Neurodevelopmental and Behavioral Outcome of Very Low Birth Weight Babies at Corrected Age of 2 Years

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1 Indian J Pediatr (2010) 77: DOI /s ORIGINAL ARTICLE Neurodevelopmental and Behavioral Outcome of Very Low Birth Weight Babies at Corrected Age of 2 Years Kanya Mukhopadhyay & Prahbhjot Malhi & Rama Mahajan & Anil Narang Received: 9 November 2009 / Accepted: 7 April 2010 / Published online: 3 September 2010 # Dr. K C Chaudhuri Foundation 2010 Abstract Objective Neurodevelopmental and behavioral assessment of very low birth weight babies (VLBW) at corrected age (CA) of 2 years. Methods 127, 110, 99 and 101 babies 34 weeks and 1500 g were followed at CA of 3, 6, 9, 12 months respectively for developmental and neurological assessment. DASII (Developmental assessment scale for Indian infants) was used at CA of 18 months and preschool behavioural checklist (PBCL) at CA 2 years. Results Of 101 VLBW babies available for follow up at CA 1 year, 3 (3%) babies had Cerebral Palsy (CP) and 3% (n=3) had suspect abnormality (mild hypotonia), 11% (n= 11) had gross motor and 8% (n=8) had language abnormality. Their mean mental (MeDQ) and motor (MoDQ) quotients were 80.4±10.7 and 77.2±13.3 and a score of<70 was found in 17% (MeDQ) and 25.7% (MoDQ) VLBW babies. High PBCL score (mean 16.8± 5.4) was seen in 84%VLBW babies. On subgroup analysis, 2 babies (5%) in subgroup1 ( n=54, 1200 g,) and 1 (1.6%) in subgroup 2 (n=78, g) had CP. Twelve (29%) in subgroup 1 had significant language delay (p=0.004) as compared to 4 (15%) in subgroup 2 at 1 year. BSID and PBCL scores were comparable. Amongst ELBW babies (<1000 g), 6.6% (n=1) had CP, 25% (n=3) and 42% (n=5) had low MeDQ and MoDQ respectively and all of them had high PBCL score. AGA and SGA had similar outcome. K. Mukhopadhyay (*) : P. Malhi : R. Mahajan : A. Narang Department of Pediatrics, PGIMER, Chandigarh , India kanyapupul@yahoo.com Conclusion VLBW babies need close and longer follow up due to high risk of neurodevelopmental and behavioral abnormality. Keywords Cerebral palsy. Behavioral outcome. MeDQ. MoDQ. Neurodevelopment. Very low birth weight babies Abbreviations VLBW Very low birth weight ELBW Extremely low birth weight DASII Developmental assessment scale for Indian infants DDST Denver Development Screening test PBCL Preschool behavioral checklist CP Cerebral Palsy MeDQ Mental developmental quotient MoDQ Motor developmental quotient AGA Appropriate for gestational age SGA Small for gestational age Introduction The emergence of highly specialized care units in neonatal intensive cares has improved the survival of very low birth weight (VLBW) infants significantly in west [1] but several reports are available regarding their adverse long term neurobehavioral outcomes [2 4]. Similar reports are also available from other developing countries [5, 6]. The survival of VLBW infants is also improving in India [7, 8] however there is paucity of published data about their long term neurodevelopmental outcome specially in extremely low birth weight (ELBW) babies in our country. Chaudhari et al. [9 11] from Pune reported long term

2 964 Indian J Pediatr (2010) 77: outcome of VLBW neonates and found adverse outcome in complicated preterms and SGA babies as compared to term control babies however they had very less number of ELBW babies in their cohort. A large number of VLBW babies in our country are also growth retarded and these babies are at a higher risk of neurodevelopmental abnormality [12]. VLBW babies are also at a risk of behavioral abnormalities [13] in the long run with an escalating risk in ELBW babies. Hence, we designed this study to evaluate the long term neurodevelopment and behavioral outcome of VLBW babies in our country so that appropriate counseling of parents can be provided. Material and Methods This prospective study was a continuation of our previous trial on human milk fortification [14]. As there was no difference in the neurodevelopmental outcome of these babies we decided to report their long term outcome as a combined group. One hundred and twenty seven high risk preterm inborn neonates