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Comparison of Infasurf (Calfactant) and Survanta (Beractant) in the Prevention and Treatment of Respiratory Distress Syndrome

Barry T. Bloom, MD^*, Reese H. Clark, MD for the Infasurf Survanta Clinical Trial Group

^* Department of Pediatrics, University of Kansas School of Medicine, Wichita, Kansas
Pediatrix Medical Group, Inc, Sunrise, Florida

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS INFASURF SURVANTA CLINICAL TRIAL... INFASURF SURVANTA CLINICAL TRIAL... REFERENCES

 
Background. In biophysical and animal testing, Infasurf develops lower surface tension and restores total surfactant activity better than Survanta.

Methods. We performed 2 prospective, randomized, masked clinical trials; 1 trial used a prophylactic strategy aimed at prevention of respiratory distress syndrome (prophylaxis trial) for infants who were born between 23 weeks, 0 days and 29 weeks, 6 days of gestation, and the second trial used a treatment strategy (treatment trial) for intubated infants with a birth weight of 401 to 2000 g who required fractional inspired oxygen of >0.4 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of <0.2) at any time before 36 hours of age. Our purpose was to determine if Infasurf (calfactant) was more effective than Survanta (beractant) at increasing the proportion of patients alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age. Informed, written, parental consent was required, and protocols were approved by the institutional review boards of all participating institutions. The dose of surfactant was 4 mL/kg (100 mg/kg) for Survanta and 3 mL/kg (105 mg/kg) for Infasurf for both trials. The assigned drug was drawn into 2 masked syringes and administered by a health care professional who, in most cases, was not directly responsible for caring for the patient. A maximum of 3 repeat treatments, at least 6 hours apart, were permitted if the neonate required fractional inspired oxygen of >0.30 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of 0.33) and the infant remained intubated for respiratory distress syndrome.

Results. Both trials were halted for not meeting enrollment targets after a 32-month recruitment period. The decision to end recruitment was made after the interim analysis of the treatment trial. We enrolled 749 infants in the prophylaxis trial and 1361 infants in the treatment trial. The primary outcome (alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age) rate in the prophylaxis trial was 52.1% for group 1 and 52.4% for group 2. In the treatment trial, the primary outcome rate was 58.7% in group 1 and 56.8% in group 2. Based on sample-size requirements for a conclusion of similarity, and the lack of statistical significance to the differences noted in the primary outcome, we have chosen not to break the investigator blind but to report the results as groups 1 and 2.

Conclusion. Early trial closure prevents us from either accepting or rejecting our null hypothesis.

Key Words: neonate • respiratory failure • surfactant • chronic lung disease

Administration of natural surfactant reduces acute respiratory disease, air leaks, bronchopulmonary dysplasia, and mortality in preterm infants.¹ In surfactant studies, the primary efficacy end point often has been survival without chronic lung disease. No clinical trial to date has been designed with sufficient sample size to test the relative efficacy of any 2 different surfactants based on this outcome measure.¹

Infasurf, an unmodified extract of bovine lung lavage, and Survanta, a modified extract of bovine lung mince, produce more rapid improvement in gas exchange, allow more rapid weaning of respiratory support, and reduce the occurrence of air leaks when compared with the synthetic surfactant Exosurf.^2–4

In biophysical testing, Infasurf develops lower surface tension than Survanta.⁵ In the excised lung model, Infasurf restores total surfactant activity, whereas Survanta restores only a portion of full activity.⁶ Dynamic compliance in the premature rabbit improved by adding large amounts of surfactant protein-B (2% by weight) to Survanta.⁷ In premature surfactant-deficient lambs, Infasurf was more effective than Survanta in improving oxygenation and increasing lung compliance, and these effects were sustained for a longer duration.⁵ Our previous smaller comparison of Infasurf and Survanta demonstrated that Infasurf led to a more rapid decrease in oxygen and mean airway support compared with Survanta¹; however, the sample size was too small to reach any conclusion in terms of lung injury, survival, or chronic lung disease.

