Effects of Individualized Developmental Care in a Randomized Trial of Preterm Infants <32 Weeks Celeste M. Maguire, Frans J.

Walther, Arwen J. Sprij, Saskia Le Cessie, Jan M. Wit, Sylvia Veen and for the Leiden Developmental Care Project Pediatrics 2009;124;1021-1030; originally published online Sep 28, 2009; DOI: 10.1542/peds.2008-1881

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/124/4/1021

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Effects of Individualized Developmental Care in a Randomized Trial of Preterm Infants 32 Weeks

AUTHORS: Celeste M. Maguire, PhD,a Frans J. Walther, MD, PhD,a Arwen J. Sprij, MD,b Saskia Le Cessie, PhD,c Jan M. Wit, MD, PhD,a and Sylvia Veen, MD, PhD,a for the Leiden Developmental Care Project
Department of Pediatrics, Division of Neonatology, and Department of Medical Statistics, Leiden University Medical Center, Leiden, Netherlands; and bDepartment of Pediatrics, Division of Neonatology, Juliana Childrens Hospital, The Hague, Netherlands
c a

WHATS KNOWN ON THIS SUBJECT: Follow-up studies of the effectiveness of NIDCAP showed conicting results and were based on trials with small sample sizes. A Cochrane meta-analysis recommended conducting larger trials with more follow-up monitoring. WHAT THIS STUDY ADDS: This large RCT comparing NIDCAP with basic developmental care showed no signicant improvement in respiratory support, days of intensive care, or growth or neuromotor development at term age.

KEY WORDS preterm infants, developmental care, Newborn Individualized Developmental Care and Assessment Program, growth, respiratory support, intensive care, neurodevelopment ABBREVIATIONS NIDCAPNewborn Individualized Developmental Care and Assessment Program RCTrandomized, controlled trial PDApatent ductus arteriosus CPAP continuous positive airway pressure GA gestational age This trial has been registered at www.trialregister.nl (identier ISRCTN84995192). www.pediatrics.org/cgi/doi/10.1542/peds.2008-1881 doi:10.1542/peds.2008-1881 Accepted for publication Apr 9, 2009 Address correspondence to Sylvia Veen, MD, PhD, Department of Pediatrics, J-6-S, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail: s.veen@lumc.nl PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2009 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

abstract
OBJECTIVE: The goal was to investigate the effects of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) on days of respiratory support and intensive care, growth, and neuromotor development at term age for infants born at 32 weeks. METHODS: Infants were assigned randomly, within 48 hours after birth, to a NIDCAP group or basic developmental care (control) group. The NIDCAP intervention consisted of weekly formal behavioral observations of the infants and caregiving recommendations and support for staff members and parents, as well as incubator covers and positioning aids. The control group infants were given basic developmental care, which consisted of only incubator covers and positioning aids. Outcome measures were respiratory support, intensive care, and weight of 1000 g. Growth parameters were measured weekly or biweekly and at term age. Neuromotor development was assessed at term age. RESULTS: A total of 164 infants met the inclusion criteria (NIDCAP: N 81; control: N 83). In-hospital mortality rates were 8 (9.9%) of 81 infants in the NIDCAP group and 3 (3.6%) of 83 infants in the control group. No differences in mean days of respiratory support (NIDCAP: 13.9 days; control: 16.3 days) or mean days of intensive care (NIDCAP: 15.2 days; control: 17.0 days) were found. Short-term growth and neuromotor development at term age showed no differences, even with correction for the duration of the intervention. CONCLUSIONS: NIDCAP developmental care had no effect on respiratory support, days of intensive care, growth, or neuromotor development at term age. Pediatrics 2009;124:10211030

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1021

Advanced technology in neonatal care has resulted in increased survival rates for preterm infants13 but not in major improvements in morbidity rates or decreased risks of developmental delays, physical disabilities, and behavioral disorders.1,4,5 Developmental care programs have been used to support infants and families in the NICU. Most research has been based on the Newborn Individualized Developmental Care and Assessment Program (NIDCAP), in which caregiving is based on the individual behavior of the infant.6 Evidence showing positive effects of NIDCAP is inconclusive, and additional randomized, controlled trials (RCTs) with larger sample sizes and long-term follow-up monitoring have been recommended.7 Between April 2000 and May 2002, our rst RCT comparing basic developmental care (incubator covers, nests, and positioning aids) with standard care showed no short-term effects.8 The aim of this RCT was to explore the effectiveness of the more-comprehensive NIDCAP, compared with basic developmental care, with respect to neonatal morbidity, neuromotor development, and growth at term age of preterm infants of gestational age (GA) of 32 weeks.

