Randomized Controlled Trial of Restrictive Fluid Management in Transient

Tachypnea of the Newborn

Annemarie Stroustrup, MD, MPH1,2,3, Leonardo Trasande, MD, MPP2,3, and Ian R. Holzman, MD1,2
Objective To determine the effect of mild fluid restriction on the hospital course of neonates with transient tachypnea of the newborn (TTN).
Study design In this pilot prospective randomized controlled trial of 64 late preterm and term neonates diagnosed
with TTN at a single tertiary care hospital in the United States, patients were randomized to receive standard fluid management or mild fluid restriction. The primary outcome was duration of respiratory support. Secondary outcomes were
duration of admission to the intensive care unit, time to first enteral feed, and total and composite hospital costs.
Results were analyzed by t-test, c2 test, Kaplan-Meier estimation, and proportional hazards regression.
Results Fluid restriction did not cause adverse events or unsafe dehydration. Fluid management strategy did not
affect primary or secondary outcomes in the total study population. Fluid restriction significantly reduced the duration of respiratory support (P = .008) and hospitalization costs (P = .017) in neonates with severe TTN.
Conclusion Mild fluid restriction appears to be safe in late preterm and term neonates with uncomplicated TTN.
Fluid restriction may be of benefit in decreasing the duration of respiratory support and reducing hospitalization
costs in term and late preterm neonates with uncomplicated severe TTN. (J Pediatr 2012;160:38-43).

ransient tachypnea of the newborn (TTN) is a self-limited respiratory distress syndrome of term and late preterm
neonates related to poor clearance of fetal lung fluid after delivery. Neonates with TTN have inefficient transition
from in utero to ex utero pulmonary function due to delayed ion channel switching in the pulmonary epithelium.1,2
The absence of mechanical forces that normally aid pulmonary fluid clearance also may contribute to TTN in neonates delivered by cesarean section.3 Signs of TTN include tachypnea, mild hypoxia, and respiratory distress. Distress from TTN typically
resolves within the first 72-96 hours of life. Supportive care for TTN includes administration of low-percentage supplemental
oxygen and/or positive end expiratory pressure via continuous positive end-expiratory pressure (CPAP), high-flow nasal CPAP
(HFNCPAP), or conventional nasal cannula (NC).
TTN results in significant social and financial burden as affected neonates require admission to the neonatal intensive care
unit (NICU). Separation from parents and clinical illness delay parentchild bonding and initiation of breast-feeding. These
costs, although individually minor, are increasingly important with the recent sharp rise in birth rate of late preterm neonates4,5
and those delivered by cesarean section,4,6 the groups at greatest risk for TTN.7 No effective treatment for TTN beyond supportive care has yet been identified.8-10 A modest reduction in TTN symptom duration in a subset of patients with TTN could
translate into savings of thousands of hospital days and millions of dollars.
Here we report a randomized controlled trial of fluid management in neonates with TTN. We hypothesized that mild fluid
restriction in the first days of life, mimicking physiological low fluid intake by exclusively breast-fed neonates, would speed
resolution of TTN-related respiratory distress. We randomized patients to receive either standard of care daily total fluids
or a more restrictive fluid management strategy. The primary study outcome was duration of respiratory support (CPAP,
HFNCPAP, or NC). Additional secondary analysis focused on the costs of hospitalization of enrolled patients.

Methods
This was a single-center study of inborn neonates at our urban tertiary care center that delivers more than 6000 babies annually.
Neonates born between 34-0/7 and 41-6/7 weeks gestational age (GA) diagnosed with uncomplicated TTN in the first 12 hours
of life were eligible for inclusion in this study. Uncomplicated TTN was defined as respiratory distress with chest x-ray findings

BUN
CPAP
DOL
GA
HFNCPAP
IV
NC
NICU
TTN

Blood urea nitrogen

Continuous positive end-expiratory pressure
Day of life
Gestational age
High-flow nasal continuous positive end-expiratory pressure
Intravenous
Nasal cannula
Neonatal intensive care unit
Transient tachypnea of the newborn

From the 1Division of Newborn Medicine, Kravis

Childrens Hospital, Mount Sinai Medical Center; and
2
Departments of Pediatrics and 3Preventive Medicine,
Mount Sinai School of Medicine, New York, NY
Supported by National Institutes of Health Grants
5KL2RR029885 (to A.S.). The authors declare no conflicts of interest.
Study was registered with ClinicalTrials.gov:
NCT01225029.
0022-3476/$ - see front matter. Copyright 2012 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2011.06.027