born over a period of 15 months, who were 34 weeks of gestation and 1500 g and discharged from neonatal intensive care unit and special care nursery after completing the initial trial were followed up till corrected age of 2 years in the neonatal follow up clinic (Fig. 1). Feeding protocol has been described in the previously published paper and all babies were predominantly breast milk fed. At corrected ages of 3, 6, 9 and 12 months development was assessed by Denver Development Screening test (DDST I) [15] and neurological examination was performed by Amiel-Tison method [16] by trained neonatologists. At CA of 18 months, babies were tested by DASII scale (Developmental assessment scales for Indian infants) [17] which is an Indian adaptation of Bayley scales of infant development ( BSID ) and at CA of 2 years behavior was assessed by preschool behavioural checklist (PBCL) [18]. Both DASII and PBCL were carried out by a trained clinical child psychologist. Standard interpretation was followed for DDST assessments to assign normal, abnormal and questionable cases. In neurological examination, cerebral palsy (CP) was diagnosed if the baby had spastic diplegia or hemiplegia or quadriplegia and suspect was assigned when mild hypotonia was persisting at CA 1 year. On DASII scale, a mental and motor quotient below 70 was considered as retarded and a quotient between 70 and 85 was considered borderline. A PBCL score of 12 was scored as abnormal. Written informed consent was obtained from all the patients and hospital research ethics committee granted the ethical clearance. If someone failed to turn up for scheduled visit, they were contacted on telephone and locals were visited by follow up discharge coordinator. As ours is a tertiary referral centre from all over north India, there was a large drop out on follow up as patients were referred from very far off places and could not be contacted subsequently inspite of their consent to come for follow-up. All results were analysed and expressed in all VLBW babies as well as in 2 subgroups subgroup 1 ( 1200 g) and subgroup 2 ( g). Subgroup analysis was also perfomed in ELBW babies (< 1000 g and 1000 g) and also according to AGA and SGA status of the baby according to Lubchenco s chart [19]. Statistical Analysis Continuous variables were analysed by using student s t test and categorical variables were analysed by using chisquare test. Results Of the 157 babies completing the initial trial, 132 were seen at corrected age of 6 weeks however 127, 110, 99, 101 babies were available at CA of 3, 6, 9 and 12 months respectively (Fig. 1) for detailed follow up. Seventy-one were assessed by DASII scale at 18 months CA and PBCL Born during the study period ( < 34 Weeks, < 1500 grams) n=372 Enrolled in human milk fortification trial n=199 discharged from hospital n=166 followed up till 2 kg after discharge n=157 seen at 40 weeks CA, n=132 seen at CA 3 mo, n=127 seen at CA 6 mo, n=110 seen at CA 9 mo, n=99 seen at CA 12 mo, n=101 seen at CA 18 mo for DASII, n=71 Died n=141, excluded for other reasons n=32 excluded due to death and other reasons, n=33 lost till reached 2 kg, n=9 seen at CA 2 years for behavioural assessment, n=51 Fig. 1 Flow chart

3 Indian J Pediatr (2010) 77: was available in 51 babies at CA 2 years. The demographic characteristics of 132 babies seen at 1st follow up visit of 6 weeks are given in Table 1. At CA 12 months, 3% of VLBW babies had CP and 3% had suspect abnormality in the form of mild hypotonia. On DDST, gross motor development was delayed in 11% (n=11) and questionable in 12.9% (n=13) babies. Language delay was found in 8% (n=8) and questionable in another 8% (n=8) cases. On DASII scale, mean mental developmental quotient (Me DQ) was 80.4±10.7 and mean motor developmental quotient (MeDQ) was 77.2±13.3.A score of less than 70 was found in 12 (16.9%) babies in MeDQ and in 18 (25.7%) babies in MoDQ. The mean PBCL score was 16.8±5.5 and 84.3% babies had a score 12 which is considered high. There were 54 babies in subgroup 1 ( 1200 g) and 78 babies in subgroup 2 ( g). At CA 1 year, 5% (n= 2) and 1.6% (n=1) had CP and 1.6% (n=1) and 5% (n=2) were