Infants in NIDCAP study

168 total infants recruited

84 NIDCAP group

84 control group

1 infant excluded due to admission <5 d 2 infant deaths <5 d

1 infant death <5 d

81 infants included

83 infants included

8 infant deaths

3 infant deaths

Remaining infants: 73

Remaining infants: 80

Infants at follow-up at term age: 73

Infants at follow-up at term age: 80

FIGURE 1
Study ow and infant deaths.

METHODS
Study Design and Intervention The study was carried out by using a standard protocol, at two locations of a tertiary NICU in the Netherlands: Leiden University Medical Center in Leiden and Juliana Childrens Hospital in the Hague. The inclusion criterion was GA of 32 weeks; exclusion criteria were major congenital anomalies, a need for major surgery, and having a drug-addicted mother. After parental informed consent was obtained, infants were assigned randomly to the NIDCAP or control group within 48 hours after birth, by using sealed en1022 MAGUIRE et al

velopes prepared in groups of 6 through computer-generated randomization. Power analysis performed before the study showed that a sample size of 140 infants was needed to show a signicant difference (P .05) with a power of 80%, on the basis of a difference of 0.5 SD in the Bayley II scores at 1 and 2 years of age, which was deemed sufcient power for the shortterm primary neonatal outcomes. The NIDCAP intervention consisted of weekly behavioral observations of the infants by trained, certied, NIDCAP developmental specialists, with the rst observation occurring within 48 hours after birth. Individual care plans that were based on these observations, with caregiving recommendations, were formulated with parents and caregivers input and were available at the infants bedside. Parents were supported in understanding their infants behavior and how to approach and to support their infant during caregiving interactions and were provided with photographic booklets explaining pre-

term infant behavior. Infants in the NIDCAP group were cared for primarily by nurses who had received extra training and support in behaviorbased, individualized, developmental care and were familiar with performing individualized care on the basis of the infants behavior and recommendations. Incubator covers, nests, and positioning aids to encourage exion and containment were used. Reection periods for discussion and support were provided for the NIDCAP care team, as was daily support for the parents. If an infant was transferred to a regional hospital, then a report with recommendations for caregiving was prepared for the parents. A NIDCAPcertied developmental psychologist supervised the intervention, conducted observations, and supported the parents and staff members. Infants in the control group received only basic developmental care (incubator covers, nests, and positioning aids). Control group nurses performed basic developmental care. No formal

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observations in which the control infants behavior was described were made. The ethics committees of both locations approved the study. Neonatal Outcomes and Follow-up Evaluations Primary medical outcomes were days of respiratory support, days of intensive care, and short-term growth. Mechanical ventilation (synchronized intermittent mandatory ventilation and/or high-frequency oscillation) and continuous positive airway pressure (CPAP) therapy were measured in days. If an infant received both mechanical ventilation and CPAP therapy in the same day, then the method of respiratory support used for more hours was chosen. Days of respiratory support were dened as total combined days of mechanical ventilation and CPAP therapy. Short-term growth (weight, head circumference, and length) was measured at term age; mean daily weight gain (in grams) and mean weekly length and head circumference growth (in centimeters) also were recorded. Discharge from intensive care was based on the infant requiring no mechanical ventilation and/or CPAP therapy for 24 hours and weighing 1000 g. Infants were seen at term age by neonatologists who were experienced in developmental assessments and were blinded to the group assignment of the infants. A standardized neurologic examination, as described by Prechtl,9 was performed, and results were dened as denitely abnormal (presence of a full neonatal neurologic syndrome, such as apathy, hyperexcitability, hypotonia, hypertonia, hyporeexia, hyperreexia, hypokinesia, or hyperkinesia, or a hemisyndrome), mildly abnormal (presence of only part of such a syndrome), or normal. Examples of minor neurologic signs are abnormal posture, abnormal head control, and
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TABLE 1 Maternal Medical and Parental Demographic Background Variables

