Effect of Delayed Versus Early Cord Clamping on Improving Anemia in Term Infants Aged Two Months or Older

systematic Review

Indian Pediatr 2020;57: 815-819

Effect of Delayed Versus Early Cord Clamping on Improving Anemia in Term Infants Aged Two Months or Older - A Meta-analysis

Xin Fu, Dan Dang, Siwen Li, Zhiyan Xu and Hui Wu

From Department of Neonatology, The First Hospital of Jilin University, Changchun 130021, China.

*Correspondence to: Dr Hui Wu, Department of Neonatology, The First Hospital of Jilin University,NO.71 Xinmin Street, Changchun, China 130 021.
Email: [email protected]

Objective: To assess the effects of delayed cord clamping (DCC) on hemoglobin (Hb), mean corpuscular volume (MCV) and ferritin level in infants 2 months or older.

Evidence acquisition: Meta-analysis of randomized control trials searched systematically from PubMed, Cochrane and Web of science. Trials published from Jan 1,1975 to Mar 12, 2018, no language and country restrictions. Twelve studies were included in this meta-analysis. In total, 993 infants were treated with DCC, while 989 cases received early cord clamping. Delayed cord clamping was defined as umbilical cord clamping time greater than 60s after delivery. Outcomes assed were (i) hemoglobin (Hb), (ii) mean corpuscular volume (MCV) and ferritin level.

Results: The results show that DCC increased hemoglobin level (SMD=0.4678 95%CI: [0.1515, 0.7841]), Ferritin level (SMD=2.1450 95%CI: [1.0431, 3.2470]) and MCV (SMD=0.5751 95%CI: [0.1637, 0.9865]) in infants between 2-12 months compared to ECC subject analysis noted the effects of Hb increase was greater in Asian infants.

Conclusions: Delayed cord clamping improved the Hb, MCV and ferritin level of infants after birth.

Keywords: Hemoglobin, Infant, Meta-analysis, Umbilical cord.

The appropriate timing of umbilical cord clamping has been a matter of debate for long. Early umbilical cord clamping (ECC) was standard practice but with emerging evidence it has started to shift to delaying cord clamping (DCC) to beyond 30-60 secs. In term infants, placental transfusion contributes between one-quarter and one-third of total potential blood volume at birth [1]. At 1-minute, newborn infants receives about 80 mL of blood while at 2-3 minutes it is about 100 mL [2].

The American Association of Obstetricians guideline, 2017, states that DCC can increase hemoglobin levels at birth, and early iron stores [3]. The guideline also recommends a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth. In addition, it can also benefit the preterm infants by decreasing the need for blood transfusion, lowering incidence of necrotizing enterocolitis and intraventricular hemorrhage. Previous systematic reviews [4,5] have reported the advantages of DCC, but mainly as a dichotomous variable, and mainly during the neonatal period [6]. The present systematic review and meta-analysis reports change in hemoglobin between ECC and DCC in infants 2 months or older.

METHODS

All relevant studies published between January 1, 1975 and March 8, 2018 were identified by searching PubMed, Cochrane reviews and Web of science. The Search strategy used the terms (((delayed cord clamping [Title/Abstract]) OR delayed cord ligation [Title/Abstract])) OR ((late cord clamping [Title/Abstract]) OR late cord ligation [Title/Abstract]))) Filters: Randomized Controlled Trial. There was no language limitation in the selection.

Studies were screened and selected by the following criteria: (a) randomized controlled trials (except quasi randomized study); (b) singleton newborns, no developmental deformity, no gestational age limit; (c) clinical trial data included hemoglobin, mean corpuscular volume (MCV) and ferritin; (d) delayed cord clamping was in intervention group, and early cord clamping was in control group; (e) the outcomes’ were measured at 2 months or more after birth. Articles were excluded if it was a conference summary; had Incomplete data; presence of maternal complications (antepartum blood loss, pregnancy-induced hyper-tension, pre-eclampsia and gestational diabetes); history of post-partum hemorrhage (PPH), there was need for neonatal resuscitation, or history of fetal distress.

The following data were extracted from each selected study: Region where study was performed, total number of participants, gestational age, follow-up time, and the effect of DCC versus ECC beyond 2 months were also compared; hemoglobin as the main outcome, MCV or ferritin as a secondary outcome.

