Delayed Cord Clamping for Preterm Infants A Simple Intervention with Great Impact

Betty Vohr M.D. and Judith S. Mercer DNSc, CNM1

Alpert Medical School of Brown UniversityBuenos Aires

September, 2011

Background:• In the United States standard obstetric practice

has been to clamp the umbilical cord immediately after delivery.

• However delaying cord clamping of 30-45 seconds and lowering the infant below the perineum or incision site has been shown to significantly ↑ transfer of blood from the placenta to the infant. (2-16ml/kg for C-section and 10-28ml/kg for vaginal delivery). Kao AC, Lancet 1969.

Benefits

• This transfer of blood represents 8-24% of blood volume.

• Therefore, ICC may deprive the VLBW infant of adequate blood volume, contribute to circulatory compromise resulting in hypotension, and poor perfusion of tissues.

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Benefits of Delayed Cord Clamping (DCC) of 30-45 seconds in Preterm Infants

• Higher blood pressures (Ibrahim, ‘00; Nelle ‘98; Rabe ‘98)

• Higher hematocrit (Ibrahim; Nelle; Kinmond ’93, Oh, ‘02)

• Increased blood volume (Narenda ‘98; Nelle) Aladangady,Pediatrics,2006

• Less need for volume expanders (Ibrahim; Nelle)

• Less need for transfusions (Ibrahim; Rabe ’00, 04; Kinmond)

• Fewer days of ventilation, oxygen use (Kinmond)

• Less IVH (Hofmeyr, 88, 93, Rabe 04)

Cochrane Review of Controlled Trials< 37w: Rabe, Reynolds and Dias Rosello 2004

• 7 Studies with DCC > 30 seconds• Findings

– ↓ Need for Transfusions– ↓ Intraventricular Hemorrhage

Meta Analysis of Controlled Trials< 37w: Rabe, Reynolds and Dias Rosello 2004

• 10 Studies with DCC > 30 seconds• Findings

– Higher circulating blood volume in 1st 24 hours– ↓ Need for Transfusions– ↓ Intraventricular Hemorrhage

Conclusion: DCC is safe and does not compromise the post partum adaptation.

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Cord Clamping Studies at Women & Infants Hospital

Providence, Rhode Island

Judith S. Mercer DNSc, CNM1,2 Debra Erickson-Owens, CNM, MS1,2

Betty Vohr MD2,3 William Oh2,3 James Padbury 2,3

1University of Rhode Island, 2A Alpert Medical School of Brown University, 3Women and Infants Hospital

NIH 1 K23 NR008027-01

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Initial StudyObjective: Compared the effects of immediate

cord clamping (ICC) and delayed cord clamping (DCC) on VLBW infants on 2 primary variables:

1) Bronchopulmonary Dysplasia (BPD) and

2) Suspected Necrotizing Enterocolitis (NEC)

Secondary variables were late-onset sepsis (LOS) and intraventricular hemorrhage (IVH)

Mercer, JS et al. (2006). Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized,

controlled trial. Pediatrics, 117(4): 1235-42)

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HypothesesVLBW infants in the DCC Group compared to the

ICC group will have:

• ↓ BPD at 36 weeks postmenstrual age

• ↓ rate of suspected NEC

• Better motor function by 7 months CA

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Methods: Neonatal ProtocolDesign: Randomized controlled trial; partially blindedProtocol: Two Groups

– ICC Group: Cord clamping in < 10 seconds– DCC Group: Cord clamping is delayed for 30 to

45 seconds & baby lowered up to 30 cm (12 inches)

Method: Time of cord clamping delay recorded with a stop watch

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Methods: Neonatal Protocol• Sample: 72 women with singleton fetuses 24 to < 32

weeks gestation

• Blocked stratified randomization to obtain equal numbers of 24-27 wk and 28-31 wk infants