Because of these biochemical and functional differences, we believed a trial with sufficient sample size to establish superiority in terms of increasing the proportion of patients alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age was warranted.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS INFASURF SURVANTA CLINICAL TRIAL... INFASURF SURVANTA CLINICAL TRIAL... REFERENCES

 
We performed 2 prospective, randomized, and masked clinical trials; 1 trial used a prophylactic strategy aimed at prevention of respiratory distress syndrome (prophylaxis trial), and the second trial used a treatment strategy and only enrolled patients with clinical evidence of respiratory distress syndrome (treatment trial). Both trials were designed to determine if either of the 2 surfactants increased the proportion of patients alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age. Informed, written, parental consent was required, and protocols were approved by the institutional review boards of all participating institutions.

Trial Subjects
Prophylaxis Trial
Consent was obtained primarily from mothers who presented and were at high risk for delivery of a viable infant who was between 23 weeks, 0 days and 29 weeks, 6 days of gestation. Enrolled individuals were not randomized until delivery was imminent.

Treatment Trial
Consent was obtained from parents whose infants met criteria for enrollment, which included a birth weight of 401 to 2000 g, need for ventilatory support and fractional inspired oxygen of >0.4 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of <0.2), time since birth of <36 hours, and no previous surfactant therapy or history of meconium aspiration.

Exclusions From Either Trial
Neonates were excluded from either trial if they had structural cyanotic congenital heart disease, diaphragmatic hernias, malformations of the lung, Potter syndrome, documented oligohydramnios for >14 days, hydrops, trisomies, or monosomies.

Randomization
Each center was assigned its own balanced randomization schedule. Twins and higher-order multiples were randomized as individuals. Sealed envelopes were prepared and assigned a surfactant type by using a computerized random-number generator.

In the prophylaxis trial, stratification was by obstetrical estimate of gestational age (23–26 and 27–29 completed weeks' gestation). In the treatment trial, stratification was by birth weight (401–750, 751–1250, and 1251–2000 g).

Surfactant Dosing
The dose of surfactant was 4 mL/kg (100 mg/kg) for Survanta and 3 mL/kg (105 mg/kg) for Infasurf for both trials. The assigned drug was drawn into 2 masked syringes and then administered by a health care professional who, in most cases, was not directly responsible for caring for the patient.

Prophylaxis Trial
Prophylaxis doses were based on estimated fetal weight. The infant could be ventilated to document endotracheal tube placement and establish that the heart rate was >100 beats per minute. As soon as the heart rate was >100 beats per minute, the infant was given the first dose. The goal was for the first dose to be administered within 20 minutes.

Treatment Trial
The clinical team used their own unit's criteria for intubation. Randomization and treatment occurred within 2 hours after the infant was intubated for the management of respiratory distress syndrome and met the fractional inspired oxygen requirement but no later than 36 hours after birth. Treatment doses were based on birth weight.

Retreatment in Either Trial
A maximum of 3 repeat treatments, at least 6 hours apart, were permitted if the neonate required fractional inspired oxygen of >0.30 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of 0.33) and the infant remained intubated for respiratory distress syndrome. The date and time of retreatment were reported.

Data Management
Information was recorded for each patient's mother's demographic profile, medical and obstetrical history, labor, and delivery. Cranial ultrasonography, echocardiograms, and chest radiographs were performed as necessary. Results were interpreted by cardiologists and radiologists at the participating units. A diagnosis of patent ductus arteriosus required ultrasound verification. The treatment and occurrence of other complications of prematurity were recorded.

Site visits were conducted to monitor the accuracy of data collection and adherence to good clinical practice. For the primary outcome, 100% of the case-report forms were checked against the source document (medical record). In addition, 1800 patients had their entire case-report form verified against the source document. Data accuracy was >97%. Once all discrepancies were resolved, the database was closed and statistical analysis was performed. The blind (as group 1 and group 2) was maintained during the statistical analysis.