For meta-analysis, RevMan 5.3 of the Cochrane Collaboration and stata 12.0 was used [6]. The Cochrane risk bias assessment tool was used to assess the bias in the included studies. Clinical and methodological heterogeneity of the included studies were analyzed, and subgroup analysis were conducted according to clinical and methodological heterogeneity. The I2 index was calculated to assess the degree of heterogeneity. In the absence of heterogeneity (P³0.05; I2£50%), a fixed effect model was used; if there was heterogeneity between studies (P<0.05; I2>50%), a random effects model was used. Sensitivity analysis was used to assess the stability of the results. Continuous data were expressed as Standard mean difference (IV, Random, 95% CI). Funnel plots was used to analyze for possible publication bias. Funnel plot asymmetry was assessed using Egger tests, and significant publication bias was defined as a P value<0.1. If publication bias existed, the trim-and-fill computation was used to estimate the effect of publication bias on the interpretation of the results.

The entire process was completed by two independent investigators, and the disagreement if any, was resolved by a third investigator.

RESULTS

A total of 325 studies was identified, with 13 publications fulfilling eligibility for inclusion. [7-19] (Fig. 1). Two articles written by Andersson, et al. [9,19] have the same patients but the follow-up time and outcomes were different. So these two articles were regarded as one trial and outcomes extracted accordingly. The characteristics of all included trials is presented in Table I. Follow-up time was between 2 months and 12 months. The effect of ECC and DCC on hemoglobin was assessed in 12 trials, ferritin in 10 trials and MCV in 5 trials. In total, 993 infants were treated with DCC, while 989 cases received ECC. All of these infants were term infants. These trials used different definition of DCC, but all were pooled, and DCC was redefined as umbilical cord clamping time greater than 60s after delivery.

Fig.1 Study selection for the meta-analysis.

Table I Characteristics of Included Studies Comparing Early and Delayed Cord Clamping

Study; place, year	Sample	Gestational age	Intervention method	Outcomes
	(DCC/ECC)	(DCC/ECC)	DCC/ECC
KC, et al. [7]; Nepal, 2017	212/188	38/38 median	³180s/£60s	Hb and ferriten level at 8-mo
Tiemersma, et al. [8];	35/38	38/38 median	120-180 s/£30s	Hb level at 2-3 mo
South Africa, 2015
Andersson, et al.* [9];	168/175	40.0/40.1 mean	³180s/£10s	Hb and MCV level at 4-mo
Sweden, 2011-2014	150/144			Ferritin level at 12-month
Ceriani Cernadas, et al. [10];	83/86	39/39 median	180s/<15s	Hb and MCV level at 6-mo
Argentina, 2010				Ferritin level at 6-mo
Chaparro, et al. [11];	171/157	38.8/39.0 mean	120s/around 10s	Hb and MCV level at 6-mo
Mexico, 2006				Ferritin level at 6-mo
Geethanath, et al. [12];	59/48	Term infants	Placenta into	Hb level at 3-mo
India, 1997			vagina/ICC	Ferritin level at 3-mo
Li, et al. [13]; China, 2012	64/94	38.6/38.7 mean	60s/15s	Hb and MCV level at 4-mo Ferritin level at 4-mo
Nesheli, et al. [14]; Iran, 2014	30/30	40/40 mean	50-60s/ICC	Hb, ferritin and MCV level at 6-mo
Venâncio, et al. [15];	115/109	39.3/39.3	60s/ICCh	Hb level at 3-mo
Brazil, 2008		median		Ferritin level at 3-mo
van Rheenen, et al. [16];	39/39	40/40 mean	>60s/20s	Hb level at 4-mo
Zambia, 2007
Gupta, et al. [17];	29/29	39.1/39.4 mean	Placenta into	Hb level at 3-mo
India, 2002			vagina/ICC
Grajeda, et al. [18];	26/21	38.8/38.5 mean	Cord stopped	Hb level at 2-mo
Guatemala, 1997			pulsating/ICC	Ferritin level at 2-mo
*Includes two articles with the same patients, the sample 168/175 at 4-month, the other at 12-month; DCC-delayed cord clamping; ECC-early cord clamping; ICC-cords clamped immediately after the birth ; Hb-hemoglobin; MCV-mean corpuscular volume.