NIDCAP (N 81) Obstetric history, n/N (%) Preexisting disease (diabetes mellitus, hypertension, or other) Pregnancy induction Disease during pregnancy, n/N (%) Diabetes mellitus gravidarum Preeclampsia, eclampsia, or HELLP syndrome Medication use during pregnancy, n/N (%) Antihypertensive agents Antibiotics Tocolytic agents Other Prenatal glucocorticoid treatment, n/N (%) 1 dose 1 course (2 doses) Mode of delivery, n/N (%) Vaginal Cesarean section PROM for 24 h, n/N (%) Primipara, n/N (%) Parental demographic background Maternal age, mean SD, y Paternal age, mean SD, y Mother white, n/N (%) Father white, n/N (%) Education level of mother, n/N (%)a Low Intermediate High Education level of father, n/N (%)a Low Intermediate High 9/81 (11.1) 13/81 (16.0) 2/81 (2.5) 13/81 (16.0) 14/81 (17.3) 32/81 (39.5) 45/81 (55.6) 7/81 (8.6) 29/80 (36.3) 33/80 (41.3) 41/81 (50.6) 40/81 (49.4) 25/81 (30.9) 54/81 (66.7) 30.0 5.2 (N 74) 32.3 5.6 (N 72) 66/80 (82.5) 63/79 (79.7) 26/72 (36.1) 25/72 (34.7) 21/72 (29.2) 19/69 (27.5) 22/69 (31.9) 28/69 (40.6) Control (N 83) 14/83 (16.9) 14/83 (16.9) 3/83 (3.6) 16/83 (19.3) 19/83 (22.9) 25/83 (30.1) 43/83 (51.8) 14/83 (16.9) 35/83 (42.2) 29/83 (34.9) 45/83 (54.2) 38/83 (45.8) 19/83 (22.9) 42/83 (50.6) 31.9 5.0 (N 78) 34.1 5.5 (N 77) 70/80 (87.5) 64/80 (80.0) 19/77 (24.7) 26/77 (33.8) 32/77 (41.6) 15/76 (19.7) 32/76 (42.1) 29/76 (38.2)

HELPP, hemolysis, elevated liver enzyme levels, and low platelet count; PROM indicates premature rupture of membranes. a Low indicates vocational training; intermediate, high school; high, college/university.

absent or abnormal responses or reexes. Secondary outcomes are dened in the tables and were described in a previous article.8 Statistical Analyses Data were analyzed by using SPSS 14.0 for Windows (SPSS Inc, Chicago, IL). Infant and parent characteristics and outcome parameters were compared with the 2 test (for trend) or the 2-sample t test or Mann-Whitney test where appropriate. P values of .05 were considered signicant. Linear regression was used to evaluate the inuence of the duration of the intervention on term age outcomes, by testing whether there was an interaction effect between the intervention duration and the 2 treatment groups. Me-

dian days of CPAP therapy, days of respiratory support, and days of intensive care were obtained from Kaplan-Meier curves and were compared by using the log-rank test, with measurements for infants who died being censored.

RESULTS
Study Groups A total of 168 infants (NIDCAP: N 84; control: N 84) were recruited between July 2002 and August 2004. Four infants (NIDCAP: n 3; control: n 1) were excluded according to protocol because they were transferred to another hospital or died within the rst 5 days of admission, leaving a total of 164 infants who met
1023

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TABLE 2 Infant Medical Background Variables for All Participating Infants

NIDCAP GA, wk Mean SD Range Birth weight, g Mean SD Range Length, cm Mean SD Range Head circumference, cm Mean SD Range Male, n/N (%) SGA, 10th and 3rd percentile, n/N (%) SGA, 3rd percentile, n/N (%) Twin, n/N (%) Inborn, n/N (%) Apgar score at 5 min Mean SD Median Range CRIB score Median Range RDS, n/N (%) Grade 1 Grade 2 Grade 3 Grade 4 Surfactant treatment, n/N (%) Hyperbilirubinemia, n/N (%) Duration of phototherapy, mean SD, d N 81 29.3 1.8 24.731.9 N 81 1215 328 5771939 N 81 37.1 3.1 29.043.0 N 81 26.8 2.2 22.432.0 46/81 (56.8) 15/81 (18.5) 3/81 (3.7) 27/81 (33.3) 51/81 (63.0) N 80 8.1 2.2 8 310 N 81 2 014 20/81 (24.7) 11/81 (13.6) 17/81 (21.0) 6/81 (7.4) 41/81 (50.6) 73/81 (90.1) 4.4 2.9 Control N 83 29.2 1.6 25.631.6 N 83 1226 343 6252060 N 83 36.8 3.3 29.044.0 N 83 26.6 2.3 21.530.5 43/83 (51.8) 10/83 (12.0) 5/83 (6.0) 34/83 (41.0) 49/83 (59.0) N 80 8.3 1.4 8 410 N 83 3 013 23/82 (28.0) 13/82 (15.9) 17/82 (20.7) 8/82 (9.8) 39/83 (47.0) 76/83 (91.6) 4.8 3.4

