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. Author manuscript; available in PMC: 2015 Oct 1.
Published in final edited form as: Am J Perinatol. 2013 Dec 17;31(9):811–822. doi: 10.1055/s-0033-1361933

Medication use in the neonatal intensive care unit

Emily M Hsieh 1,2, Christoph P Hornik 2,3, Reese H Clark 4, Matthew M Laughon 5, Daniel K Benjamin Jr 2,3, P Brian Smith 2,3, on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network
PMCID: PMC4061287  NIHMSID: NIHMS556682  PMID: 24347262

Abstract

Objective

We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.

Study Design

We performed a retrospective review (2005–2010) of a large prospectively collected administrative database.

Result

Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56–681 exposures per 1000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.

Conclusion

Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are FDA-approved in infants.

Keywords: pharmacotherapy, trends over time

Introduction

Infants in the neonatal intensive care unit (NICU) are exposed to a large number of medications, most of which are not labeled for use in infants because clinical trials for safety, dosing, and efficacy of drugs are lacking in this population.1 Hospitalized infants are often excluded from clinical trials due to ethical concerns and difficulties with recruitment.2 Furthermore, these hospitalized infants in the NICU are more likely to be pre-term, with greater proportions exhibiting renal and hepatic dysfunction. These characteristics are often exclusion criteria for many clinical trials. As a result, clinicians are forced to prescribe medications for purposes outside of their licensed indications (i.e., off-label use).3–5

Previous investigators described medication use in the NICU through 2005.6 However, clinical practice and prescribing patterns change over time as clinical trial data and new Food and Drug Administration (FDA) labeling information become available. The aims of this study were (1) to provide the most recent description of current prescribing practices in the NICU and (2) to examine changes in prescribing practices over time.

Methods

Study population

We obtained demographic, outcome, and medication administration data from infants discharged from 305 NICUs managed by the Pediatrix Medical Group from 2005–2010. Data were obtained from an administrative database that prospectively captures information from daily progress notes generated by clinicians using a computer-assisted tool on all infants cared for by the Pediatrix Medical Group. Information is collected regarding maternal history and demographics, physical exam findings, medications, laboratory results, culture results, diagnoses, and other aspects of clinical care. We excluded infants admitted after day of life 120, and all vitamins (except vitamin A), nutritional supplements, vaccines, eye drops, and topical medications.

Definitions

We used counts and proportions to describe medication use by 3 different methods. Total medication courses (frequency or raw count) represented the number of times a unique medication name was reported in the database. Exposure was defined as the number of unique medication names that were reported for each patient. Days of use was defined as the total number of days each medication was administered in the entire database. For example, if a medication was prescribed to 2 patients once and to 1 patient twice for a duration of 2 days each time, the medication would be reported as: exposure=1+1+1=3; course=1+1+2=4; days=(1*2)+(1*2)+(2*2)=8. In addition, medication exposures in extremely low birth weight (ELBW, <1000 g birth weight) infants and in infants who died prior to NICU discharge were determined.

The change in frequency of medication administration between 2005 and 2010 was described by both absolute and relative change. Relative increases in medication use were limited to medications with ≥1/1000 infant exposures in 2005, and relative decreases in medication use were limited to medication with ≥1/1000 infant exposures in 2010. We conducted the analysis using STATA 12 (College Station, TX). This study was approved by the Duke Institutional Review Board.

Results

Study population and counting method

A total of 450,386 infants were discharged during the study period, and 29,336 (6.5%) were ELBW infants. The median birth weight of the study population was 2490 g (25th, 75th percentile: 1830, 3191), and the median gestational age was 35 weeks (33, 38). The median length of hospitalization was 10 days (5, 21), and 56% of the infants were male. Overall mortality was 2.4%, which was similar to the previous study (2.7%).

We identified 1,655,397 unique medication courses for 229 medications. The mean number of medication courses per infant was 4 (1, 14) for the entire cohort and 17 (2, 45) for ELBW infants. There were minimal differences in the rankings of medications when calculated by the 3 methods. Therefore, only exposures were reported for Tables 2 through 6. The 10 most commonly reported medications, by exposure, in the NICU were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (Table 1). For ELBW infants, the 10 most commonly reported medications by exposure were gentamicin, ampicillin, caffeine citrate, vancomycin, furosemide, dopamine, beractant, indomethacin, fentanyl, and albuterol (Table 2). FDA approval status for the medications most commonly used in the ELBW population is also shown in Table 2.