Web Fig. I depicts the assessment of risk of bias in the included trials. Eight studies [7-12,13,16,17] clearly indicated the method of randomization, 9 studies [7,8,12-18] did not indicate if the study was blinded.

There was little publication bias on funnel plot (Fig. 2) and Egger test (P=0·073) in this analysis. However, further analysis with trim-and-fill test indicated that this publication bias could not impact the estimates (no trimming done because data was unchanged).

Fig. 2 Forest plots comparing effect of early and delayed cord clamping on various hematological parameters.

To study the effect of DCC compared to ECC on hemoglobin level the sample size varied significantly among the included studies and there was heterogeneity (I2=91%), so a random effects model was used to analyze the results. One trial in our study did not mention the unit [16], so outcomes have taken SMD to analyze. The results obtained show that DCC resulted in higher hemoglobin levels compared to ECC (SMD=0.47; 95% CI: 0.15, 0.78) (Fig. 3). DCC resulted in significantly higher ferritin levels compared to ECC (SMD=2.14; 95% CI: 1.04, 3.25) (Fig. 3). Similarly DCC resulted in significantly higher MCV levels compared to ECC (SMD=0.57; 95% CI: 0.16, 0.99) (Fig. 2).

Fig. 3 Funnel plot of studies comparing early and delated cord clamping.

Subgroup analysis on effect of DCC and ECC on hemoglobin was performed by race (Web Fig. 2.1), timing of DCC (120s as the critical value) (Web Fig. 2.3) and the follow-up time of DCC (6 months as the critical value) (Web Fig. 2.2). DCC improved Hb significantly compared to ECC in Asian studies, when follow-up was more than 6 months and when timing cord clamping was not beyond 120 secs. Accordingly, the race of participants, timing and follow-up time of DCC can be regarded as a source of heterogeneity.

DISCUSSION

The results obtained show that DCC could increase the level of hemoglobin, MCV and especially ferritin when compared with ECC. The influence could be different based on participants’ regional distribution, timing of umbilical cord clamping and the age of infants. The optimal time to delay umbilical cord ligation which impacted hemoglobin levels is about 60-120s.

Some studies have indicated that the differences in hematologial variables between DCC and ECC became smaller with the increased follow-up time [7,9]. A randomized controlled trial in Sweden demonstrated that DCC significantly increased stored iron at 4 months, but the effect on hemoglobin was not significantly different from ECC. When the follow-up reached 12 months, the beneficial effect on iron storage disappeared. This might be related to the postnatal iron supplementation. A previous study [11] showed that during the three-month follow-up, hematologic improvement was enhanced in iron-deficient mothers, infants with infant birth weights between 2500 and 3000 grams, and infants who did not receive infant formula or iron fortified milk. A previous meta-analysis including 6 trials about hemoglobin level showed no significant difference in the hemoglobin levels within 6 months.

The study has some limitations. Firstly, the timing of cord clamping varied from 60 seconds till descent of placenta into vagina or cord stopped pulsating, and in the latter the means used were approximate estimates. Secondly, all studies had loss to follow-up. Since acute inflammatory process could increase the ferritin concentration, there might be an error in the result of ferritin.

There is also a long way to go in the optimization of umbilical cord ligation. In addition, countries should develop DCC guidelines based on race, gender, and physical status of pregnant women in order to improve the blood volume and iron storage of newborns more effectively.

As there is a high incidence of anemia and low iron stores in Asian and African infants [7,12,16], DCC might be an effective intervention to prevent anemia and iron deficiency in developing countries.

Contributors: XF: contributed to conception and design, acquisition, analysis, and interpretation; DD: contributed to conception and design, acquisition and interpretation; SL: contributed to conception and design, acquisition; ZX: contributed to conception and design, analysis; HW: contributed to conception and design, acquisition, analysis, and interpretation. All authors drafted manuscript, critically revised manuscript, gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Funding; None; Competing interest: None stated.

WHAT IS ALREADY KNOWN?

• Delayed cord clamping provides adequate blood volume and birth iron stores, thus decreasing the risk of iron deficiency anemia during infancy

WHAT THIS STUDY ADDS?

• The optimal time to delay umbilical cord ligation is about 60-120s and it will be more conducive to the growth of hemoglobin than the longer umbilical clamping time. In contrast, Asians might gain more benefits from delayed umbilical clamping.

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