Trial End Points
Our primary end point for both studies was survival to 36 weeks' postmenstrual age without the use of supplemental oxygen. Secondary end points included incidences of death from respiratory failure, defined as an infant in whom respiratory failure (ie, refractory hypoxemia and/or hypercarbia) was the presenting feature of the life-threatening event in the absence of shock or multisystem organ failure from hemorrhage or sepsis; incidences of barotrauma (pneumothorax and/or pneumomediastinum and/or pulmonary intestinal emphysema and any air leak) and severe brain injury (severe intraventricular hemorrhage grades 3 or 4 or cystic periventricular leukomalacia); and degree of oxygen and ventilatory support on days 4, 10, 14, and 28 after birth. The highest level used for >12 hours during the 24-hour period on days 4, 10, 14, and 28 was the value recorded for both oxygen and ventilator support. For patients on a nasal cannula, the degree of oxygen support was reported as fraction of inspired oxygen of <0.3 unless the flow was >0.2 L/min of 100% oxygen, >0.25 L/min of 80% oxygen, or >0.5 L/min of >60% oxygen. In any of these instances, the degree of oxygen support recorded was 0.31 to 0.6.

Sample-Size Calculation
In our previous trial, 69% of neonates who received Survanta prophylaxis and 59% of neonates who received Survanta treatment were alive and not receiving supplemental oxygen by 36 weeks' postmenstrual age.¹ Calculations showed that 2000 neonates would be necessary to detect a 6% difference in the primary outcome in the prophylaxis trial and 2080 were needed in the treatment trial ( = .05; ß < .20).

Statistical Analysis
Interim Analysis
One interim analysis was conducted when data on outcome at 36 weeks' postmenstrual age was available from 1000 enrolled treatment-trial neonates. Three safety end points (survival without chronic lung disease, barotrauma, and severe brain injury [grades 3–4 intraventricular hemorrhage and cystic periventricular leukomalacia]) were evaluated and reviewed by the data and safety monitoring committee.

Evaluation of Comparability of Surfactant Groups
We evaluated categorical variables by using 2-tailed ² and Fisher's exact tests. Continuous variables were compared with use of a 2-tailed t test or the Kruskal-Wallis test. Ranked data were assessed with the 2-tailed Kruskal-Wallis test. In addition, comparability between treatment groups was tested by using a 2-way analysis of variance (analysis of variance) model, with treatment and center as the factors for continuous variables, and the Cochran-Mantel-Haenszel (CMH) test for categorical variables.

All data are presented based on "intent to treat." For the primary outcome, we present data on several subgroups of patients detailed below.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS INFASURF SURVANTA CLINICAL TRIAL... INFASURF SURVANTA CLINICAL TRIAL... REFERENCES

 
Both trials were halted after a 32-month recruitment period from March 2001 to November 2003. The decision to end recruitment was made based primarily on poor enrollment. All analyses are reported as surfactant group 1 and surfactant group 2, and the blind-to-surfactant type was maintained.

Enrollment
Our studies were conducted in 42 neonatal intensive care units (see the participant list at the end of the article). Twenty-one units participated only in the treatment trial, 2 participated only in the prophylaxis trial, and 19 participated in both.

Site logs showed that 12860 neonates were screened (see Fig 1). Of these 12860, 9016 (70.1%) neonates did not meet enrollment criteria. Of the 3844 eligible subjects, 2110 (54.9% of eligible subjects) neonates were randomized into our 2 trials. Of the 2110 randomized, 749 were in the prophylaxis trial (group 1: n = 375; group 2: n = 374) and 1361 were in the treatment trial (group 1: n = 673; group 2: n = 688). Only 12 (28%) sites enrolled the protocol-defined 80% of eligible infants into either trial.

View larger version (29K): [in this window] [in a new window]   Fig 1. CONSORT diagram: flowchart.