Table 2.

Medications most commonly used in extremely low birth weight infants

Rank Medication Exposure* FDA-approved in ELBW infants
1 Gentamicin 896 Yes
2 Ampicillin 881 No
3 Caffeine citrate 704 No
4 Vancomycin 559 Yes
5 Furosemide 495 No
6 Dopamine 425 No
7 Beractant 339 Yes
8 Indomethacin 334 Yes
9 Fentanyl 322 No
10 Albuterol 241 No
11 Calfactant 240 Yes
12 Midazolam 236 Yes
13 Hydrocortisone 215 No
14 Cefotaxime 214 Yes
15 Ranitidine 212 No
16 Metoclopramide 195 No
17 Morphine 194 No
18 Fluconazole 191 No
19 Dexamethasone 176 No
20 Vitamin A 174 No
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*

Per 1000 infants.

Table 6.

Greatest absolute decrease in exposure between 2005 and 2010

Rank Medication Decrease in exposure* Exposure in 2005* Exposure in 2010*
1 Metoclopramide −74 88 14
2 Ranitidine −49 80 31
3 Ampicillin −39 699 659
4 Cefotaxime −38 67 29
5 Indomethacin −35 61 26
6 Epoietin alpha −28 42 15
7 Beractant −26 93 67
8 Gentamicin −26 684 658
9 Dopamine −23 73 50
10 Calfactant −20 67 47
11 Vancomycin −17 96 79
12 Furosemide −16 89 73
13 Aminophylline −15 20 5.4
14 Albuterol −12 34 22
15 Dobutamine −12 26 14
16 Midazolam −9.3 63 54
17 Ceftazidime −8.7 17 8.5
18 Palivizumab −8.6 21 12
19 Spironolactone −6.4 17 11
20 Amphotericin B products −6.3 12 5.5
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*

Per 1000 infants.

Table 1.