38

Vol. 160, No. 1  January 2012

consistent with TTN (ie, pulmonary fluid retention), in the
absence of air leak syndrome (pneumothorax or pneumomediastinum). Respiratory distress was defined as flaring,
grunting, and accessory muscle use with or without hypoxia.
Respiratory support was initiated in patients with hypoxia
(defined as oxygen saturation #95%) and/or hypercapnia
(defined as partial pressure of CO2 $50 mm Hg on room
air). The mode of respiratory support (CPAP, HFNCPAP,
or NC) was determined by the treating physician. Respiratory
support was weaned and discontinued as respiratory distress
resolved according to standard clinical practice.
Patients were recruited at our institution from August 1,
2008, through September 2, 2010. The study was registered
with ClinicalTrials.gov (NCT01225029). Neonates with a genetic abnormality or congenital anomaly of the lungs, heart,
airway, or other system likely to produce respiratory distress
were excluded. Neonates undergoing an evaluation for sepsis (blood culture and/or antibiotic administration) also
were excluded, to avoid inadvertent inclusion of neonates
with pneumonia. Similarly, neonates born with meconium
noted at delivery were excluded, to avoid inadvertent inclusion of neonates with meconium aspiration syndrome. Patients meeting our institutional criteria for hyaline
membrane disease receiving surfactant treatment (chest xray with reticular-granular markings and hypoxia requiring
a fraction of inspired O2 $40% to maintain an O2 saturation $92%) were not eligible for study enrollment or
were removed from the study cohort at the time of diagnosis of hyaline membrane disease. Patients with any respiratory diagnosis other than TTN also were removed from the
study. Informed consent was obtained from one or both
parents before patient randomization. This study was approved by the Mount Sinai Program for the Protection of
Human Subjects.
Neonates were alternately assigned to receive standard-ofcare fluids or fluid restriction based on the diagnosis of TTN.
Standard-of-care total fluids was defined as 80 mL/kg/day on
day of life (DOL) 1 for preterm neonates (those born between
34-0/7 and 36-6/7 weeks GA) and 60 mL/kg/day on DOL 1
for term neonates (those born between 37-0/7 and 41-6/7
weeks GA). Fluid restriction was defined as 60 mL/kg/day
on DOL 1 for preterm neonates and 40 mL/kg/day on DOL
1 for term neonates. Total fluid intake was calculated as the
combination of intravenous (IV) and enteral fluid intake.
All fluid management decisions after the initial starting volume for IV fluids were made by the treating medical team.
Typically, total fluid was increased by 20 mL/kg/day daily
for all patients until 150 mL/kg/day or ad libitum feeding
was achieved. Collection of fluid intake data was discontinued when patients achieved ad libitum feeding or at 72 hours
of life. Collection of respiratory support data was discontinued when patients no longer received respiratory support.
Patients, their families, and medical staff were not blinded
to study group assignment.
Study safety was assessed daily in all enrolled patients. Predetermined indicators of dehydration, including daily
weight, daily urine output, and daily serum sodium, blood

urea nitrogen (BUN), creatinine, glucose, and bilirubin

levels, were monitored. The primary study outcome was total
duration of respiratory support. Secondary clinical outcomes
were time from birth to first enteral feed and total duration of
NICU stay. Financial outcomes included total cost of hospitalization and component costs, including physician, direct,
and indirect costs. Hospital charge data, including breakdown by fee for type of service, were obtained through hospital and physician faculty practice billing divisions at our
institution. Charges were converted to costs using conversion
information developed as part of the Healthcare Cost and
Utilization Project, a federal, state, and industry partnership
sponsored by the Agency for Healthcare Research and Quality. These cost-to-charge ratios specific for our medical center were based on all payer inpatient cost information
obtained from the hospital accounting reports collected by
the Centers for Medicare and Medicaid Services.11
Sample size determination was done assuming a meaningful difference in the duration of respiratory support of 8
hours (SD, 11 hours), a 2-sided a value of 0.05, and a power
of 80%. The calculated sample size goal of 32 patients completing treatment in each group was met. All study outcome
and financial data were evaluated on an intention-to-treat
basis. Analysis was performed using t-test, c2 analysis,
Kaplan-Meier estimation, and Cox regression modeling as
appropriate. Additional analyses were performed based on
the observed duration of respiratory support with mild
TTN defined as not requiring respiratory support during
hospitalization, moderate TTN defined as requiring respiratory support for <48 hours after birth, and severe TTN
defined as requiring respiratory support for $48 hours after
birth (Table I).