• Exclusion Criteria• Prenatally-diagnosed major congenital anomalies• Intent to withdraw care • Significant bleeding, abruption or previa

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Methods: Follow-Up Study

• Evaluation at 7 months CA included:• Bayley Scales of Infant Development II (BSID

II) - Psychomotor and Mental Developmental Index - PDI and MDI

• Neurodevelopmental assessment

• All evaluators were blinded to study group

Maternal Demographics and Clinical Care

Group (n)Group (n) ICC Group (36)ICC Group (36) DCC Group (36)DCC Group (36) P valueP valueMotherMother’’s age, n(%)s age, n(%)Private InsurancePrivate InsuranceAN SteroidsAN SteroidsMgSOMgSO44 < 24< 2400

PROM (hrs)PROM (hrs)C/SC/SReasons for BirthReasons for BirthPPROM (n)PPROM (n)Preterm LaborPreterm LaborPIHPIHPresumed ChorioPresumed Chorio

26.8 (6.6)26.8 (6.6)20 (56%)20 (56%)36 (100%)36 (100%)21 (58%)21 (58%)40 (44)40 (44)14 (39%)14 (39%)

191919195599

27.1 (6.7)27.1 (6.7)22 (63%)22 (63%)35 (100%)35 (100%)13 (37%)13 (37%)42 (47)42 (47)15 (43%)15 (43%)

181815155599

.83.83

.53.531.01.0.07.07.84.84.70.70

.90.90

.40.401.01.0.94.94

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Newborn DemographicsICC N =36ICC N =36 DCC N =36DCC N =36 p valuep value

Birth weight (G)Birth weight (G) 1151 1151 ++ 379379 1184 1184 ++ 346346 0.60.6

Gest age ( wks)Gest age ( wks)

24 to 2724 to 2766 wks wks 28 to 3128 to 3166 wkswks

28.2 28.2 ++ 2.42.4

15152121

28.4 28.4 ++ 2.12.1

13132222

0.540.54

0.70.7

MaleMale 19 (52%)19 (52%) 22 (63%)22 (63%) 0.390.39Cord Clamp (sec)Cord Clamp (sec) 7 7 ++ 44 32 32 ++ 1313 .0001.0001

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ICC N = 36ICC N = 36 DCC N =36 DCC N =36 P P ApgarsApgars

1/5 min1/5 min 6/86/8 6/8 6/8 1.01.0AdmitTemp (AdmitTemp (OOF)F) 96.8 96.8 ++ 1.5*1.5* 97.1 97.1 ++ 1.2 1.2 .24.24

Max serum Bili Max serum Bili (mg/dl)(mg/dl)

9.5 9.5 ++ 2.12.1 10.07 10.07 ++ 2.5 2.5 .26.26

Initial Hct (%)Initial Hct (%) 46 46 ++ 6*6* 49 49 ++ 77 .06.06

Mean BP @ 4 hrsMean BP @ 4 hrs 32.632.6 36.636.6 .08.08

Early Outcomes

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Results: Clinical Outcomes

ICC (n = 36)n (%)

DCC (n = 36)n (%)

P Value

BPD or deathBPD or death 9 (25)9 (25) 8 (22)8 (22) .78.78

Suspect NECSuspect NEC 20 (56)20 (56) 14 (39)14 (39) .16.16Conf NEC Conf NEC 4 (11)4 (11) 2 (6)2 (6) .39.39IVHIVH 13 (36)13 (36) 5 (14)5 (14) .03.03Conf SepsisConf Sepsis 8 (22)8 (22) 1 ( 3)1 ( 3) .03.03DeathsDeaths 33 00 .24.24

Intraventricular Hemorrhage

p = .03, OR 3.5, 95% CI 1.1, 11

(n=72)

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Suspected and Confirmed Sepsis

p = .028, OR .1, 95% CI .01-0.84

(n=72)

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ICC DCC

Boys (n = 19)

Girls (n = 17)

Boys (n = 23)

Girls (n = 13)

IVH 8 (42%)* 5 (29%) 2 (9%) 3 (23%)

Sepsis 6 (32%)* 2 (12%) 0 1 (8%)

Gender differences in IVH and Sepsis among infants with ICC and DCC

*Differences for boys between groups, p < .05, Fisher’s Exact Test.

