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

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Effects of Individualized Developmental Care in a

Randomized Trial of Preterm Infants

⬍

32 Weeks

WHAT’S KNOWN ON THIS SUBJECT: Follow-up studies of the

effectiveness of NIDCAP showed conﬂicting 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 signiﬁcant improvement in respiratory support, days of intensive care, or growth or neuromotor development at term age.

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 neuro-motor 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 obser-vations of the infants and caregiving recommendations and support for staff members and parents, as well as incubator covers and posi-tioning aids. The control group infants were given basic developmental care, which consisted of only incubator covers and positioning aids. Out-come 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 neu-romotor development at term age showed no differences, even with correction for the duration of the intervention.

CONCLUSIONS:NIDCAP developmental care had no effect on

respira-tory support, days of intensive care, growth, or neuromotor development at term age.Pediatrics2009;124:1021–1030

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

a_{Department of Pediatrics, Division of Neonatology, and} c_{Department of Medical Statistics, Leiden University Medical}

Center, Leiden, Netherlands; andb_{Department of Pediatrics,}

Division of Neonatology, Juliana Children’s Hospital, The Hague, Netherlands

KEY WORDS

preterm infants, developmental care, Newborn Individualized Developmental Care and Assessment Program, growth, respiratory support, intensive care, neurodevelopment

ABBREVIATIONS

NIDCAP—Newborn Individualized Developmental Care and Assessment Program

RCT—randomized, controlled trial PDA—patent ductus arteriosus

CPAP— continuous positive airway pressure GA— gestational age

This trial has been registered at www.trialregister.nl (identiﬁer 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: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

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Advanced technology in neonatal care has resulted in increased survival rates for preterm infants1–3_{but not in}

major improvements in morbidity rates or decreased risks of develop-mental delays, physical disabilities, and behavioral disorders.1,4,5

Develop-mental care programs have been used to support infants and families in the NICU. Most research has been based on the Newborn Individualized Devel-opmental Care and Assessment Pro-gram (NIDCAP), in which caregiving is based on the individual behavior of the infant.6 _{Evidence showing positive}

ef-fects of NIDCAP is inconclusive, and ad-ditional 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 ﬁrst RCT comparing basic develop-mental 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 effec-tiveness of the more-comprehensive NIDCAP, compared with basic develop-mental care, with respect to neonatal morbidity, neuromotor development, and growth at term age of preterm in-fants of gestational age (GA) of⬍32 weeks.

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: den University Medical Center in Lei-den and Juliana Children’s 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, in-fants were assigned randomly to the NIDCAP or control group within 48 hours after birth, by using sealed

en-velopes prepared in groups of 6 through computer-generated random-ization. Power analysis performed be-fore the study showed that a sample size of 140 infants was needed to show a signiﬁcant difference (P⬍.05) with a power of 80%, on the basis of a differ-ence of 0.5 SD in the Bayley II scores at 1 and 2 years of age, which was deemed sufﬁcient power for the short-term primary neonatal outcomes.

The NIDCAP intervention consisted of weekly behavioral observations of the infants by trained, certiﬁed, NIDCAP de-velopmental specialists, with the ﬁrst 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 infant’s bedside. Parents were sup-ported in understanding their infant’s 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 behavior-based, individualized, developmental care and were familiar with perform-ing individualized care on the basis of the infant’s behavior and recommen-dations. Incubator covers, nests, and positioning aids to encourage flexion and containment were used. Reflection periods for discussion and support were provided for the NIDCAP care team, as was daily support for the par-ents. If an infant was transferred to a regional hospital, then a report with recommendations for caregiving was prepared for the parents. A NIDCAP-certified developmental psychologist supervised the intervention, con-ducted observations, and supported the parents and staff members. In-fants in the control group received only basic developmental care (incu-bator covers, nests, and positioning aids). Control group nurses performed basic developmental care. No formal

168 total infants recruited

84 NIDCAP 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 84 control group

Infants at follow-up at term age: 73 Infants at follow-up at term age: 80 Infants in NIDCAP study

FIGURE 1

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observations in which the control in-fants’ 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 inten-sive 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 me-chanical 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 deﬁned as total com-bined 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 circum-ference growth (in centimeters) also were recorded.

