- Email: [email protected]
Medication Utilization at School Age for Children Born Preterm
BRIEF REPORTS Medication Utilization at School Age for Children Born Preterm Jo Ann D’Agostino, DNP, CRNP1,2, Molly Passarella, MS2, Ashley E. Martin, MPH2, and Scott A. Lorch, MD, MSCE1,2,3,4 We explored medication use by children born preterm at 5-8 years of age. Compared with children born at full term, children born preterm had higher medication use that included most therapeutic classifications. Although asthma and chronic lung disease influenced use, prematurity remained an independent risk factor. (J Pediatr 2019;-:1-4).
P
remature birth is associated with increased health service use after discharge from the neonatal intensive care unit.1-4 In the first year after birth, infants born prematurely have been shown to have high medication needs. In a study of 892 infants born at £32 weeks of gestation, 43% filled a prescription in the first year, with an average of 5.5 prescriptions per year (including antibiotics, respiratory medications, diuretics, gastric acid suppression and prokinetic medications, and central nervous system stimulants). Infants born preterm are twice as likely to receive a respiratory medication than infants born full term in the first year and in early childhood.3,5-9 Although medication needs for children born preterm during infancy and their need for asthma medication during childhood have been described, there is a gap in the literature regarding other medication needs for children born preterm. As adults, those who were born preterm have been shown to have an increased need for asthma, gastric acid suppression, diabetes, antipsychotic, antidepressant, hypnotic/sedative, and antiepileptic medications compared with those born at term.6,10-13 What is unclear from the literature is if the increased need for medication that children born preterm experience in the first year of life continues throughout their lifespan or if there is improvement after the neonatal period with resurgence of medication needs in adulthood. The purpose of this study was to explore medication use for children between 5 and 8 years of age born preterm compared with children born at full term in the community setting, and to assess influencing factors.
Methods A retrospective cohort was constructed from the electronic health record of 1 large 34-site pediatric network with 6 urban and 28 suburban/rural sites. The cohort included infants born between 2005 and 2008 with a documented gestational age between 23 and 44 weeks who presented for primary care by 6 months of corrected age and had ³1 primary care visit after 7 years chronological age (n = 22 525). Of those, 94% had >2 visits during the study period. Most children (75%) were seen in the suburban/rural primary sites. Infants with complex congenital heart disease, genetic syndromes,
CLD IRR
Chronic lung disease Incident rate ratio
metabolic disorders, and major birth defects were excluded because medication use may have been related to their coexisting medical conditions (n = 1392). The final cohort included 21 133 infants. This study was approved by the Institutional Review Board at The Children’s Hospital of Philadelphia. All medications in the ambulatory electronic record prescribed between 5 and 8 years of age were reviewed based on documentation by providers during ambulatory health care encounters using the EPIC Hyperspace system. Therapeutic classifications were used for analysis and were predefined in the electronic record based on Medispan’s hierarchical therapeutic classification system.14 Because the focus of this study was to explore community medication use, the following routes of administration were excluded: epidural and, intravenous. For similar reasons, diagnostic products, general anesthetics, local anesthetics, hypnotics, neuromuscular blocking agents, skeletal muscle relaxants, inotropic agents, narcotic analgesics, and vaccines were excluded. Acetaminophen and ibuprofen were excluded owing to the frequent prescription of these medications on an asneeded basis. We included prescriptions for all other overthe-counter medications. Medications administered in a primary care provider’s office, other than those excluded, were included. Historical medications, which constituted <5% of all medications, were excluded as it was unclear when these were prescribed or if the medication was still in active use. Demographic factors included gestational age, ethnicity, race, and sex. Insurance type was divided into 3 exclusive categories: any office visit without insurance during the study period of 5-8 years of age; any use of Federal Medicaid insurance without being uninsured during the study period; and sole use of private insurance during the study period. Potential confounding medical factors included chronic lung disease (CLD) and asthma as defined
From the 1Department of Pediatrics, 2Center for Perinatal and Pediatric Health Disparities Research, The Children’s Hospital of Philadelphia; 3The University of Pennsylvania School of Medicine; and 4Senior Scholar, Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA Supported by an National Institutes of Health grant (R01 HD057168). The authors declare no conflicts of interest. Portions of this study were presented as a poster at the Pediatric Academic Society annual meeting, May 5-8, 2018, Toronto, Canada. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.015
1
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children born at full term (Table I; P < .0001). There was a trend toward fewer yearly prescriptions over time from 5 to 8 years for children born preterm and those born at full term; however, children born preterm were more likely to receive prescriptions for all years compared with children born at full term (Table I). Children born extremely preterm with a gestational age between 23 and 28 weeks averaged the most prescriptions, whereas those born at moderate and late preterm averaged more medications than those who were born at full term (Figure). Children with asthma or CLD averaged more medications between 5 and 8 years of age (12.8 13.7 medications; median, 9; IQR, 4-17), than those without asthma or CLD (4.3 5.5; median, 3; IQR, 1-6). Children born preterm with asthma or CLD averaged 14.1 14.9 prescriptions (median,9; IQR, 5-19) compared with 12.6 13.4 prescriptions (median, 9; IQR, 4-16) for children born at full term with asthma or CLD.