Twenty-one neonates did not receive the trial-assigned surfactant for all doses. Thirteen patients received both surfactants, and 8 patients received the "wrong" surfactant. Five of these 8 patients received group 1 surfactant when assigned to group 2, and 3 patients received group 2 surfactant when assigned to group 1. Data on these patients were analyzed in their assigned group (intent-to-treat analysis). Reassigning these patients to the group receiving the surfactant that they actually received (by-drug analysis) does not significantly change any of the presented proportions.

Thirty-seven enrolled patients did not meet enrollment criteria. Sixteen had oligohydramnios present for >14 days before delivery; 15 had major anomalies detected after randomization; 3 were reported to have met exclusion criteria, but the criteria used was unclear; 2 had birth weights >2 kg; and 1 had lung hypoplasia.

One hundred fifty-five patients had reported protocol deviations. Sixty-seven patients received prophylaxis dose 1 beyond 20 minutes of age; 30 were given a retreatment dose early (<6 hours from the time of the previous dose); 23 received treatment dose 1 after 36 hours of age; 19 were given >4 doses; 11 received open-label surfactant; 4 were withdrawn from the trial by their physicians; and 1 was lost to follow-up because of transfer.

Within the capability of our data set to determine bias, there was no increased frequency of any of these events in group 1 or 2 in either trial.

Description of "Results" Tables
We used an intent-to-treat approach to present our results. All tables reflect "all enrolled" infants categorized by trial and assigned surfactant group. Except for the increased rate of congenital sepsis in group 2 of the prophylaxis trial, there were no significant differences in demographics or baseline characteristics for either trial (Table 1).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS INFASURF SURVANTA CLINICAL TRIAL... INFASURF SURVANTA CLINICAL TRIAL... REFERENCES

Our decision to halt both of our trials was based primarily on declining enrollment and prolonged duration of the trial enrollment periods. Interest in continuous positive airway pressure⁹ emerged early in the trial-recruitment phase, thus decreasing the number of sites interested in the prophylaxis trial. Although the protocol defined the target for enrollment at each site as a minimum of 80% of eligible infants, this rate was achieved in only a few sites. Enrollment fell despite a midtrial meeting and 14 conference calls in which the importance of meeting enrollment targets was discussed. Publication of a retrospective review of the Pediatrix database¹⁰ and the accompanying editorial¹¹ may have contributed to diminished interest in the outcomes of these trials.

In the end, it was clear that the prophylaxis trial would never be completed and the treatment trial would take 2 more years to complete. Concurrent changes in practice including, but not limited to, the reduction in the use of postnatal steroids (which decreased in the trial population from 25% in 2001 to 16% in 2003), and the introduction of nitric oxide for the prevention of chronic lung disease (which increased from 0.5% to 2% from 2001 to 2003) would make comparability of populations over this time period suspect.

A secondary intent of our trials was to provide an alternative surfactant efficacy outcome measure. We were unable to accomplish this important task. Smaller comparison studies of new surfactant preparations are being reported with a variety of end points.¹² Claims of superiority, based on these new intermediate outcomes, may be made. It is unclear whether these studies will alter practice. Some clinicians may continue to utilize well-controlled animal and in vitro studies to select an optimal preparation. Others may look to cost differences, individual bias, or comfort based on personal experience. On reflection on unit-to-unit variation in process and outcome, we would suggest that highly effective clinical teams may be able to match surfactant characteristics and unit process design, leading to superior outcomes with either preparation.

It is unclear that survival without the use of supplemental oxygen is the proper outcome for an early surfactant intervention. Clinicians know that outcomes are influenced by nonpulmonary disorders, including the occurrence of infection, necrotizing enterocolitis, and apnea. In addition, significant site variations exist in the use of oxygen at 36 weeks, thus diminishing the reliability and value of this measure of efficacy for respiratory interventions.