Discharge from intensive care was based on the infant requiring no me-chanical ventilation and/or CPAP ther-apy for 24 hours and weighingⱖ1000 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 neuro-logic examination, as described by Pre-chtl,9_{was performed, and results were}

defined as definitely abnormal (pres-ence of a full neonatal neurologic syn-drome, such as apathy, hyperexcitability, hypotonia, hypertonia, hyporeflexia, hy-perreflexia, hypokinesia, or hyperkine-sia, or a hemisyndrome), mildly abnor-mal (presence of only part of such a syndrome), or normal. Examples of mi-nor neurologic signs are abmi-normal posture, abnormal head control, and

absent or abnormal responses or re-ﬂexes. Secondary outcomes are de-ﬁned 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). In-fant and parent characteristics and outcome parameters were compared with the ␹2 _{test (for trend) or the}

2-sample ttest or Mann-Whitney test where appropriate.P values of⬍.05 were considered signiﬁcant. Linear re-gression was used to evaluate the in-ﬂuence of the duration of the interven-tion on term age outcomes, by testing whether there was an interaction ef-fect between the intervention dura-tion and the 2 treatment groups.

Me-dian days of CPAP therapy, days of respiratory support, and days of in-tensive care were obtained from Kaplan-Meier curves and were com-pared 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 be-tween July 2002 and August 2004. Four infants (NIDCAP:n⫽3; control: n ⫽ 1) were excluded according to protocol because they were trans-ferred to another hospital or died within the ﬁrst 5 days of admission, leaving a total of 164 infants who met TABLE 1 Maternal Medical and Parental Demographic Background Variables

NIDCAP (N⫽81) Control (N⫽83) Obstetric history,n/N(%)

Preexisting disease (diabetes mellitus, hypertension, or other)

9/81 (11.1) 14/83 (16.9)

Pregnancy induction 13/81 (16.0) 14/83 (16.9)

Disease during pregnancy,n/N(%)

Diabetes mellitus gravidarum 2/81 (2.5) 3/83 (3.6)

Preeclampsia, eclampsia, or HELLP syndrome 13/81 (16.0) 16/83 (19.3) Medication use during pregnancy,n/N(%)

Antihypertensive agents 14/81 (17.3) 19/83 (22.9)

Antibiotics 32/81 (39.5) 25/83 (30.1)

Tocolytic agents 45/81 (55.6) 43/83 (51.8)

Other 7/81 (8.6) 14/83 (16.9)

Prenatal glucocorticoid treatment,n/N(%)

1 dose 29/80 (36.3) 35/83 (42.2)

1 course (2 doses) 33/80 (41.3) 29/83 (34.9)

Mode of delivery,n/N(%)

Vaginal 41/81 (50.6) 45/83 (54.2)

Cesarean section 40/81 (49.4) 38/83 (45.8)

PROM for⬎24 h,n/N(%) 25/81 (30.9) 19/83 (22.9)

Primipara,n/N(%) 54/81 (66.7) 42/83 (50.6)

Parental demographic background

Maternal age, mean⫾SD, y 30.0⫾5.2 (N⫽74) 31.9⫾5.0 (N⫽78) Paternal age, mean⫾SD, y 32.3⫾5.6 (N⫽72) 34.1⫾5.5 (N⫽77)

Mother white,n/N(%) 66/80 (82.5) 70/80 (87.5)

Father white,n/N(%) 63/79 (79.7) 64/80 (80.0)

Education level of mother,n/N(%)a

Low 26/72 (36.1) 19/77 (24.7)

Intermediate 25/72 (34.7) 26/77 (33.8)

High 21/72 (29.2) 32/77 (41.6)

Education level of father,n/N(%)a

Low 19/69 (27.5) 15/76 (19.7)

Intermediate 22/69 (31.9) 32/76 (42.1)

High 28/69 (40.6) 29/76 (38.2)

HELPP, hemolysis, elevated liver enzyme levels, and low platelet count; PROM indicates premature rupture of membranes.