Results
A total of 73 neonates met the enrollment criteria, and the parents of 67 eligible neonates agreed to participate. Of these 67
neonates, 34 were assigned to standard-of-care fluid management and 33 were assigned to the restricted fluid protocol.
Two patients from the standard-of-care group and 1 patient
from the restricted fluid group were withdrawn because of
a non-TTN respiratory diagnosis; thus, 32 patients in each
group completed the study protocol and were included in
the data analysis (Figure 1; available at www.jpeds.com).

Table I. Proposed classification system for patients with

TTN
Classification

Patient description

Uncomplicated
Complicated
Mild
Moderate
Severe

No air leak (pneumothorax or pneumomediastinum)

Air leak present on chest X-ray
No respiratory support (CPAP, HFNCPAP, or NC) required
Respiratory support required for <48 hours
Respiratory support required for $48 hours

Neonates with TTN can be dichotomized into uncomplicated or complicated TTN based on the
absence or presence of air leak. Further characterization can be made to distinguish the severity of disease based on duration of respiratory support.

39

THE JOURNAL OF PEDIATRICS

www.jpeds.com

Table II. Patient characteristics and study outcomes

Full patient cohort (n = 64)

White
Black or Hispanic
Asian
Other/unreported
Male sex
Birth weight, g
GA, weeks
Multiple gestation
Received antenatal steroids
C-section delivery
In labor before C-section
Maternal preeclampsia
Maternal GDM
Maternal asthma
5-minute Apgar score = 9
Patients with severe TTN (n = 26)
White
Black or Hispanic
Asian
Other/unreported
Male sex
Birth weight, g
GA, weeks
Multiple gestation
Received antenatal steroids
C-section delivery
In labor before C-section
Maternal preeclampsia
Maternal GDM
Maternal asthma
5-minute Apgar score = 9

Standard
fluids

Restricted
fluids

P
value

21 (65.6%)
8 (25%)
2 (6.3%)
1 (3.1%)
17 (53.1%)
2620  546
35.8  1.6
13 (40.6%)
7 (21.9%)
24 (75%)
12 (37.5%)
5 (15.6%)
3 (9.4%)
2 (6.3%)
27 (84.4%)

20 (62.5%)
9 (28.2%)
3 (9.4%)
0 (0%)
16 (50%)
2739  544
36.4  1.5
10 (31.3%)
1 (3.1%)
18 (56.3%)
8 (25%)
6 (18.8%)
2 (6.3%)
3 (9.4%)
29 (90.6%)

.377

9 (69%)
3 (23%)
1 (8%)
0 (0%)
5 (38%)
2446  439
35.1  1.1
4 (31%)
4 (31%)
8 (62%)
3 (23.1%)
3 (23%)
0 (0%)
1 (8%)
11 (85%)

10 (77%)
3 (23%)
0 (0%)
0 (0%)
7 (54%)
2756  549
36.2  1.5
4 (31%)
0 (0%)
6 (62%)
4 (30.8%)
1 (8%)
0 (0%)
0 (0%)
13 (100%)

.806
.387
.160
.311
.023*
.118
.281
.745
.648
.648
.308
.522

.431
.126
.037*
1
.030*
.431
.658
.277
1
.308
.141

GDM, gestational diabetes mellitus.

Baseline study subject characteristics for both the entire patient cohort and those patients categorized as having severe TTN. Overall, the standard of care and intervention groups differed
only in receipt of antenatal steroids, although no mother received antenatal steroids within 2
weeks of delivery. Fluid-restricted patients with severe TTN were slightly more mature at birth
than those receiving standard fluid management.
*Significant results.