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Variables ICC n = 29 (%) DCC n = 28 (%) p value

Birth weight 1139 + 373 1178 + 363 .68Gest. age at birth 28.1 + 2.3 28.1 + 2.1 .91Gender, % male 15 (52) 18 (62) .43Race

WhiteHispanicBlack

17 (59)9 (31)2 (7)

12 (41)10 (36)5 (18)

.53

Maternal Ed < HS 6 8 .54Maternal Ed, years 13 13.3 .71Corrected Age at Assessment (mo.) (Range)

8.4 + 3.1(6 to 18.6)

8.9 + 3.1(6.3 to 18.3)

.57

7Month Follow7Month Follow--up data: up data: Characteristics Characteristics of Children with Motor Scores of Children with Motor Scores

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Variables ICC (n = 29) DCC (n = 28) p

Apgar 1/5 minutes 7/8 6/8 .84

IVH, all grades 10 (34) 5*(18) .13Late onset sepsis 6 (21) 1*(4) .10Suspected NEC 16 (55) 11 (39) .19NEC 1 1 1.0BPD 6 6 1.0% Wt < 10th%ile 1 1 .98

Perinatal Characteristics of Children Perinatal Characteristics of Children with Motor Assessmentswith Motor Assessments

* One child had ICC (protocol violation); (%)

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Variables ICC (n = 29) DCC (n = 28)

Wt <10% Exp. 5 6ER Visits 12 8Hospital Adm 11 13

Med. Morbidity 2.1 + 1.6 2.3 + 1.9MDI Score 88 + 11 84 + 11PDI Mean Score 82.6 + 16.5 83.9 + 19

Outcomes Outcomes at 7 at 7 Months CA Months CA

23Delayed CC Immediate CC

Effects of Cord Clamping Time and Gender on PDI Score Range at 7 Months Corrected Age

(p=0.04)

(p=ns)

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ModelsModels Main Effects Interaction

b p b p

Gestational AgeIVHBPDSepsisLate ClampMaleMale X Late Clamp

R2

-0.660.52

-12.71-18.90-3.98.33---

29%

.56

.88.01.007

.374.06

.007

-0.73.5

-17.5-16.6-13.8-0.218.3

35%

.51

.51.006.01.03.96.04

.005b = unstandardized regression coefficient

Regression Models Regression Models for for Effects of Effects of DCC on 7 Month PDIDCC on 7 Month PDI

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Factors Which May Contribute To IVH, Sepsis, And Lower Motor Scores In Infants

With ICC

1. Blood and red cell volume loss which may contribute to

a. Cardiovascular instability b. Loss of autoregulation c. Poorer perfusion of all tissues

2. Inflammation secondary to blood loss3. Loss of hematopoietic stem cells

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Discussion: Why Boys?

• Vascular reactivity patterns differ in boys and girls (Geary GG, Krause, DN, Duckles, SP., 2000)

• Estrogen may be protective of girls even at this early age (Derzbach et al 2005)

• Male infants are 2.5 times more likely to need resuscitation than girls (Frazier & Werthammer, 2007)

• Therefore, we speculated that loss of blood volume, RBCs, and stem cells may have a negative effect, especially on males

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Summary of ResultsDCC appears to be protective against IVH and

Sepsis, especially for male infants

DCC at birth appears to be protective against motor disability at 7 months CA for VLBW male infants.

Conclusions:

• Delay Cord Clamping for Preterm Infants is:• Easy to implement• Requires no additional cost• Results in improved neonatal outcomes• Is associated with improved early developmental

outcomes for boys