Medications most commonly used in the NICU

Rank Medication Exposure* Courses* Days of use*
1 Ampicillin 681 709 3069
2 Gentamicin 676 785 3521
3 Caffeine citrate 156 199 3908
4 Vancomycin 91 150 987
5 Beractant 82 91 103
6 Furosemide 81 171 668
7 Fentanyl 70 86 677
8 Dopamine 62 77 327
9 Midazolam 61 71 679
10 Calfactant 56 66 72
11 Metoclopramide 54 63 706
12 Ranitidine 52 62 591
13 Poractant alpha 51 56 61
14 Morphine 51 62 527
15 Cefotaxime 43 53 316
16 Acetaminophen 43 48 241
17 Indomethacin 39 50 121
18 Phenobarbital 38 48 427
19 Albuterol 27 35 611
20 Epoietin alpha 26 30 631
21 Lorazepam 25 28 290
22 Hydrocortisone 25 32 290
23 Tobramycin 24 34 189
24 Erythromycin 24 25 103
25 Dobutamine 20 23 78
26 Dexamethasone 20 30 159
27 Fluconazole 19 23 321
28 Clindamycin 17 19 128
29 Palivizumab 17 17 24
30 Acyclovir 16 16 82
31 Vitamin A 15 15 363
32 Insulin 14 17 73
33 Ursodeoxycholic acid 14 18 259
34 Lansoprazole 14 15 106
35 Spironolactone 14 17 251
36 Chlorothiazide 12 16 230
37 Aminophylline 12 13 165
38 Ceftazidime 12 15 99
39 Alprostadil 12 12 22
40 Nitric oxide 11 12 82
41 Piperacillin/tazobactam 11 15 115
42 Epinephrine 11 12 25
43 Amoxicillin 11 12 72
44 Metronidazole 11 13 97
45 Oxacillin 10 14 67
46 Nafcillin 9.0 11 66
47 Amphotericin B products 8.9 11 99
48 Amikacin 8.8 12 77
49 Vecuronium 8.5 9.8 33
50 Ibuprofen 8.3 11 35
51 Cefazolin 7.5 8.1 27
52 Meropenem 7.0 8.9 82
53 Simethicone 6.9 7.2 59
54 Levothyroxine 6.7 7.2 157
55 Fluticasone 6.7 8.1 170
56 Budesonide 6.6 7.6 153
57 Phenylephrine 6.6 7.3 29
58 Omeprazole 6.5 7.0 64
59 Epinephrine racemic 6.3 7.4 20
60 Cefepime 6.1 7.7 58
61 Pancuronium 6.1 6.8 22
62 Famotidine 5.3 6.2 62
63 Methadone 5.2 6.1 86
64 Digoxin 5.1 5.7 28
65 Chloral hydrate 5.0 5.5 28
66 Penicillin G 4.7 4.9 38
67 Naloxone 4.3 4.4 4.7
68 Pentobarbital 4.3 4.7 49
69 Prednisone/prednisolone 4.2 5.2 47
70 Aluminum/magnesium hydroxide 4.2 4.7 27
71 Theophylline 4.1 5.0 102
72 Filgrastim 3.8 4.4 13
73 Hydrochlorothiazide 3.7 4.5 61
74 Rifampin 3.6 3.8 36
75 Propranolol 3.4 3.7 15
76 THAM acetate 3.1 4.0 5.2
77 Imipenem+cilastatin 3.0 3.3 29
78 Milrinone 2.9 3.0 15
79 Hyaluronidase 2.8 2.9 3.1
80 Bumetanide 2.8 3.8 26
81 Hydralazine 2.5 2.8 28
82 Surfactant (unknown type) 2.4 2.6 3.9
83 Captopril 2.3 2.6 24
84 Beclomethasone 2.1 2.8 32
85 Adenosine 2.1 2.5 4.0
86 Acetazolamide 2.1 3.7 24
87 Sodium polystyrene sulfonate 2.1 2.3 5.3
88 Diazepam 2.0 2.4 28
89 Zidovudine 1.9 2.0 15
90 Cephalexin 1.9 2.0 9.5
91 Ceftriaxone 1.8 1.8 5.7
92 Ipratropium 1.7 1.9 42
93 Dornase Alpha 1.6 2.2 16
94 Sulfamethoxazole+trimethoprim 1.6 1.8 16
95 Enalapril 1.5 1.8 13
96 Cefoxitin 1.5 1.6 4.9
97 Doxapram 1.4 2.0 25
98 Fosphenytoin 1.4 1.6 10
99 Sildenafil 1.4 1.6 27
100 Linezolid 1.3 1.6 14
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*

Units for courses, exposure, and days of use, per 1000 infants.

Medication use between 2005 and 2010

Drugs with the greatest relative increase in medication exposure from 2005 to 2010 included azithromycin, sildenafil, milrinone, ibuprofen, linezolid, cefoxitin, methadone, vitamin A, hyaluronidase, and poractant alpha (Table 3). Those with the greatest absolute increase in medication exposure from 2005 to 2010 included poractant alpha, vitamin A, ibuprofen, fluconazole, piperacillin/tazobactam, lansoprazole, methadone, morphine, meropenem, and nitric oxide (Table 4). Medications appearing on both lists included ibuprofen, methadone, and vitamin A.

Table 3.

Greatest relative increase in exposure between 2005 and 2010 (≥1/1000 infant exposures in 2010)

Rank Medication % Change Exposure (2005)* Exposure (2010)*
1 Azithromycin 2900 0.1 3.0
2 Sildenafil 1050 0.2 2.3
3 Milrinone 900 0.4 4.0
4 Ibuprofen 650 1.4 11
5 Linezolid 500 0.4 2.4
6 Cefoxitin 350 0.4 1.8
7 Methadone 158 3.1 8.0
8 Vitamin A 152 8.3 21
9 Hyaluronidase 107 1.5 3.1
10 Poractant alpha 101 32 63
11 Meropenem 100 4.5 9.0
12 Piperacillin/tazobactam 97 6.2 12
13 Cefepime 70 4.6 7.8
14 Famotidine 60 4.7 7.5
15 Lansoprazole 58 9.8 16
16 Fluconazole 44 14 21
17 Diazepam 44 1.6 2.3
18 Nitric oxide 42 8.9 13
19 Cefazolin 38 6.3 8.7
20 Prednisone/Prednisolone 36 3.9 5.3
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*

Per 1000 infants.

Table 4.

