PROTOCOL FOR SUBMISSION OF THESIS FOR THE DEGREE OF MD/MS

THESIS FOR THE DEGREE OF DOCTOR OF MEDICINE (PEDIATRICS) UNIVERSITY OF DELHI SESSION 2011-2012

By Dr Aditi Kalawati Saran Childrens Hospital Lady Hardinge Medical College

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

PROTOCOL FOR SUBMISSION OF THESIS FOR THE DEGREE OF MD (PAEDIATRICS) TITLE- A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (3436weeks) on short term neurodevelopmental outcome. NAME OF THE INSTITUTION NAME OF THE CANDIDATESIGNATURENAME OF THE SUPERVISORDr.Vikram Datta Professor, Department of paediatrics Lady Hardinge Medical College & associated hospitals ,New Delhi SIGNATURENAME OF THE CO SUPERVISOR Department of Gynaecology Lady Hardinge Medical college & associated hospitals ,New Delhi SIGNATURENAME OF THE HEAD OF THE DEPARTMENT : Dr.A.K.Dutta Director and Professor Department of paediatrics, Lady Hardinge Medical College & associated hospitals ,New Delhi SIGNATURELady Hardinge Medical College and associated hospitals ,New Delhi Dr. Aditi

NAME OF HEAD OF THE INSTITUTION :

Dr. Atul Murari Director,, Lady Hardinge Medical College , New Delhi

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

DECLARATION I , hereby declare that to the best of my knowledge , no such work has been done on the topic in delhi university in the past five years.

Dr. Aditi ( candidate )

Dr.Vikram Datta (Supervisor) Professor Department of Paediatrics Lady Hardinge Medical College & Associated Hospitals ,New Delhi

Dr. (Co-Supervisor) Department of Gynaecology Lady Hardinge Medical College & Associated Hospitals New Delhi :

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

Lady Hardinge Medical College & Smt S.K.Hospital, New Delhi UNDERTAKING I/We agree to abide by the ethical guidelines for biomedical research on human subject (as per ICMR guidelines) while conducting the research project being submitted for Ethical Committee consideration: 1. Project is considered to be absolutely essential for the advancement of knowledge and for the benefit of all.
2. Only subjects, who volunteer for the project will be included. Their informed consent shall be

obtained prior to commencement of the research project, and subjects will be kept fully appraised of all the consequences. 3. Privacy and confidentiality of the subjects shall be maintained and without the consent of the subject no disclosure will be made. 4. Proper precautions shall be taken so as to minimize risk and prevent irreversible adverse effects. 5. Research will be conducted by the professionally competent persons. 6. Research will be conducted in a fair , honest, impartial and transparent manner. Research will be accountable for maintaining proper records. 7. Research will be conducted keeping in view the public interest at large . 8. Research report s ,materials ,and data will be preserved (as per institutional guidelines) 9. Result of research will be made through scientific publications. 10. Professional and moral responsibilities will be of the researchers , directly or indirectly connected with the research.
11. Only , those drugs which are approved by the Drug Controller of India for a specific purpose will

be used for the research project Dr. Vikram Datta

Supervisor Professor Department of Pediatrics Lady Hardinge Medical College & Associated Hospitals New Delhi

Professor Department of Obstetrics & Gynaecology Lady Hardinge Medical College & Associated Hospitals New Delhi

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

Dr Aditi (investigator)

INTRODUCTION

Delayed cord clamping (DCC) : Well described phenomenon in term infants . The optimal timing of clamping of umbilical cord in preterm infants : A subject of debate. Even a brief delay in cord clamping leads to an additional transfer of iron amounting to 40-50 mg/kg which may prevent iron deficiency. This low cost intervention can have significant public health importance in resource constrained settings. The effect of this intervention on neurobehaviour of preterm neonates has not been assessed. This aspect has been identified by WHO and Cochrane as a potentially researchable area

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

REVIEW OF LITERATURE
CORD CLAMPING Component of third stage of labor (between the

delivery of infant and placenta)

PROCEDURE Two clamps are applied and cord is cut in between without

blood loss to the mother or the baby.