Baseline characteristics of the 2 groups are summarized in

Table II.
Patients were admitted to the study with initiation of fluid
and respiratory support as indicated between 30 minutes and
8 hours of life. No neonate enrolled in the study experienced
an adverse event or unsafe fluid or glycemic balance related
to the study protocol (Table III). Urine output after the first
12 hours of life was significantly lower in the neonates in the
restricted fluids group (P = .008), but never fell below the
predetermined safety threshold of 1 mL/kg/hour in any
patient in any 12-hour period. Serum sodium, creatinine,
and BUN did not differ between the 2 groups at any point
in time, and never deviated from the predetermined safety
criteria ranges. No patient lost more than the predetermined
threshold of 10% of birth weight. There was no difference in
the incidence of hypoglycemia or hyperbilirubinemia
requiring phototherapy based on published guidelines12,13
between the 2 groups. No patient in the study received
a diuretic or vasopressor during the neonatal hospitalization.
As was intended, patients in the standard-of-care group
received significantly greater total fluids during the study period compared with in the restricted fluid group (P < .001)
(Table III). Analysis of the entire patient cohort revealed
40

Vol. 160, No. 1

no significant difference between the study groups in terms
of the primary or secondary study outcomes. Kaplan-Meier
survival curves based on the duration of respiratory
support demonstrated no significant difference between the
2 groups (Figure 2, A). There was no relationship between
age at inititation of study protocol and duration of
respiratory support.
Post hoc classification of patients as having mild, moderate, or severe TTN proved enlightening. Kaplan-Meier curves
for the subpopulation of 26 neonates with severe TTN
showed a significantly shorter duration of respiratory support in the restricted fluids group (P = .019) (Figure 2, B).
This effect persisted in Cox regression analysis adjusting for
GA and receipt of antenatal steroids, the only baseline
characteristics that differed significantly between the 2
groups (P = .008) (Figure 2, C). Secondary outcomes were
not affected by the study intervention in either the full
patient cohort or in any disease category cohort.
Mean total hospital costs were $7034 for the standard-ofcare fluid management group and $7073 for the restricted fluid
management group (P > .05) (Table III). Subgroup analyses of
patients with severe TTN found significant between-group
differences in hospital and physician costs. In the patients
with severe TTN, the mean total hospital cost was $13 555 in
the standard-of-care fluid management group and $7747 in
the restricted fluid management group (P = .017). This
significant savings persisted at the level of physician costs,
hospital direct costs, and hospital indirect costs.

Discussion
This prospective evaluation of fluid management in late
preterm and term neonates with TTN has 3 major findings:
(1) mild fluid restriction appears to be safe in term and late
preterm neonates with uncomplicated TTN; (2) fluid
restriction significantly decreases the duration of respiratory
support in neonates with severe uncomplicated TTN; and (3)
fluid restriction is associated with significant cost savings in
neonates with severe uncomplicated TTN.
At the time of diagnosis of uncomplicated TTN, patients
can be categorized into mild or moderatesevere TTN. The
distinction between moderate and severe TTN cannot be
made until 48 hours of life. However, because our fluid
restriction protocol appears to be safe in all patients with
TTN, we suggest initiating fluid restriction for all patients
with moderate or severe uncomplicated TTN, to benefit
those who ultimately demonstrate severe disease.
Given that fluid restriction in late preterm and term neonates
with respiratory distress is a novel therapy, there was significant
concern among both treating physicians in our NICU and committee members of our Institutional Review Board that patients
in our intervention cohort would face significant dehydration,
weight loss, and/or hypoglycemia. With safety concerns in
mind, the decision was made not to blind caregivers to patient
group assignment. The fidelity of group assignment to total
fluids received in this study reinforces our belief that mild fluid
Stroustrup, Trasande, and Holzman

ORIGINAL ARTICLES

January 2012

Table III. Intention to treat analysis of safety parameters

Full patient cohort (n = 64)
% of birth weight lost
UOP, mL/kg/hour
Serum sodium, mEq/L
Serum creatinine, mg/dL
Serum BUN, mg/dL
Hyperbilirubinemia requiring phototherapy
Hypoglycemia (blood glucose <40 mg/dL)
Total fluids received, mL/kg/day, 0-12 hours (n = 64)
Total fluids received, mL/kg/day, 0-24 hours (n = 60)
Total fluids received, mL/kg/day, 0-48 hours (n = 45)
Total fluids received, mL/kg/day, 0-72 hours (n = 36)
Duration of respiratory support, hours
Duration of stay in the NICU, calendar days
Time to first enteral feed, hours
Total cost of hospitalization, US$
Total direct costs, US$
Total indirect costs, US$
Physician costs, US$
Patients with severe TTN (n = 26)
% of birth weight lost
UOP, mL/kg/hour
Serum sodium, mEq/L
Serum creatinine, mg/dL
Serum BUN, mg/dL
Hyperbilirubinemia requiring phototherapy
Hypoglycemia (blood glucose <40 mg/dL)
Total fluids received, mL/kg/day, 0-12 hours (n = 64)
Total fluids received, mL/kg/day, 0-24 hours (n = 60)
Total fluids received, mL/kg/day, 0-48 hours (n = 45)
Total fluids received, mL/kg/day, 0-72 hours (n = 36)
Duration of respiratory support, hours
Duration of stay in the NICU, calendar days
Time to first enteral feed, hours
Total cost of hospitalization, US$
Total direct costs, US$
Total indirect costs, US$
Physician costs, US$