better in the Leiden hospital site and slightly worse in the Juliana Childrens Hospital site. Secondary Outcomes No differences were found between groups in the total length of stay from birth to discharge from the hospital or the GA of infants at discharge from the hospital. There was no difference between the 2 groups in the days of oxygen therapy, numbers of infants who required oxygen after 28 days, or incidence of bronchopulmonary dysplasia. A total of 7 (8.6%) of 81 infants in the NIDCAP group required postnatal corticosteroid treatment, compared with 11 (13.3%) of 83 infants in the control group (P .35), with twice as many infants in the control group requiring corticosteroid treatment for 2 weeks. There were signicantly more infants in the NIDCAP group (25 [30.9%] of 81 infants) than in the control group (11 [13.3%] of 83 infants) with patent ductus arteriosus (PDA) requiring medication and/or surgical ligation. Of the 25 infants with PDA in the NIDCAP group, 6 (24%) of 25 died in the hospital; 1 (9%) of 11 infants with PDA in the control group died. Among the surviving infants, the NIDCAP group still had twice as many infants with PDA (19 [26%] of 73 infants), compared with the control group (10 [12.5%] of 80 infants; P .03). No signicant differences in the remaining secondary outcomes were found (Table 4). Survivor Analyses A Kaplan-Meier analysis that included respiratory data for infants who died in the hospital was performed, with no differences found in the total population (Fig 2). Because of the signicant difference in the incidence of PDA between the groups (Table 4), a posthoc analysis was performed and stratied with respect to infants with PDA requiring medication/surgery versus infants without signicant PDA. In the

Comparisons were performed by using 2 tests (for linear trend) or t tests where appropriate. SGA indicates small for GA; CRIB, Clinical Risk Index for Babies; RDS, respiratory distress syndrome.16

the inclusion criteria. Of these infants, 8 (9.9%) of 81 in the NIDCAP group and 3 (3.6%) of 83 in the control group died during hospitalization, with the main cause of death being cerebral or pulmonary complications. The mortality rate and loss to follow-up monitoring are shown in Fig 1. Parent and infant characteristics were similar, with no signicant differences being found (Tables 1 and 2). Primary Outcomes No signicant differences in the days of intensive care, days of respiratory support, or growth were found between the NIDCAP and control groups. There were no signicant differences between the NIDCAP and control groups in the neurologic outcomes or
1024 MAGUIRE et al

growth parameters at term age, in daily weight gain, or in weekly length and head circumference growth (Table 3). Linear regression analysis showed no interaction effect between the intervention duration and the 2 treatment groups with respect to neurologic outcome (P .72) or term age growth, including head circumference (P .94), weight (P .28), and length (P .54). No interaction effect was found between the 2 sites in total days of ventilatory support (P .7), weight at term age (P .07), or head circumference at term age (P .07). Differences were not signicant except for term length in the Leiden Hospital site (mean SD: control: 48.4 2.9 cm; intervention: 49.9 2.1 cm; P .006); the intervention group performed slightly

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TABLE 3 Comparison of Data on Primary Outcome Measures

