Role of delayed cord clamping in prevention of necrotizing enterocolitis in preterm neonates: a systematic review

Background: Necrotizing enterocolitis (NEC) is one of the leading causes of neonatal mortality and morbidity particularly in very-low-birth-weight (VLBW) neonates. The incidence of NEC varies across countries and neonatal centers in between 7% and 14%.

Aims: The aim of this study is to evaluate the role of delayed cord clamping (DCC) for prevention of NEC in preterm neonates.

Method: The literature search was done for various randomized control trial (RCT) by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, ongoing clinical trials, and abstract of conferences.

Results: This review included six RCTs that fulfilled inclusion criteria. There was statistically significant reduction in the incidence of NEC in DCC group (12.2% versus 20.6%; risk ratio (RR) 0.59; 95% CI 0.37–0.94; p?=?.02; number needed to treat (NNT) 12). However, mortality due to any cause before hospital discharge was not statistically significant (RR 0.80; 95% CI 0.33–2.00; p?=?.64).

Conclusion: The role of DCC in the prevention of NEC is supported by the current evidences. However, given the small sample sizes and other limitations of these studies, current evidences are not sufficient. We need large high-quality trials, with sufficient power to reliably assess clinically relevant differences in important outcomes.

Trial registration: ClinicalTrials.gov identifier: NCT02996799.

Trial registration: ClinicalTrials.gov identifier: NCT02092103.     

A review of benefits of cord milking over delayed cord clamping in the preterm infant and future directions of research

Purpose of review: The recommended method of handling the umbilical cord has undergone a complete 360° turn over the years and current knowledge and research has led the direction to delayed clamping and cord milking. This practice has also been supported by American College of Obstetrics and Gynecology (ACOG) in 2012. This review is a summary of current evidence on delayed cord clamping (DCC), umbilical cord milking (UCM), and comparison between the two and future directions.

Recent findings: Multiple studies have been published establishing the safety of umbilical cord milking. Data comparing UCM to DCC favor milking specifically in terms of improved systemic perfusion and higher hemoglobin concentrations.

Summary: UCM is emerging as a safe, quick alternative to DCC and more advantageous especially among premature infants and those delivered via cesarean section.     

Clamp late and maintain perfusion (CLAMP) policy: delayed cord clamping in preterm infants

Objective: Randomized controlled trials have demonstrated that delayed umbilical cord clamping (DCC) in preterm infants results in improved neonatal outcomes, including increased hematocrit, and decreased rates of intraventricular hemorrhage (IVH) and packed red blood cell transfusions. We hypothesized that implementation of a DCC policy in preterm infants would result in similarly improved outcomes, despite initial clinician resistance.

Study design: A DCC policy (30–60?s) for singleton infants <35 weeks gestation was implemented in September 2011. We conducted a pre-test/post-test analysis of neonatal outcomes among singletons delivered between 24 0/7 weeks and 34 6/7 weeks gestation from 2009 to 2013 (2 years pre-implementation and 2 years post-implementation). The primary outcomes were rates of policy compliance and four neonatal outcomes.

Results: Despite multiple routes of policy dissemination, DCC was attempted in only 49% of the deliveries. In spite of this, infants delivered post-policy implementation (n?=?196) had a significant decrease in IVH, significant increase in initial hematocrits, and improved temperatures compared with infants delivered pre-implementation (n?=?204).

Conclusion: After implementation of a DCC policy, preterm singleton infants had improved temperatures, increased hematocrits and a decreased prevalence of IVH without significant differences in adverse outcomes, suggesting that the benefits of DCC outweighed the risks.     

Early term births: considerations in management

The frequency of early term birth varies depending on patient, provider, and system characteristics. Early term deliveries are associated with suboptimal neonatal outcomes without evidence of maternal benefit. Some early term births are either unavoidable or absolutely indicated for maternal and/or fetal benefit in the setting of medical or obstetric risks. Demonstrated fetal lung maturity before early term birth reduces the risk of respiratory and other morbidities relative to gestational age-matched counterparts but may not reduce the risks to the low levels at 39 to 40 weeks. For some risk situations, it remains controversial whether earlier delivery is beneficial. The assessment of the provider and patient’s desires should direct care. In the absence of any obstetric or medical risks, early term delivery should be avoided. A simple intervention that includes administrative support, review of indications, and feedback to providers can dramatically reduce the frequency of early term births over time.     

Placental transfusion: umbilical cord clamping and preterm infants.