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the inclusion criteria. Of these in-fants, 8 (9.9%) of 81 in the NIDCAP group and 3 (3.6%) of 83 in the con-trol group died during hospitaliza-tion, with the main cause of death being cerebral or pulmonary compli-cations. The mortality rate and loss to follow-up monitoring are shown in Fig 1. Parent and infant characteris-tics were similar, with no signiﬁcant differences being found (Tables 1 and 2).

Primary Outcomes

No signiﬁcant differences in the days of intensive care, days of respiratory support, or growth were found be-tween the NIDCAP and control groups. There were no signiﬁcant differences between the NIDCAP and control groups in the neurologic outcomes or

growth parameters at term age, in daily weight gain, or in weekly length and head circumference growth (Ta-ble 3). Linear regression analysis showed no interaction effect between the intervention duration and the 2 treatment groups with respect to neu-rologic 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 circum-ference at term age (P⫽.07). Differ-ences were not signiﬁcant except for term length in the Leiden Hospital site (mean⫾SD: control: 48.4⫾2.9 cm; in-tervention: 49.9⫾2.1 cm;P⫽.006); the intervention group performed slightly

better in the Leiden hospital site and slightly worse in the Juliana Children’s 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 be-tween the 2 groups in the days of oxy-gen therapy, numbers of infants who required oxygen after 28 days, or inci-dence of bronchopulmonary dysplasia. A total of 7 (8.6%) of 81 infants in the NIDCAP group required postnatal cor-ticosteroid treatment, compared with 11 (13.3%) of 83 infants in the control group (P⫽ .35), with twice as many infants in the control group requir-ing corticosteroid treatment for ⬎2 weeks. There were signiﬁcantly 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 hospi-tal; 1 (9%) of 11 infants with PDA in the control group died. Among the surviv-ing 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 in-fants;P ⫽ .03). No signiﬁcant differ-ences in the remaining secondary out-comes 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 popula-tion (Fig 2). Because of the significant difference in the incidence of PDA be-tween the groups (Table 4), a posthoc analysis was performed and stratified with respect to infants with PDA re-quiring medication/surgery versus in-fants without significant PDA. In the TABLE 2 Infant Medical Background Variables for All Participating Infants

NIDCAP Control

GA, wk N⫽81 N⫽83

Mean⫾SD 29.3⫾1.8 29.2⫾1.6

Range 24.7–31.9 25.6–31.6

Birth weight, g N⫽81 N⫽83

Mean⫾SD 1215⫾328 1226⫾343

Range 577–1939 625–2060

Length, cm N⫽81 N⫽83

Mean⫾SD 37.1⫾3.1 36.8⫾3.3

Range 29.0–43.0 29.0–44.0

Head circumference, cm N⫽81 N⫽83

Mean⫾SD 26.8⫾2.2 26.6⫾2.3

Range 22.4–32.0 21.5–30.5

Male,n/N(%) 46/81 (56.8) 43/83 (51.8)

SGA,⬍10th andⱖ3rd percentile,n/N(%) 15/81 (18.5) 10/83 (12.0) SGA,⬍3rd percentile,n/N(%) 3/81 (3.7) 5/83 (6.0)

Twin,n/N(%) 27/81 (33.3) 34/83 (41.0)

Inborn,n/N(%) 51/81 (63.0) 49/83 (59.0)

Apgar score at 5 min N⫽80 N⫽80

Mean⫾SD 8.1⫾2.2 8.3⫾1.4

Median 8 8

Range 3–10 4–10

CRIB score N⫽81 N⫽83

Median 2 3

Range 0–14 0–13

RDS,n/N(%)