Standard fluids

Restricted fluids

P value

3.8  2.3
2.8  0.6
137.4  2.7
0.8  0.2
11.0  3.1
23 patients
0 cases
65.5  16.7
71.9  19.8
87.6  21.2
112.7  21.2
45 (26-85)
8 (5-12)
31 (21-51)
7034 (4541-12 369)
3062 (1539-4998)
2349 (1243-3777)
2120 (1365-3453)

3.0  2.6
2.2  0.4
137.6  3.6
0.8  0.1
11.0  3.7
21 patients
0 cases
48.6  16.6
52.8  12.2
63.4  13.7
92.2  18.6
42 (26-69)
7 (4-10)
35 (23-44)
7073 (5153-10 104)
2731 (1659-4109)
2057 (1437-3194)
2366 (1533-2688)

.238
.008*
.836
.508
1
.59
1
<.001*
<.001*
<.001*
.004*
.209
.589
.667
.718
.832
.763
.533

3.9  2.4
2.8  0.7
136.3  2.3
0.8  0.1
12.1  2.9
11 patients
0 cases
66.1  17.5
71.7  16.0
81.0  16.7
109.0  16.7
113 (71-141)
12 (9-13)
51 (31-76)
13 555 (10 677-15 547)
5294 (4108-5955)
4052 (3125-4594)
4067 (4489-4445)

2.3  2.5
2.2  0.4
136.5  4.1
0.8  0.1
12.3  4.2
11 patients
0 cases
48.8  10.8
50.4  9.9
60.1  11.4
89.1  17.2
75 (67-86)
7 (7-9)
50 (28-66)
7747 (6535-9641)
2810 (2666-3786)
2117 (2040-2908)
2564 (2061-3076)

.120
.066
.908
.637
.874
1
1
.002*
.001*
.002*
.014*
.048*
.096
.42
.017*
.033*
.031*
.005*

UOP, urine output.

Study outcomes for both the entire patient cohort and those patients categorized as having severe TTN. Results are displayed as mean  SD for normally distributed data and as median (IQR) for
skewed data. Weight loss, urine output, and serum electrolytes are reported from the study endpoint DOL 3.
*Significant results.

restriction is safe in late preterm and term neonates, because no

significant corrections to fluid or glycemic balance were required to maintain weight, urine output, and measured electrolytes within the normal range.
A significant strength of this study is the lack of antibiotic
use in our patient cohort. Although we recognize that it is standard practice in many NICU settings in the United States to
initiate antibiotic coverage for presumptive pneumonia in all
neonates presenting with respiratory distress, we feel that this
practice is unnecessary. It has been a long-standing practice
in our unit to not initiate an evaluation for sepsis in neonates
without either historical risk factors for neonatal sepsis (eg, intrapartum maternal fever, inadequately prophylaxed maternal
group B streptococcus) or clinical depression at birth. No neonate enrolled in our study received antibiotic therapy, and no
neonate manifested neonatal pneumonia or bacteremia; thus,
we are confident that our patient population contained no
cases of congenital pneumonia. Because of the exclusion of neonates born with meconium noted at delivery, we can make
similar inferences about meconium aspiration syndrome.

We found a significant ($5808) total cost savings per

patient with severe TTN that received restricted fluid management. In 2007, there were 4 316 233 live births in the United
States4; published results14 as well as unpublished data from
our group estimate the current incidence of TTN at 1%-2%
of live births. In the present study, 40% of patients met the criteria for severe TTN. If the savings and patient demographics
seen in our study were replicated nationally, then, using even
a conservative estimate of the true incidence of TTN, mild
fluid restriction could result in an annual savings of more
than $100 million in the United States alone. Even greater
savings could be seen abroad, where TTN is more common
because of a higher incidence of cesarean section delivery.15
This study has several possible limitations. Because this
was a small, single-center study, our results might not be fully
generalizable to the TTN patient population in all hospital
types on a national level. Our study was underpowered to
detect the primary endpoint. Because no study on this topic
has been published to date, we made an empiric estimation of
effect size and SD that proved to be incorrect, resulting in