Greatest absolute increase in exposure between 2005 and 2010

Rank Medication Exposure increase* Exposure in 2005* Exposure in 2010*
1 Poractant alpha 32 32 63
2 Vitamin A 13 8.3 21
3 Ibuprofen 9.1 1.4 11
4 Fluconazole 6.4 14 21
5 Piperacillin/tazobactam 6.0 6.2 12
6 Lansoprazole 5.7 9.8 16
7 Methadone 4.9 3.1 8.0
8 Morphine 4.8 49 54
9 Meropenem 4.5 4.5 9.0
10 Nitric oxide 3.7 8.9 13
11 Milrinone 3.6 0.4 4.0
12 Cefepime 3.2 4.6 7.8
13 Lorazepam 3.0 23 26
14 Azithromycin 2.9 0.1 3.0
15 Metronidazole 2.9 8.4 11
16 Famotidine 2.8 4.7 7.5
17 Acyclovir 2.4 16 18
18 Cefazolin 2.4 6.3 8.7
19 Sildenafil 2.1 0.2 2.3
20 Linezolid 2.0 0.4 2.4
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*

Per 1000 infants.

Medication decreases between 2005 and 2010

Drugs with the greatest relative decrease in medication exposure from 2005 to 2010 included theophylline, metoclopramide, doxapram, aminophylline, epoietin alpha, imipenem+cilastatin, ranitidine, sodium polystyrene sulfonate, and bethanechol (Table 5). Those with the greatest absolute decrease in medication exposure from 2005 to 2010 included metoclopramide, ranitidine, ampicillin, cefotaxime, indomethacin, epoietin alpha, beractant, gentamicin, dopamine, and calfactant (Table 6). Medication use in ELBW infants is shown in Tables 7–10.

Table 5.

Greatest relative decrease in exposure between 2005 and 2010 (≥1/1000 infant exposures in 2005)

Rank Medication % Change Exposure (2005)* Exposure (2010)*
1 Theophylline −84 6.9 1.1
2 Metoclopramide −84 88 14
3 Doxapram −74 2.3 0.6
4 Aminophylline −73 20 5.4
5 Epoietin alpha −66 42 15
6 Imipenem+cilastatin −63 4.8 1.8
7 Ranitidine −61 80 31
8 Sodium polystyrene sulfonate −61 3.1 1.2
9 Bethanechol −59 2.2 0.9
10 Indomethacin −58 61 26
11 Cefotaxime −56 67 29
12 Amphotericin B products −53 12 5.5
13 Ipratropium −52 2.7 1.3
14 Ceftazidime −51 17 8.5
15 Acetylcysteine −47 1.7 0.9
16 Oxacillin −46 12 6.4
17 Dobutamine −46 26 14
18 Ceftriaxone −46 2.4 1.3
19 Rifampin −45 4.2 2.3
20 Palivizumab −42 20.5 11.9
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*

Per 1000 infants.

Table 7.

Greatest relative increase in exposure between 2005 and 2010 in ELBW infants (≥1/1000 infant exposures in 2010)

Rank Medication % Change Exposure (2005)* Exposure (2010)*
1 Azithromycin 2050 0.4 8.6
2 Ibuprofen 1340 7.8 112
3 Sildenafil 1125 1.6 20
4 Carnitine 733 3.6 30
5 Cefuroxime 700 0.2 1.6
6 Milrinone 525 1.6 10
7 Linezolid 464 3.1 18
8 Amlodipine 291 1.1 4.3
9 Ganciclovir 236 1.1 3.7
10 Cefoxitin 219 2.7 8.6
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*

Per 1000 infants.

Table 10.

Greatest absolute decrease in exposure between 2005 and 2010 in ELBW infants

Rank Medication Decrease in exposure* Exposure in 2005* Exposure in 2010*
1 Metoclopramide −236 298 62
2 Ranitidine −152 293 141
3 Epoietin alpha −143 223 81
4 Indomethacin −139 424 285
5 Cefotaxime −118 282 164
6 Aminophylline −64 94 30
7 Albuterol −60 283 223
8 Dopamine −57 449 392
9 Ceftazidime −55 130 84
10 Dobutamine −51 162 110
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*

Per 1000 infants.