NIDCAP (N 81) Duration of hospitalization, d Mean SD Median (range) Duration of intensive care, d Mean SD Median (range) Required respiratory support, n/N (%) Duration of mechanical ventilation, db Mean SD Median (range) Duration of CPAP therapy, d Mean SD Median (range) Total duration of ventilatory support, dc Mean SD Median (range) Growth parameters at term age Age, mean SD, wk Weight, mean SD, kg Daily weight gain, mean SD, g Head circumference, mean SD, cmd Weekly head circumference growth, mean SD, cmd Length, mean SD, cm Weekly length growth, mean SD, cm Neurologic outcome at term Normal Mildly abnormal Denitely abnormal Control (N 83) Difference, Estimate (95% CI) 1.1 (11.8 to 9.5) 1.8 (3.1 to 6.6) 2.6 (11.2 to 5.9) 0.8 (1.9 to 3.4) 1.6 (1.8 to 5.0) 2.4 (2.7 to 7.4) 0 (0.60 to 0.65) 0.1 (2.1 to 1.7) 0.1 (0.39 to 0.59) 0.5 (1.5 to 0.35) 2.1 (13.8 to 18.1) 12.1 (27.4 to 3.2) 9.9 (0.4 to 19.5) P

41.5 30.9a 37 (6159) 15.2 14.8 9 (054) 73/81 (90.1) 5.6 7.0 2.0 (025) 8.4 9.9 4.0 (036) 13.9 14.6 9.0 (152) 41.1 1.9 (N 72) 3.11 0.63 (N 72) 23.9 5.8 (N 72) 35.5 1.6 (N 70) 0.76 0.14 (N 70) 49.0 2.8 (N 72) 1.00 0.22 (N 72) N 73 39/73 (53.4) 23/73 (31.5) 11/73 (15.1)

40.4 37.9 30 (5285) 17.0 16.5 11 (080) 77/83 (92.8) 6.4 9.3 2.0 (041) 10.0 11.0 6.0 (067) 16.3 16.7 10.0 (179) 41.1 2.0 (N 80) 3.10 0.57 (N 80) 22.9 5.2 (N 80) 35.6 1.5 (N 79) 0.76 0.12 (N 79) 48.5 2.9 (N 77) 0.99 0.19 (N 77) N 78e 40/78 (51.3) 34/78 (43.6) 4/78 (5.1)

.83

.46 .54 .60

.35

.35

.94 .86 .25 .62 .90 .23 .29 .47

Comparisons were performed by using 2 tests (for linear trend), t tests, or Mann-Whitney tests where appropriate. CI indicates condence interval. a Also indicates number of days intervention was given. b Synchronized intermittent mandatory ventilation and/or high-frequency oscillation. c Total days of synchronized intermittent mandatory ventilation, high-frequency oscillation, and CPAP therapy combined. d Infants with posthemorrhagic ventricular dilation (NIDCAP: n 2; control: n 1) were excluded from head circumference analyses. e Two infants were not assessed according to the method of Prechtl.9

subgroup of infants with no PDA, the NIDCAP group required fewer days of CPAP therapy (P .02), total respiratory support (P .02), and intensive care (P .06), compared with the control group (Fig 3). Because phototherapy may inuence the closure and/or reopening of a PDA,10 days of phototherapy were compared, but no difference between the groups was found (mean: NIDCAP: 4.4 days; control: 4.8 days).

age of infants born at 32 weeks, no signicant positive effects of the intervention on the need for respiratory support or days of intensive care were found. No differences between the NIDCAP and control groups with respect to growth and neurologic outcomes at term age were found with correction for days of intervention. Respiratory Support A Cochrane meta-analysis found that infants who received NIDCAP care showed signicantly fewer days of ventilation and no differences in days of oxygen therapy; the authors stated that the results were conicting and, because the studies showed much heterogeneity, the results should be viewed with caution.11 A RCT of 25 infants who

DISCUSSION
Overall Findings In this RCT examining short-term effects of the comprehensive NIDCAP, compared with basic developmental care, on neonatal morbidity, neurologic outcomes, and growth at term
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were born at GA of 32 weeks and required ventilatory support at 24 hours showed no signicant difference in days of mechanical ventilation, a trend in days of CPAP therapy in favor of the NIDCAP group (NIDCAP: 43.9 days; control: 26.1 days; P .045), and a younger postconceptual age of oxygen withdrawal.12 The number of patients included in that study was small (NIDCAP: N 12; control: N 13), because the trial needed to be terminated earlier than expected.12 Earlier NIDCAP studies by Als et al13 and Fleischer et al14 also showed positive results concerning the need for ventilatory support; however, only infants born at GA of 30 weeks and birth weight of 1250 g were included, and specic ventilation inclusion criteria were used. A 3-center trial showed signicant differ1025