Randomized Controlled Trial of Restrictive Fluid Management in Transient Tachypnea of the Newborn

41

THE JOURNAL OF PEDIATRICS

www.jpeds.com

Vol. 160, No. 1

disease not meeting the criteria for exogenous surfactant administration. There was no blinding to study group assignment. The randomization strategy used in this study was
alternate assignment by order of diagnosis (most closely approximating order of birth). Although we believe that order
of birth provided random patient assignment, as supported
by the similarities between the 2 study groups at enrollment,
it is possible that patient assignment could have been biased
for patients born in close temporal proximity. Finally, decisions to increase total fluids and to initiate or adjust respiratory support were left to the treating medical team based on
their standard practice and extensive experience managing
TTN. We used these real world criteria in our study because we felt that a protocol with strict criteria would not
produce results generalizable to clinical care. There are no
published guidelines for respiratory support management
for patients with TTN; support is generally initiated and later
weaned based on clinical performance of the individual neonate. Of note, in our unit most decisions regarding weaning
and cessation of respiratory support were made by bedside
nurses who were largely unaware of patient group assignment. Larger multicenter studies are needed to address these
deficiencies.
Here we report the first randomized controlled trial of
fluid management in TTN. We demonstrate the safety of
mild fluid restriction in late preterm and term neonates
with TTN, and propose an evidence-based management
strategy to speed symptom resolution in neonates with severe
TTN. Moreover, we propose a new classification system for
patients with TTN to better identify those who will benefit
from fluid restriction. Our management strategy provides
significant clinical and financial benefits to neonates with uncomplicated severe TTN. This is the first description of an effective management strategy that speeds the resolution of
TTN in any patient cohort. n

Figure 2. Survival analysis of the effect of fluid management

on duration of respiratory support. Solid lines represent
standard fluid management; dashed lines, restrictive fluid
management. A, In the overall study cohort, there was no
statistically significant effect of fluid management strategy on
duration of respiratory support. In patients with severe TTN,
B, an unadjusted model and C, a model adjusted for GA and
receipt of antenatal steroids demonstrated a significantly
decreased duration of respiratory support in neonates receiving restricted total fluids.

a power of only 20% to detect the primary outcome. In addition, our patient mix is likely biased toward more severe cases
of TTN, given that we enrolled only patients on the neonatology service, and the fact that patients with TTN who do not
require respiratory support may be cared for by private
practice-based pediatricians at our institution. Some patients
enrolled in the study may have had mild hyaline membrane
42

We thank the families of patients in our NICU for their willingness to

allow their neonates to participate in this investigation. Additional
thanks go to the nursing and medical staff who aided with subject identification and embraced the study protocol. Thanks also to Debra Lunburg, Nelson Roberts, and Doran Ricks for their assistance in obtaining
financial information for our study patients. Special thanks to Robert
Green, MD, for statistical support.
Submitted for publication Mar 7, 2011; last revision received Apr 26, 2011;
accepted Jun 22, 2011.
Reprint requests: Annemarie Stroustrup, MD, MPH, Division of Newborn
Medicine, Kravis Childrens Hospital, Mount Sinai Medical Center, One
Gustave L. Levy Place, Box 1508, New York, NY 10029. E-mail: Annemarie.
Stroustrup@mssm.edu

References
1. Helve O, Janer C, Pitkanen O, Andersson S. Expression of the epithelial
sodium channel in airway epithelium of newborn infants depends on
gestational age. Pediatrics 2007;120:1311-6.
2. Jain L, Eaton DC. Physiology of fetal lung fluid clearance and the effect of
labor. Semin Perinatol 2006;30:34-43.