Grade 1 20/81 (24.7) 23/82 (28.0)

Grade 2 11/81 (13.6) 13/82 (15.9)

Grade 3 17/81 (21.0) 17/82 (20.7)

Grade 4 6/81 (7.4) 8/82 (9.8)

Surfactant treatment,n/N(%) 41/81 (50.6) 39/83 (47.0) Hyperbilirubinemia,n/N(%) 73/81 (90.1) 76/83 (91.6) Duration of phototherapy, mean⫾SD, d 4.4⫾2.9 4.8⫾3.4

Comparisons were performed by using␹2_{tests (for linear trend) or}_t_{tests where appropriate. SGA indicates small for GA;}

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subgroup of infants with no PDA, the NIDCAP group required fewer days of CPAP therapy (P⫽.02), total respira-tory support (P⫽.02), and intensive care (P⫽.06), compared with the con-trol group (Fig 3). Because photother-apy may inﬂuence the closure and/or reopening of a PDA,10 _{days of}

photo-therapy were compared, but no differ-ence between the groups was found (mean: NIDCAP: 4.4 days; control: 4.8 days).

DISCUSSION

Overall Findings

In this RCT examining short-term ef-fects of the comprehensive NIDCAP, compared with basic developmental care, on neonatal morbidity, neuro-logic outcomes, and growth at term

age of infants born at⬍32 weeks, no signiﬁcant positive effects of the inter-vention on the need for respiratory support or days of intensive care were found. No differences between the NIDCAP and control groups with re-spect to growth and neurologic out-comes 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 signiﬁcantly fewer days of ven-tilation and no differences in days of oxygen therapy; the authors stated that the results were conﬂicting and, be-cause the studies showed much hetero-geneity, the results should be viewed with caution.11_{A RCT of 25 infants who}

were born at GA of⬍32 weeks and re-quired ventilatory support at 24 hours showed no signiﬁcant 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 postcon-ceptual age of oxygen withdrawal.12_The

number of patients included in that study was small (NIDCAP:N⫽12; con-trol: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}

re-sults concerning the need for ventilatory support; however, only infants born at GA of ⬍30 weeks and birth weight of ⬍1250 g were included, and speciﬁc ventilation inclusion criteria were used. A 3-center trial showed signiﬁcant differ-TABLE 3 Comparison of Data on Primary Outcome Measures

NIDCAP (N⫽81) Control (N⫽83) Difference, Estimate (95% CI)

P

Duration of hospitalization, d

Mean⫾SD 41.5⫾30.9a _40.4⫾_37.9 _{1.1 (}⫺_{11.8 to 9.5)} _.83

Median (range) 37 (6–159) 30 (5–285)

Duration of intensive care, d

Mean⫾SD 15.2⫾14.8 17.0⫾16.5 ⫺1.8 (⫺3.1 to 6.6) .46

Median (range) 9 (0–54) 11 (0–80)

Required respiratory support,n/N(%) 73/81 (90.1) 77/83 (92.8) ⫺2.6 (⫺11.2 to 5.9) .54 Duration of mechanical ventilation, db

Mean⫾SD 5.6⫾7.0 6.4⫾9.3 ⫺0.8 (⫺1.9 to 3.4) .60

Median (range) 2.0 (0–25) 2.0 (0–41)

Duration of CPAP therapy, d

Mean⫾SD 8.4⫾9.9 10.0⫾11.0 ⫺1.6 (⫺1.8 to 5.0) .35

Median (range) 4.0 (0–36) 6.0 (0–67)

Total duration of ventilatory support, dc

Mean⫾SD 13.9⫾14.6 16.3⫾16.7 ⫺2.4 (⫺2.7 to 7.4) .35

Median (range) 9.0 (1–52) 10.0 (1–79)

