Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.

BACKGROUND
Infants born preterm (before 37 weeks' gestation) have poorer outcomes than infants at term, particularly if born before 32 weeks. Early cord clamping has been standard practice over many years, and enables quick transfer of the infant to neonatal care. Delayed clamping allows blood flow between the placenta, umbilical cord and baby to continue, and may aid transition. Keeping baby at the mother's side enables neonatal care with the cord intact and this, along with delayed clamping, may improve outcomes. Umbilical cord milking (UCM) is proposed for increasing placental transfusion when immediate care for the preterm baby is needed. This Cochrane Review is a further update of a review first published in 2004 and updated in 2012.


OBJECTIVES
To assess the effects on infants born at less than 37 weeks' gestation, and their mothers of: 1) delayed cord clamping (DCC) compared with early cord clamping (ECC) both with immediate neonatal care after cord clamping; 2) DCC with immediate neonatal care with cord intact compared with ECC with immediate neonatal care after cord clamping; 3) DCC with immediate neonatal care after cord clamping compared with UCM; 4) UCM compared with ECC with immediate neonatal care after cord clamping.


SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 November 2017), and reference lists of retrieved studies. We updated the search in November 2018 and added nine new trial reports to the awaiting classification section to be assessed at the next update.


SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing delayed with early clamping of the umbilical cord (with immediate neonatal care after cord clamping or with cord intact) and UCM for births before 37 weeks' gestation. Quasi-RCTs were excluded.


DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Random-effects are used in all meta-analyses. Review authors assessed the certainty of the evidence using the GRADE approach.


MAIN RESULTS
This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias.All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias.Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers)DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)).No studies reported on 'Death or neurodevelopmental impairment' in the early years'.DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty).DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty).Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty).We identified no important heterogeneity in subgroup or sensitivity analyses.Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers)There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision.Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers)There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty).


AUTHORS' CONCLUSIONS
Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM.The nine new reports awaiting further classification may alter the conclusions of the review once assessed.

T his review update analyzes what regimens of cord clamping improve outcomes for preterm neonates (less than 37 weeks of gestation). Delayed cord clamping is thought to be associated with improved outcomes owing to improved blood circulation during the immediate transition to life outside of the uterus. The authors reviewed four different strategies for management, but only one had enough data to draw reliable conclusions: delayed cord clamping compared with early cord clamping, both with immediate neonatal care after clamping. Data were available from 40 studies reporting on 4,884 neonates. Delayed cord clamping in the trials typically ranged from 30 to 180 seconds. The authors found that, compared with early cord clamping, delayed cord clamping probably reduces the number of preterm neonates who die before discharge (average risk ratio [aRR] 0.73, 95% CI 0.54-0.98, moderate-certainty evidence) and may slightly reduce the number of neonates with any grade of intraventricular hemorrhage (aRR 0.83, 95% CI 0.7-0.99). Delayed cord clamping had little or no effect on chronic lung disease, and there was insufficient evidence for other outcomes. Comparisons of umbilical cord milking with delayed cord clamping or early cord clamping demonstrated either little or no differences in outcomes or had insufficient evidence to draw conclusions.
In line with this review, the American College of Obstetricians and Gynecologists currently recommends delayed cord clamping for 30-60 seconds for preterm neonates owing to significant neonatal benefits, including lower risks of necrotizing enterocolitis and intraventricular hemorrhage as well as a decreased need for blood transfusions. Furthermore, it was not noted to increase risk of postpartum hemorrhage or blood transfusion in the mother. 1 Bottom Line: Delayed cord clamping likely reduces mortality risk for preterm neonates, but there is insufficient evidence to conclude what duration is optimal, whether neonatal care should be administered before or after cord clamping, or whether umbilical cord milking is beneficial.

Mechanical Methods for Induction of Labour
This large review update compared safety and efficacy of various mechanical methods for labor induction with pharmacologic methods across 113 trials of 22,373 women. Comparisons included: 1) specific mechanical methods (balloon catheter, laminaria tents, and extra-amniotic space injection) compared with prostaglandins (varied types and routes) or oxytocin; 2) single compared with double balloon; and 3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone. There were 21 total comparisons made in the review. The authors found that mechanical induction with a balloon is likely as effective as vaginal prostaglandin E 2 in achieving vaginal delivery within 24 hours (primary outcome, low-certainty evidence) and also has a more favorable safety profile, with reduced risk of hyperstimulation with fetal heart rate changes (risk ratio 0.35, 95% CI 0.18-0.67), serious neonatal morbidity or mortality (risk ratio 0.48, 95% CI 0.25-0.93), and neonatal intensive care unit admission (risk ratio 0.82, 95% CI 0.65-1.04). Compared with misoprostol, balloon catheter was found to probably increase the risk of vaginal delivery not occurring within 24 hours when compared with oral misoprostol (risk ratio 1.28, 95% CI 1.13-1.46), but it was uncertain whether there was a difference in this outcome compared with vaginal misoprostol. However, the balloon catheter slightly increased the risk of cesarean delivery compared with vaginal and oral misoprostol (risk ratio 1.28 and 1.17, respectively). A balloon catheter probably reduces the risk of uterine hyperstimulation with fetal heart rate changes compared with vaginal misoprostol, but it was uncertain whether there was a difference compared with oral misoprostol. Other comparisons did not have sufficient evidence to make conclusions or were uncertain as to whether there was a difference.
Bottom Line: Balloon catheters are safer and just as effective as vaginal prostaglandin E 2 and may be slightly less effective than oral misoprostol, but it remains unclear whether there is a difference in safety outcomes for the neonate. When compared with vaginal misoprostol, evidence shows a balloon may be as effective and may have a better safety profile.
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