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TABLE 4 Comparison of Data on Secondary Outcome Measures

NIDCAP (N 81) In-hospital death, n/N (%) Early neonatal deatha Late neonatal deatha LOS, d Mean SD Median (range) GA at discharge to home, mean SD, wk Total time of supplemental oxygen treatment, d Mean SD Median (range) Oxygen requirement at 28 d of life, n/N (%) BPD (oxygen dependence after 36 wk of postconceptual age), n/N (%) Postnatal corticosteroid treatment, n/N (%)b 7 d 714 d 1520 d 20 d IVH, n/N (%) Grade III Grade III (and periventricular echodensity) Posthemorrhagic ventricular dilation, n/N (%) NEC, n/N (%) Sepsis, n/N (%) Meningitis, n/N (%) PDA (indomethacin and/or surgery), n/N (%) Dopamine/dobutamine treatment, n/N (%) ROP, n/N (%) PVL at follow-up evaluation at term age, n/N (%) Grade 1 Grade 2 Grade 3 Grade 4 Physical therapy required at term age, n/N (%) 8/81 (9.9) 1/81 (1.2) 7/81 (8.6) N 70 61.9 24.5 57.5 (32159) 38.5 2.7 (N 70) 17.2 22.6 6 (0100) 25/81 (30.9) 12/80 (15.0) Control (N 83) 3/83 (3.6) 0/83 (0) 3/83 (3.6) N 74 67.6 34.2 58.5 (30285) 38.9 4.4 (N 74) 16.4 25.4 3 (0121) 24/82 (29.3) 16/81 (19.8) P .14

.24

.50 .84 .82 .43

study found no signicant difference in days of intensive care between NIDCAP and conventional care but also did not dene the criteria for days of intensive care and included only infants with GAs of 30 weeks.17 Other NIDCAP studies reported total days of hospitalization but not days of intensive care. Growth One study by Als et al15 showed signicantly better average daily weight gain and better growth (weight, head circumference, and height) to term age for the infants receiving NIDCAP, whereas the study by Westrup et al12 showed no signicant effect on growth (weight gain and head growth) up to postconceptual age of 35 weeks. The Cochrane meta-analysis,11 which excluded the multicenter trial by Als et al15 because of site differences, concluded that NIDCAP did not affect growth for infants surviving to corrected age of 9 months. Our short-term growth results are comparable to those ndings. Neurobehavioral Outcomes Two previous NIDCAP studies showed signicant improvements in neurobehavioral outcomes, according to the method described by Prechtl,9 which they dened with 12 summary variables and a total score showing the proportion of abnormal scores in each group.18,19 We found no signicant difference in our study, in which neurobehavioral outcomes, according to the method described by Prechtl,9 were dened as denitely abnormal, mildly abnormal, or normal. Incidence of PDA After random assignment, our study showed signicantly more infants in the NIDCAP group with PDA requiring medication or surgery (Table 4). The mean days of phototherapy, which can inuence ductal reopening, were similar for the 2 groups; therefore, there is

1/81 (1.2) 2/81 (2.5) 2/81 (2.5) 2/81 (2.5) 17/81 (21.0) 6/81 (7.4) 2/81 (2.5) 3/81 (3.7) 38/81 (46.9) 1/81 (1.2) 25/81 (30.9) 22/81 (27.2) 8/70 (11.4) 5/72 (6.9) 1/72 (1.4) 1/72 (1.4) 0 (0) 16/73 (21.9)

1/83 (1.2) 2/83 (2.4) 7/83 (8.4) 1/83 (1.2) 19/83 (22.9) 4/83 (4.8) 6/83 (7.2) 3/83 (3.6) 45/83 (54.2) 1/83 (1.2) 11/83 (13.3) 23/83 (27.7) 10/73 (13.7) 10/80 (12.5) 0 (0) 1/80 (1.3) 0 (0) 11/80 (13.8)