Mortality alone is not an appropriate outcome in small sample studies used for surfactant comparisons. It is a low-frequency event, it depends on unit characteristics and processes, and it may reflect the desire and attitudes of the parents and providers. When pooling multiple, small, selected samples from a variety of units, differences may be overinterpreted. In previous work, a difference in mortality was noted in infants with a birth weight of <600 g. This raised concern about a negative impact of 1 of the drugs.¹ Although this subgroup was not stratified in the randomization process in these trials, we noted that 22 of 44 (50%) of infants in group 1 and 21 of 46 (47%) in group 2 survived in the treatment trial. Twenty-two infants in each group died, and 3 infants in group 2 did not have this outcome reported. In the prophylaxis trial, 33 of 50 (66%) in group 1 and 31 of 49 (63%) in group 2 survived, and 1 infant in group 1 did not have this outcome reported.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS INFASURF SURVANTA CLINICAL TRIAL... INFASURF SURVANTA CLINICAL TRIAL... REFERENCES

 
Because of inadequate sample sizes, early trial closures prevent us from either accepting or rejecting our null hypotheses because of the substantial risks of type II errors. Questions about relative safety and efficacy for surfactant preparations will remain unanswered until clinical investigators are willing to complete the difficult tasks involved in participation in the large-scale, randomized, clinical trial.

	INFASURF SURVANTA CLINICAL TRIAL GROUP AUTHORS

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Jim Cummings, MD (Pitt County Memorial Hospital, Greenville, NC), Mary Ann Dimaguila, MD (Women's Hospital of Greensboro, Greensboro, NC), Paul Stobie, MD (Presbyterian Healthcare Services, Albuquerque, NM), Jeffrey L. Loughead, MD (Central DuPage Hospital, Winfield, IL), Michael Graff, MD (Jersey Shore Medical Center, Neptune, NJ), Juan Longhi, MD (St Luke's Hospital, Kansas City, MO), E. Bernard Cartaya, MD (Parkway Regional Medical Center, North Miami Beach, FL), Edward Co, MD (Integris Baptist Medical Center, Oklahoma City, OK), Thomas Kueser, MD (Carolinas Medical Center, Charlotte, NC), Michael J. Horgan, MD (Children's Hospital, Albany, NY), Bakulesh Patel, MD (Geisinger Medical Center, Danville, PA), Daniel T. Murai, MD (Kapi'olani Medical Center, Honolulu, HI), Ihor Bilyk, MD (Parkview Hospital, Ft Wayne, IN), Mark Polak, MD (West Virginia University Hospital, Morgantown, WV), Pratibha Ankola, MD (Metropolitan Hospital Center, New York, NY), R. Dhanireddy, MD (Louisiana State University Health Services Center, Shreveport, LA), Ashima Madan, MD (El Camino Hospital, Mountain View, CA), Guillermo Godoy, MD (Northport Medical Center and DCH Regional Medical Center, Tuscaloosa, AL), and Zubair Aghai, MD (Cooper Hospital, Camden, NJ).