suspect in subgroup 1 and 2 respectively. In DDST, 10 (25%) babies were either abnormal or questionable in gross motor in subgroup 1 as compared to 14 (23%) in subgroup 2 babies however the difference was statistically not significant. In language, 12 babies (30%) were significantly (p=0.004) abnormal or questionable in subgroup 1 as compared to 4 babies (6.5%) in subgroup 2. In other sectors of fine motor and personal-social, both the groups were comparable at CA 1 year. The mean MeDQ were 81.25±12.5 and 79.7±8.9 and MoDQ were 78.5±13.9 and 76.2±12.9 in subgroups 1 and 2 respectively and there was no statistical difference (p= and ). Proportion of babies with a score of < 70 in both MeDQ and MoDQ were similar in both the subgroups (Table 2). Table 1 Demographic characteristics of VLBW babies Variables n=132 Birth weight, gms 1228 (190) Gestation, wks 30.9 (2.1) SFD 52 (39) Male (n,%) 86 (65) 28 week (n, %) 21 (15.9) <1000 g (n, %) 20 (15.2) Antenatal steroid (62) Ventilated (n, %) 47 (35) Sepsis (n, %) 36 (27) PDA (n, %) 8 (6) Necrotizing enterocolitis (n,%) 8 (6) Chronic lung disease (n,%) 11 (8.3) IVH (n,%), any grade 26 (19.6) Values are expressed as Mean (SD) and n(%) Mean PBCL scores (15.8±5.6 and 17.6±5.3) were also comparable (p=0.25) in 2 subgroups though the mean scores in both the groups were high. Eighty four percent babies had a high PBCL score ( 12) and the proportion of babies with high PBCL was found in both the groups (Table 2) at a similar rate. There were 20 babies (15.2%) who were ELBW (< 1000 g) and 50% (n=10) of them were SGA. The mean birth weight and gestation were 888 (105) grams and 28.5 (1.9) wks respectively. At corrected age of 1 year, 15 ELBW babies were available on follow up. There was 1 baby (6.6%) who had CP, gross motor abnormal or questionable was seen in 4 (26.6%) and language was abnormal or questionable in 4 (26.6%) cases. The mean MeDQ, MoDQ and PBCL scores were comparable with the babies who were equal to or more than 1000 g (Table 3). Amongst the ELBW babies, 25% (n=3) and 42% (n=5) had MeDQ and MoDQ less than 70 respectively and all babies (n=10) had PBCL score 12. There were 81 (61%) babies who were AGA and 51 (39%) babies were SGA. There was no difference in neurological and developmental assessment in AGA and SGA babies. DASII scores were comparable in 2 groups (Table 4) and no of babies with score of < 70 in MeDQ and MoDQ were also comparable (p=0.964 and 0.875). Similarly mean PBCL score (Table 4) and subgroups with a score of 12 were also similar (p=0.952). Discussion This is the first study from India to report long term outcome of high risk very low birth weight babies which also includes a large number of ELBW babies. We had a nearly similar rate of cerebral palsy (CP) as compared to the Pune low birth weight follow up study which included babies who were preterm and had birth weight upto 2 kg and the rate of CP was 4% [9]. However all our babies were smaller in weight and gestation and 35% were ventilated as compared to none in the Pune group. This reflects that inspite of having survival at lower gestation age and weight, CP rate continues to be similar, which could be probably due to improvements in perinatal and neonatal care in India. The report from a Malaysian nursery also reported the CP rate of 3.9% in VLBW babies [6]. There is a declining trend in CP rate amongst VLBW babies as reported by European database study [20] and the rate fell from 60.6 per 1000 live born VLBW infants in 1980 to 39.5 in On developmental assessment the mean mental and motor quotients of our VLBW babies were lower than the Pune study group babies [9], and probably this can be explained due to lesser gestation and birth weight and nature of sickness in our babies. It was also noticed that

