. 2012;120:1522–6
   http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Timing-of-Umbilical-Cord-Clamping-After-Birth
7. AAP Empfehlungen 2015, Part 13 Neonatal Resuscitation, No. 3 Umbilical Cord Management 
   https://eccguidelines.heart.org/index.php/circulation/cpr-ecc-guidelines-2/part-13-neonatal-resuscitation/     COPIED.