OBJECTIVE: To investigate the clinical effects of early versus late cord clamping in preterm infants. STUDY DESIGN: A total of 32 premature infants were prospectively randomized. The following parameters were measured: Initial spun hematocrit (Hct), hemoglobin (Hgb), red blood cell (RBC) counts, frequency of blood transfusions, peak serum bilirubin, mean blood pressure (MBP), oxygen index, intraventricular hemorrhage, and significant patent ductus arteriosus (PDA). RESULTS: Over the 4-week study period, the delayed cord clamping (DCC) group exhibited a decrease in the frequency of blood transfusion (p < 0.001) and also a decrease in albumin transfusions over the first 24 hours (p < 0.03). MBP in the first 4 hours was higher in the DCC group (p < 0.01), and there were statistically significant increases in Hct (21%), Hgb (23%), and RBC count (21%) compared with the early cord clamping group. The risks of patent ductus arteriosus, hyperbilirubinemia, or intraventricular hemorrhage were similar in both groups. Late clamping of the umbilical cord had little or no effect on the oxygen index. CONCLUSION: DCC significantly reduced the requirement for blood and albumin transfusion. It also increased the initial Hct, RBC count, Hgb levels, and MBP.     

Delayed cord clamping and inotrope use in preterm infants

Objective: To evaluate the impact of delayed cord clamping (DCC) on need for inotropic support and mean arterial blood pressure (MABP).

Methods: This is a single-center, prospective case-control study of premature infants, born <32 weeks gestation, who underwent DCC in comparison to a matched control group who underwent immediate cord clamping (ICC). The primary outcomes were the differences in MABP and inotropic medication used over the first week of life. Secondary outcomes included the admission hemoglobin, need for blood transfusion, and rates of intraventricular hemorrhage (IVH). Infants were matched on EGA, birth weight, sex, antenatal corticosteroid and magnesium exposure, and presence of chorioamnionitis.

Results: Hundred and fifty-eight infants (DCC n?=?79, ICC n?=?79) were included. Demographic factors were similar between groups. DCC infants had a higher admission hemoglobin (p?p?=?.03), fewer median transfusions (p?=?.03), and were discharged at an earlier post-menstrual age (p?=?.04). When controlling for other factors, DCC was not associated with a reduction in inotrope use (p?=?.22) but was associated with a reduction in high-grade IVH (p?=?.01). There was no difference in MABP between the groups.

Conclusions: DCC is not associated with a reduction in the use of inotropes or a difference in MABP.     

Effects and safety of delayed versus early umbilical cord clamping in newborns of HIV-infected mothers

Objective: To investigate the effect of a 2 minutes-delayed cord clamp (DCC) versus early cord clamp (ECC) on neonate haemoglobin concentration 24 hours and 1 month after birth, and assess the safety of DCC concerning the risk of HIV infection.

Design: Sixty-four mother-infant peers were enrolled. All mothers were on stable ARV therapy. Viral load, CD4⁺ count and blood haemoglobin (Hb) concentrations 24 hours before delivery were collected from all mothers and their infants.

Methods: All patients were enrolled at the Department of Paediatrics, AO FBF Sacco Hospital in Milan, and were followed until 18 months after birth. Women with haematological diseases and obstetrical complications were excluded. All of 64 mother and infants couples (32 ECC group and 32 DCC group) completed the study. ECC and DCC are defined as application of umbilical clamp within 30 seconds and 120 seconds after birth, respectively.

Results: Mean birth weight was significantly higher in the DCC compared with ECC group. Mean Hb levels at birth were significantly higher in DCC than in ECC group (p?=?.05): this difference persisted at 1 month of life. All newborns showed negative viral load.

Conclusions: DCC 2 minutes after birth is proven to be a safe procedure, particularly beneficial in newborns from HIV mothers. The risk of anemia is significantly decreased at 24 hours after birth and persists at age of 1 month without any increased risk of neonatal jaundice or polycitemia.     

A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants

BACKGROUND: The optimal timing of clamping the umbilical cord in preterm infants at birth is the subject of continuing debate. Objective: To investigate the effects of a brief delay in cord clamping on the outcome of babies born prematurely. METHODS: A retrospective meta-analysis of randomised trials in preterm infants was conducted. Data were collected from published studies identified by a structured literature search in EMBASE, PubMed, CINAHL and the Cochrane Library. All infants born below 37 weeks gestation and enrolled into a randomised study of delayed cord clamping (30 s or more) versus immediate cord clamping (less than 20 s) after birth were included. Systematic search and analysis of the data were done according to the methodology of the Cochrane collaboration. RESULTS: Ten studies describing a total of 454 preterm infants were identified which met the inclusion and assessment criteria. Major benefits of the intervention were higher circulating blood volume during the first 24 h of life, less need for blood transfusions (p = 0.004) and less incidence of intraventricular hemorrhage (p = 0.002). CONCLUSIONS: The procedure of a delayed cord clamping time of at least 30 s is safe to use and does not compromise the preterm infant in the initial post-partum adaptation phase.     