4 966 Indian J Pediatr (2010) 77: Table 2 DASII and PBCL sub scores in 1200 g (subgroup1) and g (subgroup 2) babies Values are expressed in Mean (SD) Variable Scores All babies (n=71) Subgroup1 (n=28) Subgroup2 (n=43) p MeDQ (n,%) <70 12 (17%) 5 (17.8%) 7 (16.2%) (83%) MoDQ (n,%) <70 18 (25%) 8 (32%) 10 (21%) (75%) PBCL (n=23,28) <12 8 (15.6%) (84.4%) 19 (82.6%) 24 (85.7%) both the scores were significantly lower in complicated preterm as compared to their controls who were term and in uncomplicated preterms.ho et al. [6] also showed that the GQ on Griffiths test was lower in a group of VLBW babies as compared to controls and 27.3% babies had GQ one or more SD below mean. We had a relatively large number of ELBW babies as compared to Pune group which included 3 babies who were 1000 g and 1 baby was <28 weeks. In our ELBW babies, the CP rate was lower as compared to western literature probably due to higher gestation in our babies and nearly 50% of our ELBW babies were SGA. Wilson-Costello et al. reported improved survival in ELBW babies during period as compared to during period (from 49% to 67%) however the CP rate also increased along with improved survival rate (16% to 25%) and neurodevelopmental abnormality increased from 26% to 36% [1]. However subsequently (during ) there was an improving trend in the outcomes of ELBW due to improvements in neonatal care and recorded rate of cerebral palsy declined from 13% to 5% and adverse neurodevelopmental outcome from 35% to 23% [2]. In NICHD trial [4], 25% ELBW babies had abnormal neurological examination, on Bayley scale, with mental developmental index and psychomotor developmental index of <70 seen in 37% and 29%, babies respectively. The mean gestation was 26 [2] wks and mean birth weight was 796 (135) gms in that cohort. In our ELBW babies, a large number had low mental and motor quotients though low mental quotients were observed in a lesser proportion and low motor quotients were seen in a higher proportion of babies as compared to NICHD trial group. According to the report of high risk follow up group from Hong Kong, the rates of cerebral palsy and intellectual impairment were reported as 12% and 16% in ELBW babies [5] and the mean gestational age was 26.2 (1.8) wks and mean birth weight was 789 (125) gms in that cohort. The behavioral outcome in our study showed that large number of VLBW babies had an abnormal high score and all ELBW babies had high PBCL score. These babies need long term behavioral follow up to pick up attention deficit hyperactivity disorders at the earliest. Behavioral abnormalities were not reported by Pune group but a report from New Zealand [12] showed significantly higher rates of problems and poorer levels of functioning as compared to general child sample at 7 8 years in a national very low birth weight cohort. They found that these differences persisted even after control for variability in social, family, degree of sensorineural disability. Though the NICHD trial did not report the outcomes separately in SGA babies, Gutbrod et al. [12] reported long term developmental outcomes in VLBW SGA babies at 20 months. They found SGA babies had poor head growth, early developmental delay and later language problem. Pune study also reported that preterm AGA babies show earlier catch up than preterm SGA babies [9] and at 6 years preterm SGA had lowest IQ scores [11]. However, we did not find such difference which probably can be explained due to shorter duration of study. The strength of our study is that this is the first published report of this kind in high risk preterm babies from our country which included a large number of babies who are less than 1200 g and we have their neurological as well as developmental and behavioral outcome. The biggest draw back of our study was a large drop out rate since discharge (approximately 30% at 1 year, 50% at 18 months and 61% at 2 years). The reason was that being a tertiary referral centre, these patients came from far off places and could Table 3 DASII and PBCL scores in <1000 g and 1000 g babies Variable <1000g (n=20) 1000g (n=51) p MeDQ 76.8 (8.8) 81.5 (10.9) MoDQ 74.5 (16) 78.2 (12.5) PBCL (n=10,41) 17.4 (4) 16.6 (5.8) Values are expressed in Mean (SD) Table 4 DASII and PBCL scores in AGA and SGA babies Variable AGA (n=41) SGA (n=30) p MeDQ 80.8(9.7) 79.7(12) MoDQ 77.1(14) 77.4(12.6) PBCL (n=26,25) 17.4(6.1) 16.2(4.7) Values are expressed in Mean (SD)