TIMING -NO CONSENSUS ON PRECISE TIMING

EARLY(ECC) immediately after birth till 20 sec LATE (DCC) uptil 2-3 mins. Or cessation of cord pulsation. BRIEF DELAY minimum time for brief delay is defined as 30 sec

Benefits of Delayed Cord Clamping in Preterm Neonates A higher hematocrit at 6 weeks of postnatal age A higher circulating blood volume during the first 24 hours of life , a lesser need for blood transfusions a lesser incidence of intraventricular hemorrhage No effect on Apgar score , cord pH and temperature on admission Lower incidence of late onset sepsis and intraventricular hemorrhage Additional immunological competence

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

STUDIES ON CORD CLAMPING EARLY VERSUS DELAYED IN PRETERM INFANTS

Setting

Participants DCC(n) ECC(n) O utcom es 90sec (23) ICC (23) H ct, m ean b lo o d vo lu m e CRIB sco re ,tran sfu sio n need

U .K. (A lad angad24 w ks ) -32 2005 Sw itzerlan d -32 w ks 24 (B aezin ger) So u th A frica w ks <35 (H o fm eyer) 1993

60 sec <20 secM o rtality, H ct, cerebral -90 (15) (24) blo o d flo w , tissu e o xygen atio n 60 sec ICC (24) (24) M o rtality, cereb(6- U SG ral 72h rs) ap gar sco re , b irth w eight, SB P, co rd b lo o d gas

Israel 24 w ks -32 (Ku gelm an)

30 sec 5-10 sec M o rtality,M ct, H , -45 h BP,IV (30) (35) BT n eed ,P T n eed , p eak b iliru b in

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

Is ra e l 2 43 5 w k s 3 04 5 s e c 5-1 0 s e c L e v e ls oIg MC G f Ig 3 (K u g e lm a n ) (3 0 ) (3 5 ) C 4 (a t b ir t h ) se p sis ,d a y s o f A B ,in fe c t io n s in fir st m o n th A u st r a lia 2 63 3 w k s3 0 s e c (M D o n n e l) c (3 0 ) 1997 IC C (3 5 ) M o r t a lit y, pHgcatr, A s co r e , te m p e ra t u r e , M V n e e d , B T v o lu m e , p e a k ,U SG s k u ll

U SA 2 43 2 w k s 3 04 5 s e c 5-1 0 s e c M o r t a lit y , n o o f (M e r c e r ) (3 6 ) (3 6 ) t r a n sf u sio n s , IV H , B P D 2006 s u s p e c te C ,s e p sis , NEd LO N S H o lla n d (U lte e ) CA 2007 3 43 6 w k s 3 m in (2 1 ) <3 0 se c H c t a t 1 0 w k s ,H b (1 h r 1 0 (2 0 ) w k s) g lu c o s e , b il fe r r it in (1 0 w k s)

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

U .K . 2 -42 8 w k s 3 -04 5 s e c 5-1 0 e c s ( WO h , (1 6 ) (1 7 ) F a n a ro ff A A ) 2002

H c t (4 h r s ) ,B T ,r e s u s c ita t io n ,A p g a r s c o r e, , RI V HP , O L O S ,P D A

G e r m a n y< 3 3 w k s 4 5 s e c ( R a Hb )e (1 9 ) 2000

< 2 0 s eNc o o f t r a n s f u s io n s (2 0 ) v o lu m e t ra n s f u s e d A p ga r sco re B P ,R D ,IV H , P D A , P T n e e d a n d d u r a t io n

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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CONCLUSION FROM PREVIOUS SYSTEMATIC REVIEWS/ META-ANALYSIS

Mathew : 2011 : (Timing of umbilical cord clamping in term and preterm deliveries and infant and maternal outcomes : A systematic review of Randomised Controlled Trial)