	INFASURF SURVANTA CLINICAL TRIAL GROUP CONTRIBUTORS

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Alexandria Hospital (Alexandria, VA): Michael Holliday, MD; Baptist Hospital of Miami (Miami, FL): Andrew B. Kairalla, MD, and Veronica Vega; Brandon Regional Hospital (Brandon, FL): Nancy Landfish, MD; Carilion Roanoke Community Hospital (Roanoke, VA): Ellen Szego, MD; Central DuPage Hospital (Winfield, IL): Rita Brennan, RNC, MS; Children's Hospital Central California (Madera, CA): Nadarasa Visveshwara, MD; Community Memorial Hospital (Ventura, CA): John van Houten, MD; Cooper Hospital (Camden, NJ): Zubair Aghai, MD, Judy Saslow, MD, and Jim Hart RRT; El Camino Hospital (Mountain View, CA): Ashima Madan, MD; Integris Baptist Medical Center (Oklahoma City, OK): Debbie S. Rogers, ARNP; Jersey Shore Medical Center (Neptune, NJ): Kristine Rovell, MSN, RNC; Kapi'olani Medical Center (Honolulu, HI): Daniel T. Murai, MD; Medical College of Georgia Hospital (Augusta, GA): Chantrapa Bunyapen, MD, and Danene Carter, RN; Metropolitan Hospital Center (New York, NY): Shahana Perveen, MD, and Emad Ghaly, MD; Miami Valley Hospital (Dayton, OH): Marc Belcastro, DO: Parkview Hospital (Ft Wayne, IN): Ihor Bilyk, MD; Parkway Regional Medical Center (North Miami Beach, FL): Maribel Soto, RNC; Phoebe Putney Memorial Hospital (Albany, GA): Carla Weis, MD, and Lynda Chancey, RN, MSN; Pinnacle Health System (Harrisburg, PA): Margaret Donahue, MD; Plantation General (Plantation, FL): Mitchell Stern, MD; Presbyterian Healthcare Services (Albuquerque, NM): Laurel Hampton; Research Medical Center (Kansas City, MO): William Topper, MD; St Agnes Healthcare (Baltimore, MD): Karen Broderick, MD; St Francis Hospital (Tulsa, OK): Hany Elsayed, MD; St John's Hospital (Springfield, IL): Dennis Crouse, MD, PhD, and Brenda Bigley, RN, CNNP; St John's Regional Health Center (Springfield, MO): Consolacion Sison, MD, and Carla Weber, MS, RNC; Stormont Vail Regional Health Center (Topeka, KS): Jose Gierbolini, MD; T.C. Thompson Children's Hospital (Chattanooga, TN): Victor Thomas, MD, and Lizbeth Kennedy, MD; Children's Hospital at Albany (Albany, NY): Susan Boynton, RN, BSN; and Pauline Graziano, RN, BSN; Thomas Jefferson University (Philadelphia, PA): Susan Adeniyi-Jones, MD; University of Mississippi Medical Center (Jackson, MS): Christina Glick, MD; University of South Alabama Children's and Women's Hospital (Mobile, AL): Fabien Eyal, MD, and Ellen M. Dean, RNC; and Wake Medical Center (Raleigh, NC): Michele Vickers, MD.

	FOOTNOTES

 
Accepted Mar 24, 2005.

Address correspondence to Barry T. Bloom, MD, Department of Pediatrics, University of Kansas School of Medicine, Wesley Medical Center, 550 N Hillside, Wichita, KS 67214. E-mail address: barrybloom{at}aol.com

Conflict of interest: These trials were sponsored by Pediatrix Medical Group, Inc, ONY, Inc, and Forest Laboratories and managed by the Department of Research at The Center for Research and Education at Pediatrix Medical Group, Inc. Forest Laboratories provided funding for the trials through a grant to Pediatrix Medical Group, Inc.

	REFERENCES

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1. Soll RF. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2004;(2):CD000144
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3. Horbar JD, Wright LL, Soll RF, et al. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1993;123 :757 –766[ISI][Medline]
4. Hudak ML, Farrell EE, Rosenberg AA, et al. A multicenter randomized, masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome. J Pediatr. 1996;128 :396 –406[CrossRef][ISI][Medline]
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9. de Paoli AG, Morley C, Davis PG. Nasal CPAP for neonates: what do we know in 2003? Arch Dis Child Fetal Neonatal Ed. 2003;88 :F168 –F172[Abstract/Free Full Text]
10. Clark RH, Auten RL, Peabody J. A comparison of the outcomes of neonates treated with two different natural surfactants. J Pediatr. 2001;139 :828 –831[CrossRef][ISI][Medline]
11. Jobe AH. Which surfactant for RDS? J Pediatr. 2001;139 :828
12. Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K; North American Study Group. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol. 2004;21 :109 –119[CrossRef][ISI][Medline]

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Bloom, B. T. Search for Related Content PubMed PubMed Citation Articles by Bloom, B. T. Related Collections Premature & Newborn

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