5 Indian J Pediatr (2010) 77: not come regularly for follow up subsequently inspite of our best efforts. The Hong Kong study had 60% babies followed up at months. Future research directions in our country should be to follow up high risk babies including SGA babies for a much longer period which should include developmental, behavioral as well as school performance and intelligence and also in relation with their prenatal and postnatal nutrition and growth pattern and socioeconomic status. This will also help in appropriate counseling of parents. Contributions KM responsible for protocol development, patient screening, enrollment, outcome assessment, preliminary data analysis and writing the manuscript. RM helped in collection and compilation of data, PM primarily responsible for developmental assessment and also contributed to the writing of the manuscripts. AN did the critical review of the manuscript and helped in designing the study. Conflict of Interest None Role of Funding Source PGI Research scheme. References Partial financial support was obtained from 1. Stevenson DK, Wright LL, Lemons JA, Oh W, Korenes SB, Papile LA, et al. Very low birth weight outcomes of the National Institute of Child Health and Human development Neonatal Research Network, January 1993 through December Am J Obstet Gynecol. 1998;179: Wilson-Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics. 2005;115: Wilson-Costello D, Friedman H, Minich N, Siner B, Taylor G, Schluchter M, et al. Improved neurodevelopmental outcomes for extremely low birth weight infants in Pediatrics. 2007;119: Vohr BR, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human development Neonatal Research Network, Pediatrics. 2000;105: High risk follow-up working group ( Kowloon Region). Neurodevelopmental outcomes of extremely low birth weight infants born between 2001 and Hong Kong Med J. 2008;14: Ho JJ, Amar HS, Mohan AJ, Hon TH. Neurodevelopmental outcome of very low birth weight babies admitted to a Malaysian nursery. J Pediatr Child Health. 1999;35: National Neonatal Perinatal database, report for the year 2000, National Neonatology Forum, India. 8. National Neonatal Perinatal database, report for the year , National Neonatology Forum, India. 9. Chaudhari S, Kulkarni S, Pajnigar F, Pandit AN, Desmukh S. A longitudinal follow up of development of preterm infants. Indian Pediatr. 1991;28: Chaudhari S, Kulkarni S, Barve S, Pandit AN, Sonak U, Sarpotdar N. Neurologic sequelae in high risk infants a three year follow up. Indian Pediatr. 1996;33: Chaudhari S, Bhalerao MR, Chitale A, Pandit AN, Nene U. Pune low birth weight study a six year follow up. Indian Pediatr. 1999;36: Gutbrod T, Wolke D, Soehne B, Ohrt B, Riegel K. Effects of gestation and birth weight on the growth and development of very low birth weight small for gestational age infants: a matched group comparison. Arch Dis Child Fetal Neonatal Ed. 2000;82: F Horwood LJ, Mogridge N, Darlow BA. Cognitive, educational and behavioural outcome at 7 8 years in a national very low birth weight cohort. Arch Dis Child Fetal Neonatal Ed. 1998;79:F Mukhopadhyay K, Narang A, Mahajan R. Effect of human milk fortification in appropriate for gestation and small for gestation preterm babies: a randomized controlled trial. Indian Pediatr. 2007;44: Frankenburg WK. The Denver approach to early case finding. In: Frankenburg WK, Emde RN, Sullivan JW, editors. Early identification of children at risk. New York: Plenum; p Amiel-Tison C, Grenier A. Neurological assessment during first year of life. New York: Oxford University Press; p Misra N, Pathak P. Developmental assessment scales for Indian Infants (DASII): Manual, Baroda, M.S. University of Baroda, McGuuire J, Richman N. Screening for behavior problems in nurseries. The reliability and validity of the Pre-School Behavior Checklist. J Child Psychol Psychiatry. 1986;27: Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimate from live born birth weight data at 24 to 42 weeks of gestation. Pediatrics. 1963;32: Platt MJ, Cans C, Johnson A, Surman G, Topp M, Torrioli MG, et al. Trends in cerebral palsy among infants of very low birth weight (<1500 g) or born prematurely (< 32 weeks) in 16 European centers: a database study. Lancet. 2007;369:43 50.