For preterms , delayed cord clamping results in significantly reduced risk of IVH & marginal hemodynamic benefits in newborns

Rabe et al: 2008 : (A systematic review and meta-analysis of brief delay in clamping the umbilical cord of preterm infants)

A higher circulating blood volume during the first 24 hours of life. A lesser need for blood transfusions A lesser incidence of intraventricular hemorrhage No effect on cord blood pH , Apgar score, temperature

Abalos E : 2009 : (Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes )

For the baby: increase in newborn Hb levels, increased ferritin levels. No effect on APGAR score, respiratory distress , polycythemia , pathological jaundice

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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Proposed mechanism for better neurobehavioural outcome

DCC

Increased Hem ato crit

Increased vascular stability

Increased im m uno co m petence

Increased iro n stores Increased o2 carrying capacity Better cognitive func

Less IVH

Less LO NS Less neuro lo gical insult

Better neurobehavioural outcome

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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SCALE USED TO ASSESS SHORT TERM NEUROBEHAVIOUR NAPI (NEUROBEHAVIOURAL ASSESSMENT OF PRETERM INFANT) The NAPI is appropriate for infants between 32 weeks post conceptional age (PCA) and term. It assesses the relative maturity of functioning of preterm infants, with higher scores reflecting higher maturity, and can differentiate 2 weeks PCA.The clinical validity and sensitivity of NAPI were established using an index of medical complications based on a 1-5 classification range of degrees of complication. The items in the motor development cluster include ventral suspension, prone head raising, the crawling reflex, forearm recoil power of active movements and vigor of spontaneous movements. The alertness and orientation items include percent of time in an alert state, duration and quality of alertness , quantitative response to inanimate and animate visual and auditory stimulation and qualitative ratings that express the nature of response. Neurobehavioural assessment of preterm infant (N.A.P.I.) Is used for monitoring the developmental progress of individual infants. To identify persistent lags in the development of specific functions. To assess the effect of intervention studies or clinical trials or changes in medical care To identify gross neurological dysfunction Instrument designed to measure relative maturity of functioning in preterms aged 32wks to term. NAPI has a positive co-relation with the neurobehavioural status at 18mths as assessed by Bayley scales of infant development(BSID) Thus, short term neurobehavioural assessment is a useful tool for identification and rehabilitation of infants at risk for a poor outcome

LACUNAE IN EXISTING KNOWLEDGE IMPLICATION FOR RESEARCH WHO RHL 2009 : Short and long term neonatal outcomes such as neurodevelopment , need to be evaluated. RATIONALE FOR THE STUDY DCC is a low cost intervention and its implementation would be particularly relevant in under resourced setting. When a Medline search was carried out on the subject it did not return any result.

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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Currently there is no study which tries to explore the short term neurobehavioural outcome of DCC on pre terms. The present study is thus planned to evaluate the role of brief delay in cord clamping on short term neurodevelopmental outcomes in preterms .

AIMS &OBJECTIVES To study the effect of brief delay in cord clamping on short term neurobehavioral outcome of preterm neonates(34 to 36 weeks)

RESEARCH QUESTION In preterm neonates ( 34-36 weeks){P} does a brief delay in cord clamping{I} as compared to early cord clamping{C} lead to a better short term neurobehavioural outcome {O} when assessed by neurobehavioural assessment of preterm infants (NAPI )at 37 weeks of post conceptional age?