Neonatal mortality and morbidity rates in late preterm births compared with births at term

OBJECTIVE: To analyze neonatal mortality and morbidity rates at 34, 35, and 36 weeks of gestation compared with births at term over the past 18 years at our hospital and to estimate the magnitude of increased risk associated with late preterm births compared with births later in gestation. METHODS: We performed a retrospective cohort study of births at our hospital over the past 18 years. The study included all liveborn singleton infants between 34 and 40 weeks of gestation and without anomalies that were delivered to women who received prenatal care in our hospital system. Neonatal outcomes for late preterm births were compared with those for infants delivered at 39 weeks. RESULTS: Late preterm singleton live births constituted approximately 9% of all deliveries at our hospital and accounted for 76% of all preterm births. Late preterm neonatal mortality rates per 1,000 live births were 1.1, 1.5, and 0.5 at 34, 35, and 36 weeks, respectively, compared with 0.2 at 39 weeks (P<.001). Neonatal morbidity was significantly increased at 34, 35, and 36 weeks, including ventilator-treated respiratory distress, transient tachypnea, grades 1 or 2 intraventricular hemorrhage, sepsis work-ups, culture-proven sepsis, phototherapy for hyperbilirubinemia, and intubation in the delivery room. Approximately 80% of late preterm births were attributed to idiopathic preterm labor or ruptured membranes and 20% to obstetric complications. CONCLUSION: Late preterm births are common and associated with significantly increased neonatal mortality and morbidity compared with births at 39 weeks. Preterm labor was the most common cause (45%) for late preterm births. LEVEL OF EVIDENCE: II.     

Umbilical cord prostaglandins in term and preterm parturition

Objective: Prostaglandins (PGs) are considered the universal mediators of parturition. Amniotic fluid PGE₂ and PGF_2α concentrations increase before the onset of spontaneous labor at term, as well as during labor. This study was conducted to determine if the concentrations of umbilical cord PGE₂ and PGF₂α change with advancing gestational age, spontaneous labor at term, and preterm labor (with and without funisitis).

Methods: Umbilical cord (UC) tissue samples were obtained from women (N?=?158) with singleton pregnancies in the following groups: (1) term deliveries without labor (TNL; n?=?20); (2) term deliveries with labor (TIL; n?=?20); (3) spontaneous preterm deliveries (sPTD) with (n?=?20) and without acute funisitis (n?=?20); and (4) preeclampsia without labor (n?=?78). The concentrations of PGs were determined in different locations of the UC. PGE₂ and PGF_2α were measured by specific immunoassays. Non-parametric statistics were used for analysis.

Results: (1) In spontaneous preterm deliveries, the median UC PGE₂ concentration was higher in cases with funisitis than in those without funisitis (233.7?pg/µg versus 87.4?pg/µg of total protein, p?=?0.001); (2) the median UC PGE₂ concentration in sPTD with funisitis was also higher than that obtained from samples who had undergone labor at term (233.7?pg/µg versus 116.1?pg/µg of total protein, p?=?0.03); (3) the UC PGE₂ and PGF_2α concentration increased as a function of advancing gestational age before 36 weeks (PGE₂: ρ?=?0.59, p?<?0.001; PGF_2α: ρ?=?0.39, p?=?0.01), but not after 36 weeks (PGE₂: ρ?=??0.1, p?=?0.5; PGF_2α: ρ?=??0.2, p?=?0.2); (4) the median UC concentrations of PGE₂ and PGF_2α at term was similar in samples obtained from women with and without labor (PGE₂: TNL 133.7?pg/µg versus TIL 116.1?pg/µg of total protein, p?=?0.9; PGF_2α: TNL 8.4?pg/µg versus TIL 8.1?pg/µg of total protein, p?=?0.7); and (5) there was no correlation between UC PG concentration and gestational age at term pregnancy (PGE₂: ρ?=?0.01, p?=?0.9; PGF_2α: ρ?=?0.07, p?=?0.7).

Conclusions: (1) PGE₂ concentrations in the UC are higher in the presence of acute funisitis than in the absence of this lesion; (2) spontaneous labor at term was not associated with a change in the UC concentration of PGE₂ and PGF_2α; and (3) the UC concentrations of PGE₂ and PGF_2α increased as a function of gestational age. We propose that UC PGs act as inflammatory mediators generated in the context of fetal systemic inflammation.     

Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study

The purpose of this study was to test whether delayed versus immediate cord clamping would result in higher blood pressure (BP) and hematocrit (Hct), and to assess its clinical effects on the neonatal course in premature neonates (< 35 weeks). This was a prospective, masked, randomized, controlled study. Prior to delivery, 35 neonates were randomly assigned to immediate cord clamping (ICC) at 5 to 10 seconds, and a comparable group of 30 neonates were randomly assigned to delayed cord clamping (DCC) at 30 to 45 seconds. Intention-to-treat analyses revealed that the DCC group tended to have higher initial diastolic BP and higher Hct (especially in vaginally delivered neonates). Infants weighing < 1500 g with DCC tended to have higher mean BP, and needed less mechanical ventilation and surfactant compared with ICC neonates. Infants with DCC did not experience more polycythemia (Hct > 60%), but had a trend toward higher bilirubin levels with no differences in the phototherapy needs. DCC seems to be safe and may be beneficial when compared with ICC in premature neonates. However, the differences between the two methods were modest and the clinical relevance needs to be assessed further by larger studies and additional meta-analysis of randomized trials.     

Term babies with delayed cord clamping: an approach in preventing anemia*

Objective: We investigated the effects of delayed and early clamping of the cord on the hematologic status of the baby at birth and at the end of second month.

Methods: Umbilical cord of 74 babies were clamped in the first 30?s (Group 1) and 76 were clamped at 90–120?s (Group 2). Levels of hemoglobin, hematocrit, iron and ferritin were analyzed from the umbilical cord blood at birth and from the venous samples at the end of second month.

Results: Hemoglobin, hematocrit, iron and ferritin levels of cord blood were similar in both groups. However, their levels other than ferritin were higher in Group 2 at the end of second month. Two babies had respiratory distress and twelve neonates received phototherapy in Group 2 whereas only five neonates received phototherapy in Group 1.

Conclusion: Term babies to whom delayed cord clamping was performed had improved hematological parameters at the end of second month. Therefore, delaying cord clamping in these babies may be a favorible approach in preventing anemia.     

Circadian incidence of premature rupture of the membranes in term and preterm births

A highly circadian incidence of premature rupture of the fetal membranes was found in the Collaborative Perinatal Project data base. Among term deliveries without membranitis, the peak incidence of premature rupture of the membranes occurred at 3:00 AM, and the amplitude of a fitted sinusoid was 45%. Rupture hour was markedly influenced by latent interval and by membranitis. In the absence of membranitis, in term cases with a latent interval of less than three hours, rupture hour peaked at 2:00 AM, with an amplitude of 64%. Those with a latent interval of three to 35 hours peaked at 4:15 AM, with an amplitude of 37%. Those with 36 or more hours' latent interval showed little circadian variation. Preterm premature rupture of the membranes was also segregated into subgroups by latent interval. Preterm premature rupture of the membranes with a three- to 35-hour latent interval peaked at 4:00 AM, with an amplitude of 31%, similar to the corresponding term group. A circadian factor thus appears to cause most cases of premature rupture of the membranes in term and preterm births when membranitis is absent. The observed stratification by latent interval indicates that the mechanisms of premature rupture of the membranes may differ between the subgroups. With membranitis, the early-morning peak in premature rupture of the membranes was not statistically demonstrable in any of the term or preterm latent interval subgroups. This indicates that there may be unique rupture mechanisms associated with membranitis. The data in this study should assist efforts to classify premature rupture of the membranes and study its mechanisms.     

Effect of delayed umbilical cord clamping on blood gas analysis

Objective

To ascertain if there are differences in umbilical cord blood gas analysis between immediate and delayed cord clamping.

Study design

In a prospective observational study on 60 vaginally delivered healthy term newborns, we sampled umbilical cord blood immediately after delivery and at the time umbilical cord pulsation spontaneously ceased.

Results

There were significant decreases in pH, oxygen saturation (sO₂), glycemia, oxygen content (ctO₂), bicarbonate (HCO₃⁻) and base excess (BE). Lactate and PCO₂$P_{{\text{CO}}_2}$ increased. Delayed cord clamping pH correlated with immediate cord clamping pH, PO₂$P_{{\text{O}}_2}$, ctHb, sO₂ and time (r² = 0.77, p < 0.000). Delayed cord clamping lactate was associated with immediate cord clamping lactate and time (r² = 0.83, p < 0.000). Delayed BE was associated with previous pH, lactate, glycemia, ctHb and time (r² = 0.83, p < 0.000).

Conclusions

Delayed cord clamping alters acid–base parameters and lactate values compared to immediate cord clamping. Those variations depend mainly on time, prior pH and lactate.