Growth parameters at term age

Age, mean⫾SD, wk 41.1⫾1.9 (N⫽72) 41.1⫾2.0 (N⫽80) 0 (⫺0.60 to 0.65) .94 Weight, mean⫾SD, kg 3.11⫾0.63 (N⫽72) 3.10⫾0.57 (N⫽80) 0.1 (⫺2.1 to 1.7) .86

Daily weight gain, mean⫾SD, g 23.9⫾5.8 (N⫽72) 22.9⫾5.2 (N⫽80) .25

Head circumference, mean⫾SD, cmd _35.5⫾_{1.6 (}_N⫽₇₀₎ _35.6⫾_{1.5 (}_N⫽₇₉₎ ⫺_{0.1 (}⫺_{0.39 to 0.59)} _.62

Weekly head circumference growth, mean⫾SD, cmd _0.76⫾_{0.14 (}_N⫽₇₀₎ _0.76⫾_{0.12 (}_N⫽₇₉₎ _.90

Length, mean⫾SD, cm 49.0⫾2.8 (N⫽72) 48.5⫾2.9 (N⫽77) 0.5 (⫺1.5 to 0.35) .23 Weekly length growth, mean⫾SD, cm 1.00⫾0.22 (N⫽72) 0.99⫾0.19 (N⫽77) .29

Neurologic outcome at term N⫽73 N⫽78e

Normal 39/73 (53.4) 40/78 (51.3) 2.1 (⫺13.8 to 18.1) .47

Mildly abnormal 23/73 (31.5) 34/78 (43.6) ⫺12.1 (⫺27.4 to 3.2)

Deﬁnitely abnormal 11/73 (15.1) 4/78 (5.1) 9.9 (0.4 to 19.5)

Comparisons were performed by using␹2_{tests (for linear trend),}_t_{tests, or Mann-Whitney tests where appropriate. CI indicates conﬁdence 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.}

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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 ﬁrst 12 hours of life.

Days of Intensive Care

A 3-center RCT of 92 preterm infants with birth weights of⬍1250 g and GAs

of ⬍28 weeks showed signiﬁcantly fewer days of intensive care for the NIDCAP group.15 _{We were not able to}

duplicate those findings 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 reflects the different populations or different definitions of days of inten-sive care, because the criteria for days of intensive care were not defined in the multicenter trial. Another Dutch

study found no signiﬁcant difference in days of intensive care between NIDCAP and conventional care but also did not deﬁne the criteria for days of intensive care and included only infants with GAs of ⬍30 weeks.17 _{Other NIDCAP}

studies reported total days of hospital-ization but not days of intensive care.

Growth

One study by Als et al15_showed

signiﬁ-cantly better average daily weight gain and better growth (weight, head cir-cumference, and height) to term age for the infants receiving NIDCAP, whereas the study by Westrup et al12

showed no signiﬁcant effect on growth (weight gain and head growth) up to postconceptual age of 35 weeks. The Cochrane meta-analysis,11 _which

ex-cluded the multicenter trial by Als et al15_{because of site differences,}

con-cluded that NIDCAP did not affect growth for infants surviving to cor-rected age of 9 months. Our short-term growth results are comparable to those ﬁndings.

Neurobehavioral Outcomes

Two previous NIDCAP studies showed signiﬁcant improvements in neurobe-havioral outcomes, according to the method described by Prechtl,9 _which

they deﬁned with 12 summary vari-ables and a total score showing the proportion of abnormal scores in each group.18,19_{We found no signiﬁcant}

dif-ference in our study, in which neurobe-havioral outcomes, according to the method described by Prechtl,9 _were

deﬁned as deﬁnitely abnormal, mildly abnormal, or normal.