Stroustrup, Trasande, and Holzman

ORIGINAL ARTICLES

January 2012
3. Jain L, Dudell GG. Respiratory transition in infants delivered by cesarean
section. Semin Perinatol 2006;30:296-304.
4. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Kirmeyer S,
et al. Births: final data for 2007. Natl Vital Stat Rep 2010;58:1-85.
5. Martin JA, Kirmeyer S, Osterman M, Shepherd RA. Born a bit too early:
recent trends in late preterm births. NCHS Data Brief 2009;24:1-8.
6. Ramachandrappa A, Jain L. Elective cesarean section: its impact on neonatal respiratory outcome. Clin Perinatol 2008;35:373-93.
7. Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, Hoffman M, et al.
Respiratory morbidity in late preterm births. JAMA 2010;304:419-25.
8. Kao B, Stewart de Ramirez SA, Belfort MB, Hansen A. Inhaled epinephrine for the treatment of transient tachypnea of the newborn. J Perinatol
2008;28:205-10.
9. Lewis V, Whitelaw A. Furosemide for transient tachypnea of the newborn. Cochrane Database Syst Rev 2002;CD003064.
10. Yurdakok M. Transient tachypnea of the newborn: what is new? J Matern
Fetal Neonatal Med 2010;23(Suppl 3):24-6.

11. Healthcare Cost and Utilization Project (HCUP). HCUP Cost-toCharge Ratio Files (CCR). Rockville, MD: Agency for Healthcare
Research and Quality; 2009.
12. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia.
Management of hyperbilirubinemia in the newborn infant 35 or more
weeks of gestation. Pediatrics 2004;114:297-316.
13. Wong RJ, DeSandre GH, Sibley E, Stevenson DK. Neonatal jaundice and
liver disease. In: Fanaroff AA, Martin RJ, Walsh MC, eds. Fanaroff and
Martins Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant.
8th ed. Philadelphia: Mosby Elsevier; 2006. p. 1419-66.
14. Dani C, Reali MF, Bertini G, Wiechmann L, Spagnolo A, Tangucci M,
et al., Italian Group of Neonatal Pneumology. Risk factors for the development of respiratory distress syndrome and transient tachypnoea in
newborn infants. Eur Respir J 1999;14:155-9.
15. Derbent A, Tatli MM, Duran M, Tonbul A, Kafali H, Akyol M, et al.
Transient tachypnea of the newborn: effects of labor and delivery type
in term and preterm pregnancies. Arch Gynecol Obstet 2011;283:947-51.

50 Years Ago in THE JOURNAL OF PEDIATRICS

Urinary Constituents in the Newborn Infant
Rhodes PG, Hammel CL, Berman LB. J Pediatrics 1962;60:18-23

ver since physicians have been interested in kidney disease, they have been studying the urine and other body fluids
as a reflection of what pathophysiological process is occurring in the human body.1 Centuries ago, physicians
examined, boiled, and even tasted urine as a method to investigate kidney disease.
In 1962, Rhodes et al described what normal results of urinalysis were in 67 unselected newborns infants during the
first 10 days of life to define what normal urinalysis results were in this population. Fifteen of the infants were defined
as premature, and all were clinically healthy. Several of the urinalysis results demonstrated minor abnormalities, including low grade proteinuria, glycosuria, and sediment changes of squamous epithelial cells, tubular epithelial cells,
and occasional pyuria. Red blood cells were seen in only one infant. Simple hyaline casts and granular casts were found
less often. Urate crystals were very common. These abnormalities were noted in urine obtained shortly after birth and
were less common in neonates older than 3 days, and the authors suggested that the rigors of birth were likely to induce
transient abnormalities.
Today, we continue to perform urinalysis and to investigate urine in additional ways; microarray analysis and urine
proteomics have been applied to multiple kidney disease with interesting, promising, and potential novel findings.2
Investigation of urinary biomarkers for acute and chronic kidney disease has been intensely investigated in the past
several years.3 It is likely that physicians will continue to develop novel methods to study urine and body fluids in
the future.
Sharon P. Andreoli, MD
Division of Pediatric Nephrology
James Whitcomb Riley Hospital for Children
Indianapolis, Indiana
10.1016/j.jpeds.2011.08.035

References
1. Fogazzi GB. Urine microscopy from the seventeenth century to the present day. Kidney Int 1995;50:1058-68.
2. Groenen P.J. T.A., van den Heuvel L.P.W.J. Teaching molecular genetics: proteomics nephrology. Pediatr Nephrol 1996;21:661-618.
3. Al-Ismaili Z, Palijan A, Zappitelli M. Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application. Pediatr
Nephrol 2011;26:29-40.

Randomized Controlled Trial of Restrictive Fluid Management in Transient Tachypnea of the Newborn

43

THE JOURNAL OF PEDIATRICS

www.jpeds.com

Vol. 160, No. 1

Figure 1. Patient enrollment. All patients approached for study enrollment and eventual severity classification of disease are
depicted.

43.e1

Stroustrup, Trasande, and Holzman