.35

.72 .16 .86 .35 .99 .01c .94 .82 .76

.32

Comparisons were performed by using 2 tests (for linear trend) or t tests where appropriate. LOS indicates length of stay until discharge to home; BPD, bronchopulmonary dysplasia22; IVH, intraventricular hemorrhage23; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; PVL, periventricular leukomalacia.24 a Early neonatal death denotes death within the rst 7 days of life; late neonatal death denotes death after 7 days but before 28 days of life. b Postnatal steroid treatment involved a maximal dosage of 0.2 mg/kg per day, tapered off over a period of 16 days. c P .05 was considered signicant.

ences in respiratory support between the NIDCAP group and the control group, but there were differences between sites (parental demographic and infant medical background variables).11,15 Our study included infants who were born at 32 weeks, regardless of their need for ventilatory support, and had lower Clinical Risk Index for Babies scores,16 which indicated that they were in more-stable condition in the rst 12 hours of life. Days of Intensive Care A 3-center RCT of 92 preterm infants with birth weights of 1250 g and GAs
1026 MAGUIRE et al

of 28 weeks showed signicantly fewer days of intensive care for the NIDCAP group.15 We were not able to duplicate those ndings in our study; however, our population was different, in that we included older infants with GAs of 32 weeks, with no restriction on birth weight. The total number of days of intensive care in our study was considerably less than that in the aforementioned study, which perhaps reects the different populations or different denitions of days of intensive care, because the criteria for days of intensive care were not dened in the multicenter trial. Another Dutch

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A100
80

Control/intervention group Control Intervention Control-censored Interventioncensored

B 100
80

Control/intervention group Control Intervention Control-censored Interventioncensored

Percentage

Percentage

60

60

40

40

20

20

0 0 10 20 30 40 50 60 70

0 0 20 40 60 80

Total days CPAP

Total days respiratory support

Control/intervention group Control Intervention Control-censored Interventioncensored

C 100
80

Percentage

60

40

20

0 0 20 40 60 80

Total days IC
FIGURE 2
Kaplan-Meier analysis comparison of days of CPAP therapy (A), respiratory support (B), and intensive care (IC) (C) for all participating infants.

no plausible reason why infants in the NIDCAP group had signicantly more cases of PDA that needed treatment.10 Most of the infants (NIDCAP: 17 of 19 infants; control: 9 of 10 infants) were given a 3-dose course of indomethacin, which successfully closed the PDA. Two infants in the NIDCAP group and 2 in the control group were given a course of indomethacin and then treated with surgical ligation. These ndings differ from the outcomes in the Cochrane
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meta-analysis,11 in which no inuence of the NIDCAP intervention on the incidence of PDA was found. Because PDA may inuence days of ventilation and days of intensive care, weperformedfurtheranalysis(KaplanMeier analysis). In the subgroup of infants with no PDA (NIDCAP: n 56; control: n 72), we found signicant differences in days of CPAP therapy and total respiratory support in favor of the NIDCAP group. We assume, on

clinical grounds, that most of the PDA cases were diagnosed after inclusion (within 48 hours after birth) in the study. Although there may be a possible benet from NIDCAP in days of respiratory support for a subgroup of infants without PDA, these ndings should be interpreted with caution. The presence of PDA did seem to inuence neurodevelopmental outcomes, because 7 (64%) of 11 infants in the NIDCAP group with denitely abnormal
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100

80

Percentage

60

Control/intervention group Control Intervention Control-censored Interventioncensored

40

20

0 0 10 20 30 40 50 60

Total days respiratory support

100

80

Percentage

Control/intervention group Control Intervention Control-censored Interventioncensored

background characteristics of the 2 groups (NIDCAP-treated infants were smaller and included fewer multiple births, compared with the conventional care group, and the NIDCAPtreated infants developed signicantly more pneumonia, possibly because of an outbreak of a nosocomial infection in the NICU during the NIDCAP implementation). One advantage of a phaselag study is the ability to implement a program such as NIDCAP throughout the entire department; however, the disadvantage of having different periods of research, in which there may be changes in the department, may affect results. Therefore, the authors stated that their results should be interpreted with caution.17 A meta-analysis of 3 studies13,18,20 showed no evidence that NIDCAP affected the incidence of grade 3 or 4 intraventricular hemorrhage,11 and there was not a signicant difference in either the Swedish trial12 or the 3-center trial.15 Our study was comparable, in that no differences in the outcomes of intraventricular hemorrhage and/or periventricular leukomalacia were found. A signicant effect of NIDCAP on moderate/severe chronic lung disease was found in the Cochrane review.11 In our study, although the control group required more postnatal corticosteroid treatment than did the NIDCAP group, there was no difference in the incidence of bronchopulmonary dysplasia. Total days of intervention were less than in previous NIDCAP trials, which is a limitation of our study, because this would affect the number of days on which NIDCAP developmental care would be given. When we compared the number of days of intensive care and the total days of hospitalization, the infants in our study required fewer days of intensive care and were transferred to regional hospitals earlier; therefore, the number of days of inter-