Incidence of PDA

After random assignment, our study showed signiﬁcantly more infants in the NIDCAP group with PDA requiring medication or surgery (Table 4). The mean days of phototherapy, which can inﬂuence ductal reopening, were simi-lar for the 2 groups; therefore, there is TABLE 4 Comparison of Data on Secondary Outcome Measures

NIDCAP (N⫽81) Control (N⫽83) P

In-hospital death,n/N(%) 8/81 (9.9) 3/83 (3.6) .14

Early neonatal deatha _{1/81 (1.2)} _{0/83 (0)}

Late neonatal deatha _{7/81 (8.6)} _{3/83 (3.6)}

LOS, d N⫽70 N⫽74 .24

Mean⫾SD 61.9⫾24.5 67.6⫾34.2

Median (range) 57.5 (32–159) 58.5 (30–285)

GA at discharge to home, mean⫾SD, wk 38.5⫾2.7 (N⫽70) 38.9⫾4.4 (N⫽74) .50 Total time of supplemental oxygen treatment, d

Mean⫾SD 17.2⫾22.6 16.4⫾25.4 .84

Median (range) 6 (0–100) 3 (0–121)

Oxygen requirement at⬎28 d of life,n/N(%) 25/81 (30.9) 24/82 (29.3) .82 BPD (oxygen dependence after 36 wk of

postconceptual age),n/N(%)

12/80 (15.0) 16/81 (19.8) .43

Postnatal corticosteroid treatment,n/N(%)b

⬍7 d 1/81 (1.2) 1/83 (1.2) .35

7–14 d 2/81 (2.5) 2/83 (2.4)

15–20 d 2/81 (2.5) 7/83 (8.4)

⬎20 d 2/81 (2.5) 1/83 (1.2)

IVH,n/N(%)

Grade I–II 17/81 (21.0) 19/83 (22.9) .72

Grade III (and periventricular echodensity) 6/81 (7.4) 4/83 (4.8)

Posthemorrhagic ventricular dilation,n/N(%) 2/81 (2.5) 6/83 (7.2) .16

NEC,n/N(%) 3/81 (3.7) 3/83 (3.6) .86

Sepsis,n/N(%) 38/81 (46.9) 45/83 (54.2) .35

Meningitis,n/N(%) 1/81 (1.2) 1/83 (1.2) .99

PDA (indomethacin and/or surgery),n/N(%) 25/81 (30.9) 11/83 (13.3) .01c

Dopamine/dobutamine treatment,n/N(%) 22/81 (27.2) 23/83 (27.7) .94

ROP,n/N(%) 8/70 (11.4) 10/73 (13.7) .82

PVL at follow-up evaluation at term age,n/N(%)

Grade 1 5/72 (6.9) 10/80 (12.5) .76

Grade 2 1/72 (1.4) 0 (0)

Grade 3 1/72 (1.4) 1/80 (1.3)

Grade 4 0 (0) 0 (0)

Physical therapy required at term age,n/N(%) 16/73 (21.9) 11/80 (13.8) .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 hemorrhage}23_{; NEC, necrotizing}

entero-colitis; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; PVL, periventricular leukomalacia.24

a_{Early neonatal death denotes death within the ﬁrst 7 days of life; late neonatal death denotes death after 7 days but before}

28 days of life.

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no plausible reason why infants in the NIDCAP group had signiﬁcantly 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 ﬁndings differ from the outcomes in the Cochrane

meta-analysis,11_{in which no inﬂuence}

of the NIDCAP intervention on the inci-dence of PDA was found.

Because PDA may inﬂuence days of ventilation and days of intensive care, we performed further analysis (Kaplan-Meier analysis). In the subgroup of in-fants with no PDA (NIDCAP:n⫽56; con-trol: n ⫽ 72), we found signiﬁcant 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 possi-ble benefit from NIDCAP in days of re-spiratory support for a subgroup of in-fants without PDA, these findings should be interpreted with caution. The presence of PDA did seem to influ-ence neurodevelopmental outcomes, because 7 (64%) of 11 infants in the NIDCAP group with definitely abnormal

70 60 50 40 30 20 10 0 100

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Intervention-censored Control-censored Intervention Control