RESEARCH HYPOTHESIS Brief delay(>30 sec to <60 sec ) in cord clamping as compared to early cord clamping (< 20 sec) leads to a better short term neurobehavioural outcome in preterm (34-36 wks) neonates when assessed by neurobehavioral assessment of preterm infants (n.a.p.i.) at 37 weeks of post conceptional age

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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MATERIALS AND METHODOLGY STUDY DESIGN : Randomised Controlled Trial (Open label)

PARTICIPANTS : Inclusion criterion All preterm deliveries infants born at 34 weeks 0 days to 36 weeks +6 days gestational age as estimated by LMP or early USG scan. Infants delivered vaginally or by caesarean section in cephalic presentation Singleton pregnancy Parental consent

Exclusion Criteria Fetus with gross congenital anomaly Fetus with hydrops Rh negative pregnancy

Period of study : Nov 2011 April 2013 Place of study : Neonatal unit, Dept of Pediatrics , KSCH Dept of Obstetrics n Gynecology , SSKH

Timing of research : candidate will be present to time the clamping of the cord using a standard stop watch.

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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S YS H TUD C EME:INTER VENTION All pregnant women satisfying the inclusion criterion and not having the exclusion criterion (SCREENING) Informed written consent from either the parent or caregiver (ENROLLMENT) Randomisation GROUP A (CONTROL) ICC-In which umblical cord will be clamped within 20 second after delivery of the neonate. GROUP B (INTERVENTION) BRIEF DCC-In which umblical cord will be clamped at more than 30 seconds but less than 60 seconds after delivery of neonate

NAPI at D1 and 40 wks Analysis

NAPI at D1 and 40 wks Analysis

At the time of enrollment day 1and 40 weeks post conceptional age ,each patient will undergo an assessment for neurobehavioral status according to the NAPI score. Assessment will be done by research candidate in neonatal unit and scoring will be done according to the record forms provide with standard NAPI kit.

Assessment clusters : 2clusters namely Motor Development and vigor (MDV) Alertness and Orientation (AO) Scorecalculation : Raw scores transposed into percentage scores to ensure comparability between items ,combined n averaged into clusters.

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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COMPARISON & OUTCOME Primary outcome Short term neurobehavioral outcome at 40 weeks post conceptional age using NAPI score in the two groups

SAMPLE SIZE CALCULATION

Two samples comparison of means was used . A power of 80% with an alpha of .05 and an assumed improvement in mean NAPI score (MDV) in the intervention group of 20% , the estimated sample size was 53 in each limb . Assuming a lost to follow up/drop out rate of 10%, a total of 120 preterm neonates will be enrolled.

RANDOMISATION SEQUENCE GENERATION Block randomisation using computer generated random sequences will be used . ALLOCATION CONCEALMENT opaque sealed envelopes sequentially labeled according to randomisation code available BLINDING
A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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open label study, blinding not possible

STATISTICAL ANALYSIS ANALYSIS Using adequate statistical software CALCULATION Descriptive statistics (mean & standard deviation and 95% CI) o COMPARISON OF MEANS : t- test o COMPARISON OF PROPORTIONS: Chi square test

INDEX OF REFERENCES 1 .WHO RHL 2009 Pisacane A :Neonatal prevention of iron deficiency BMJ. 1996 ; 312 :136-137 2 .Cochrane meta-analysis Early Vs delayed cord clamping in preterm infants : Heike Rabe, Graham J Reynolds, 2004 3. A systematic review and meta-analysis of brief delay in clamping the umbilical cord of preterm infants Rabe et al, Graham Reynolds, Jose Diaz Rossello 2006 Karger 4. WHO RHL effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcome commentary by Abalos E 2009 5. Effects of delayed cord clamping in very low birth weight infants: W Oh, AA Fanaroff, Journal of Perinatology 2011 : 31 : 568-571 6 . Delayed Cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late onset sepsis :a Rct : Judith S Mercer, Betty R Vohr ; Official Journal of AAP 2006 ; 117 ;1235 7 . Cord blood as a source of hematopoietic progenitor cells for trasplantation : Kurtzberg NEJM 1996 ; 325: 167 -170 8. Bonnie et al 2010 9 . Ultee C A :delayed cord clamping in preterm infants delivered at 34-36 wks gestation.

A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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A randomised controlled trial to evaluate the role of brief delay in cord clamping in preterm neonates (34-36weeks) on short term neurodevelopmental outcome.

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