60

40

20

0 0 20 40 60 80

Total days respiratory support

FIGURE 3
Kaplan-Meier analysis comparison of days of respiratory support for infants with no PDA (A) and infants with PDA (B).

scores on the Prechtl examination at term age had PDA and only 1 (25%) of 4 control infants with denitely abnormal scores had PDA, which reects the higher incidence of PDA in the NIDCAP group. There also were more boys (57.9% vs 30%) and small-for-GA infants (31.6% vs 20%) with PDA in the NIDCAP group than in the control group.
1028 MAGUIRE et al

Secondary Outcomes Wielenga et al17 showed that NIDCAPtreated infants had a lower incidence of severe cerebral damage in a phaselag study of infants born at 30 weeks of gestation, in which 26 infants received conventional treatment, followed by 25 infants who received NIDCAP developmental care. There were signicant differences in the neonatal

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ARTICLES
1 trial,21 we were not able to nd any signicant differences in our primary outcomes. Future research on NIDCAP should include not only neonatal intensive care centers but also the regional hospitals to which infants are transferred.

vention was, for a proportion of our participating infants, smaller than in previously reported studies. Because of the regionalization of neonatal intensive care in the Dutch neonatal health care system, infants often are transferred to regional hospitals that can provide postintensive care and intermediate care. Thirty-three (41%) of 80 surviving infants in the control group and 37 (51%) of 73 surviving infants in the NIDCAP group remained in the participating hospitals for 6 weeks. Because of this variation, we did correct for the number of days of intervention, but this did not change the term age outcomes. This study is, to our knowledge, the largest RCT examining the effects of NIDCAP developmental care on preterm infants. All except 2 of the surviving 153 infants were seen at follow-up evaluations at term age. The infants were assigned randomly in an appropriate manner; however, there could REFERENCES

be no blinding of the intervention, because all infants were cared for in the same unit and the NIDCAP-treated infants had recommendations for caregiving at their bedside. The amount of respiratory support given to an infant was decided on by several neonatologists and was not inuenced by the study group in which the infant participated. Discharge from the NICU was based on 2 criteria, that is, the infant required no mechanical ventilation and/or CPAP therapy for 24 hours and weighed 1000 g; therefore, days of intensive care also could not be inuenced by group participation. Follow-up evaluations at term age were conducted by neonatologists blinded to the participation group. Despite the large sample size, compared with previous NIDCAP studies, and well-dened outcome measurements, as well as the addressing of methodologic concerns identied in

ACKNOWLEDGMENTS
This study was funded by the Netherlands Organisation for Health Research and Development (grant 2100.0072) and the Health Care Efciency Research Fund of the Leiden University Medical Center. We thank Sylvia M. van der Pal, PhD, Monique Rijken, MD, PhD, Shirley Martens, MD, and Monique de Haan, MD, and the NIDCAP nurses (Annemieke de Waal, Thayla Halfwerk, Thea van Engelenberg, Karima Balarbi, Els van Veldhuijzen, and Hanneke Entrop) for their contribution to this research project.

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Effects of Individualized Developmental Care in a Randomized Trial of Preterm Infants <32 Weeks Celeste M. Maguire, Frans J. Walther, Arwen J. Sprij, Saskia Le Cessie, Jan M. Wit, Sylvia Veen and for the Leiden Developmental Care Project Pediatrics 2009;124;1021-1030; originally published online Sep 28, 2009; DOI: 10.1542/peds.2008-1881
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/124/4/1021 This article cites 17 articles, 9 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/124/4/1021#BIBL This article has been cited by 2 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/124/4/1021#otherartic les This article, along with others on similar topics, appears in the following collection(s): Premature & Newborn http://www.pediatrics.org/cgi/collection/premature_and_newbor n Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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