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FIGURE 2

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

Secondary Outcomes

Wielenga et al17_{showed that}

NIDCAP-treated infants had a lower incidence of severe cerebral damage in a phase-lag study of infants born at⬍30 weeks of gestation, in which 26 infants re-ceived conventional treatment, fol-lowed by 25 infants who received NIDCAP developmental care. There were signiﬁcant differences in the neonatal

background characteristics of the 2 groups (NIDCAP-treated infants were smaller and included fewer multiple births, compared with the conven-tional care group, and the NIDCAP-treated infants developed signiﬁcantly more pneumonia, possibly because of an outbreak of a nosocomial infection in the NICU during the NIDCAP imple-mentation). One advantage of a phase-lag study is the ability to implement a program such as NIDCAP throughout the entire department; however, the disadvantage of having different peri-ods of research, in which there may be changes in the department, may affect results. Therefore, the authors stated that their results should be inter-preted with caution.17

A meta-analysis of 3 studies13,18,20

showed no evidence that NIDCAP af-fected the incidence of grade 3 or 4 intraventricular hemorrhage,11 _and

there was not a signiﬁcant difference in either the Swedish trial12 _{or the}

3-center trial.15_{Our study was}

compa-rable, in that no differences in the out-comes of intraventricular hemorrhage and/or periventricular leukomalacia were found.

A signiﬁcant effect of NIDCAP on mod-erate/severe chronic lung disease was found in the Cochrane review.11_{In our}

study, although the control group re-quired more postnatal corticosteroid treatment than did the NIDCAP group, there was no difference in the inci-dence 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 trans-ferred to regional hospitals earlier; therefore, the number of days of inter-60

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30 20

10 0

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80

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Percentage

80 60

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0 100

80

60

40

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ge

A

B

FIGURE 3

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vention was, for a proportion of our participating infants, smaller than in previously reported studies. Because of the regionalization of neonatal in-tensive care in the Dutch neonatal health care system, infants often are transferred to regional hospitals that can provide postintensive care and in-termediate care. Thirty-three (41%) of 80 surviving infants in the control group and 37 (51%) of 73 surviving in-fants in the NIDCAP group remained in the participating hospitals for ⱖ6 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 pre-term infants. All except 2 of the surviv-ing 153 infants were seen at follow-up evaluations at term age. The infants were assigned randomly in an appro-priate manner; however, there could

be no blinding of the intervention, be-cause all infants were cared for in the same unit and the NIDCAP-treated in-fants had recommendations for care-giving at their bedside. The amount of respiratory support given to an infant was decided on by several neonatolo-gists and was not inﬂuenced by the study group in which the infant partic-ipated. 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 ⱖ1000 g; therefore, days of intensive care also could not be inﬂuenced by group participa-tion. Follow-up evaluations at term age were conducted by neonatolo-gists blinded to the participation group.

Despite the large sample size, com-pared with previous NIDCAP studies, and well-deﬁned outcome measure-ments, as well as the addressing of methodologic concerns identiﬁed in

ⱖ1 trial,21 _{we were not able to ﬁnd}

any signiﬁcant differences in our pri-mary outcomes. Future research on NIDCAP should include not only neo-natal intensive care centers but also the regional hospitals to which in-fants are transferred.

ACKNOWLEDGMENTS

This study was funded by the Nether-lands Organisation for Health

Re-search and Development (grant

2100.0072) and the Health Care Efﬁ-ciency Research Fund of the Leiden University Medical Center.

We thank Sylvia M. van der Pal, PhD, Monique Rijken, MD, PhD, Shirley Mar-tens, MD, and Monique de Haan, MD, and the NIDCAP nurses (Annemieke de Waal, Thayla Halfwerk, Thea van Enge-lenberg, Karima Balarbi, Els van Veldhuijzen, and Hanneke Entrop) for their contribution to this research project.

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DOI: 10.1542/peds.2008-1881 originally published online September 28, 2009;

2009;124;1021

Pediatrics

and Sylvia Veen

Celeste M. Maguire, Frans J. Walther, Arwen J. Sprij, Saskia Le Cessie, Jan M. Wit

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