Discussion

Of the most commonly reported medications identified in our study, only 35% are FDA-approved in the newborn. From 1997–2010, 28 drugs had 24 FDA labeling changes in neonates. Only 2, famotidine and linezolid, were among the top 100 medications (#62 and #100, respectively). Such off-label drug use is concerning because, frequently, little is known about the drugs’ potential side effects and adverse events; furthermore, dangerous errors may be made in adjusting adult doses and formulations for infants and children. In fact, off-label drug use is associated with increased adverse drug reactions,7 and the incidence of death and injury associated with adverse drug events in infants and children is likely substantially higher than what is actually reported.8

Several factors may have influenced the changes in medication use observed over time. An increasing number of studies investigating safety and pharmacokinetic properties of specific molecules have led to a better understanding of their effects in the target population. For example, emerging evidence has demonstrated the effectiveness of fluconazole prophylaxis in preventing invasive Candida infection in ELBW infants at high risk of invasive candidiasis.9–11 In addition, the dosing of fluconazole has been described for both treatment and prophylaxis.12 This increased understanding of the dosing, safety, and efficacy around fluconazole use likely accounts for the increase in its use (ranked 4th in absolute increase and 18th in relative increase).

On the other hand, little evidence exists for the efficacy of metoclopramide use for gastroesophageal reflux disease (GERD) in infants, which showed the second largest relative decrease in use between 2005 and 2010. A 2006 systematic literature review of metoclopramide for GERD in infants aged 0 to 23 months identified 4 studies that reported adverse effects of therapy, including irritability, dystonic reactions, drowsiness, oculogyric crisis, emesis, and apnea.13 In 2009, the FDA required manufacturers to add a box warning to their drug labels about the risk of metoclopramide’s long-term or high-dose use: chronic use of metoclopramide has been linked to tardive dyskinesia even after therapy has been discontinued.14 During the time period of our study, Pediatrix Medical Group implemented a new electronic module dedicated to clinical quality improvement initiatives,15 the success of which can be observed with the decrease in anti-reflux medication use.16 Even with the decrease in metoclopramide use, however, metoclopramide was one top 20 most commonly used medications in the NICU.

Similarly, although ranitidine remained in the top 15 most commonly used medications in both the NICU, it experienced the second largest absolute decrease in medication use from 2005 to 2010. During this time, data were published linking the use of H2 blockers to necrotizing enterocolitis (NEC) in very low birth weight (<1500 g birth weight) infants (odds ratio = 1.71 [95% confidence interval: 1.34–2.19]).17

In addition, medications that have increased in use may have their own risks and adverse effects. There has been a decrease in third-generation cephalosporin use after their use was associated with increased risk of Candida infections.18 This decrease corresponded with an increased use of piperacillin-tazobactam (ranked 5th in absolute increase and 14th in relative increase) and meropenem (ranked 9th in absolute increase and 13th in relative increase). These agents may carry similar risks given their broad spectrum of antimicrobial activity.

The introduction of newer and potentially safer medications may also drive changes in medication use. For example, indomethacin has been the conventional treatment for patent ductus arteriosus (PDA) in premature infants. In April 2006, the FDA approved ibuprofen lysine for closure of clinically significant PDA in premature infants because studies have shown ibuprofen to be safer and equally as effective as indomethacin.19 Subsequently, there has been a rise in the use of ibuprofen (3rd largest absolute increase in medication use) and a fall in indomethacin use (5th largest absolute decrease in medication use). However, in spite of these changes in prescribing patterns, indomethacin is still a commonly used medication in the ELBW infants (ranked 8th).

One of the most common complications of premature birth is bronchopulmonary dysplasia (BPD),20 and up to 20% of infants with BPD develop pulmonary hypertension. As a result, sildenafil, approved for pulmonary hypertension in adults, has increased in use since 2005 (2nd greatest relative increase). However, the FDA recently recommended against the use of sildenafil in children ages 1 though 17 for the treatment of pulmonary arterial hypertension. This recommendation was based on a recent long-term pediatric clinical trial showing that children taking a high dose of sildenafil had a higher risk of death when compared to children taking a low dose, and that the low dose of sildenafil was not effective in improving exercise ability.21

The strengths of our study include the use of a large, representative cohort, as well as daily documentation of medication prescriptions for infants in the NICU. Our study is limited by the use of administrative data for the analysis. These data are not from a prospective clinical trial that has undergone the scrutiny of independent monitoring, but rather are derived from prospectively collected electronic documentation.

In summary, we identified the most commonly reported medications used in the NICU and how medication use has changed over time. Frequent studies of medication use patterns should be conducted to facilitate optimal prioritization of drug studies in infants. As many of the drugs used in the NICU are used off-label and have not been adequately studied in this population, these data are useful for researchers and NIH in setting research priorities.

Table 8.

Greatest absolute increase in exposure between 2005 and 2010 in ELBW infants

Rank Medication Exposure increase* Exposure in 2005* Exposure in 2010*
1 Vitamin A 179 93 273
2 Caffeine citrate 176 620 796
3 Poractant alpha 135 100 235
4 Ibuprofen 105 7.8 112
5 Fluconazole 95 141 236
6 Gentamicin 67 853 920
7 Fentanyl 47 295 342
8 Meropenem 45 36 81
9 Piperacillin/Tazobactam 44 45 89
10 Lorazepam 38 76 114
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*

Per 1000 infants.

Table 9.

Greatest relative decrease in exposure between 2005 and 2010 in ELBW infants (≥1/1000 infant exposures in 2005)

Rank Medication % Change Exposure (2005)* Exposure (2010)*
1 Cromolyn −93 2.7 0.2
2 Terbutaline −88 3.4 0.4
3 Scopolamine −87 4.5 0.6
4 Norepinephrine −85 1.3 0.2
5 Metoclopramide −79 298 62
6 Ceftizoxime −75 1.6 0.4
7 Aztreonam −74 3.8 1.0
8 Theophylline −73 38 10
9 Doxapram −70 22 6.7
10 Chlorpromazine −69 1.3 0.4
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*

Per 1000 infants.

Acknowledgments

This work was funded under NICHD contract HHSN2752010000031 for the Pediatric Trials Network. The NICHD played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. P. Brian Smith had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr. Benjamin receives support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, and NICHD contract HHSN275201000003I) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Smith receives support for research from the National Institutes of Health and the U.S. Department of Health and Human Services (NICHD 1K23HD060040-01, DHHS-1R18AE000028-01, and HHSN267200700051C); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Laughon receives support from the U.S. government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Benjamin, under the Best Pharmaceuticals for Children Act) and from NICHD 1K23HL092225-01.

The PTN Administrative Core Committee

Daniel K. Benjamin Jr., Duke Clinical Research Institute, Durham, NC; Katherine Berezny, Duke Clinical Research Institute, Durham, NC; Jeffrey Barrett, Children’s Hospital of Philadelphia, Philadelphia, PA; Edmund Capparelli, University of California–San Diego, San Diego, CA; Michael Cohen-Wolkowiez, Duke Clinical Research Institute, Durham, NC; Gregory L. Kearns, Children’s Mercy Hospital, Kansas City, MO; Matthew Laughon, University of North Carolina at Chapel Hill, Chapel Hill, NC; Andre Muelenaer, Virginia Tech Carilion School of Medicine, Roanoke, VA; T. Michael O’Shea, Wake Forest Baptist Medical Center, Winston Salem, NC; Ian M. Paul, Penn State College of Medicine, Hershey, PA; P. Brian Smith, Duke Clinical Research Institute Durham, NC; John van den Anker, George Washington University School of Medicine and Health, Washington, DC; Kelly Wade, Children’s Hospital of Philadelphia, Philadelphia, PA

The Eunice Kennedy Shriver National Institute of Child Health and Human Development: David Siegel, Perdita Taylor-Zapata, Anne Zajicek, Katerina Tsilou, Alice Pagan

The EMMES Corporation (Data Coordinating Center): Ravinder Anand, Diane Brandt, Traci Clemons, Gina Simone

Footnotes

Conflicts of interest

Drs. Hsieh, Hornik, and Clark have nothing to disclose.

Contributor Information

Emily M. Hsieh, Email: emily.m.hsieh@gmail.com.

Christoph P. Hornik, Email: christoph.hornik@dm.duke.edu.

Reese H. Clark, Email: Reese_Clark@pediatrix.com.

Matthew M. Laughon, Email: matt_laughon@med.unc.edu.

Daniel K. Benjamin, Jr., Email: danny.benjamin@dm.duke.edu.

P. Brian Smith, Email: Brian.Smith@dm.duke.edu.

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