Statistical Analyses Descriptive analysis included the c2 and Kruskal-Wallis tests. The ratios of prescriptions by therapeutic classification were calculated using Poisson regression for those who were born preterm (33-36, 29-32, and 23-28 weeks) compared with those who were born at full term (³37 weeks) gestation. Multivariate Poisson regression identified the independent association of gestational age on the rate of prescription use after adjusting for socioeconomic status and medical factors listed above, through calculation of an incident rate ratio (IRR). These analyses were performed for all medications and by therapeutic classification after the calculation of standard errors accounting for clustering of patients at the site of primary care. We found no difference in the results when clustering on primary care site vs using fixed or random effects.
Univariate Results by Therapeutic Classification Preterm children were more likely than children born at full term to receive medications from 11 of 14 therapeutic classifications (Table II; available at www.jpeds.com). Of the 3 most commonly prescribed medications in each therapeutic classification, the top 2 medications were the same for both preterm and children born at full term in most classifications except in 2 situations: for gastrointestinal medications, children born preterm were more likely to receive a proton pump inhibitor and children born at full term an histamine-2 receptor antagonist; whereas for neuromuscular medications, children born preterm were
Results The cohort included 18 698 children (88.48%) born at full term and 2435 children (11.52%) born preterm. Children born preterm were more likely to be black, non-Hispanic, receive Medicaid, and were more likely to have asthma and CLD compared with those who were born at full term (Table I). Overall 87.86% of the cohort received a prescription between 5 and 8 years of age. Children born preterm were prescribed medications more frequently than
Table I. Demographics Variables
Total
Number (%) Gestational age, wk 33-36 29-32 23-28 Race/ethnicity White Non-Hispanic 11 168 (52.85%) Black Non-Hispanic 6260 (29.62%) Other Non-Hispanic 2573 (12.18%) Hispanic 1132 (5.36%) Insurance Private 12 451 (58.92%) Medicaid 7182 (33.98%) Self-pay 1500 (7.1%) Male sex 10 662 (50.45%) Asthma 7126 (33.72%) CLD 141 (0.67%) Number of children receiving prescriptions 5-8 years Total 18 567 (87.86%) 5-6 years 14 232 (67.34%) 6-7 years 13 511 (63.93%) 7-8 years 12 627 (59.75%) Average number of prescriptions by age (mean SD) 5-8 years Total 7.22 9.97 5-6 years 2.55 3.95 6-7 years 2.45 4.01 7-8 years 2.22 3.86 2
Full term
95% CI
18 698 (88.48)
Preterm
95% CI
P value
2435 (11.52)
– – –
1845 (75.77%) 404 (16.59%) 186 (7.64%) <.0001
10 046 (53.73%) 5336 (28.54%) 2324 (12.43%) 992 (5.31%)
(53.01-54.44) (27.89-29.19) (11.96-12.91) (4.99-5.64)
1122 (46.08%) 924 (37.95%) 249 (10.23%) 140 (5.75%)
(44.11-48.06) (36.04-39.89) (9.08-11.49) (4.89-6.75)
11 205 (59.93%) 6175 (33.02%) 1318 (7.05%) 9450 (50.54%) 6070 (32.46%) 10 (0.05%)
(59.22-60.63) (32.35-33.70) (6.69-7.42) (49.82-51.26) (37.80-33.14) (0.02-0.01)
1246 (51.17%) 1007 (41.36%) 182 (7.47%) 1212 (49.77%) 1056 (43.37%) 131 (5.38%)
(49.18-53.15) (39.41-43.32) (6.49-8.59) (47.79-51.76) (41.41-45.35) (4.55-6.35)
.477 <.0001 <.0001
16 388 (87.65%) 12 496 (66.83%) 11 862 (63.44%) 11 083 (59.27%)
(87.17-88.11) (66.15-67.50) (62.75-64.13) (58.57-59.98)
2179 (89.49%) 1736 (71.29%) 1649 (67.72%) 1544 (63.41%)
(88.20-90.64) (69.46-73.06) (65.84-69.55) (61.48-65.30)
.0089 <.0001 <.0001 <.0001
(6.85-7.13) (2.42-2.52) (2.32-2.43) (2.10-2.20)
8.99 12.27 3.15 5.03 3.05 4.55 2.78 4.57
(8.50-9.47) (2.95-3.35) (2.86-3.24) (2.60-2.97)
<.0001 <.0001 <.0001 <.0001
<.0001
6.99 9.61 2.47 3.78 2.37 3.89 2.15 3.75
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BRIEF REPORTS
Figure. Average number of prescriptions by demographic factors.
more likely to receive levetiracetam and children born at full term were more likely to receive oxcarbazepine (Table III; available at www.jpeds.com). Multivariate Results Controlling for socioeconomic status and CLD, prematurity was a significant predictor for medications at 5-8 years of age compared with children born at full term (IRR, 1.17; 95% CI, 1.1-1.24). When asthma was added into the model, prematurity remained a significant predictor for medications (IRR, 1.07; 95% CI, 1.01-1.13) (Table IV; available at www.jpeds. com). Children with asthma (IRR, 2.8; 95% CI, 2.56-3.05), CLD (IRR, 1.45; 95% CI, 1.2-1.74), Medicaid (IRR, 1.43; 95% CI, 1.36-1.51), and male sex (IRR, 1.05; 95% CI, 1.021.08) were more likely to receive prescriptions. Compared with non-Hispanic white infants, those who were Hispanic (IRR, 0.88; CI, 0.79-0.99) and other non-Hispanic (IRR, 0.88; CI, 0.83-0.93) were less likely to received prescriptions.
Discussion In this study using ambulatory records, children born preterm were more likely to receive medication prescriptions in the community setting between 5 and 8 years of age than children born at full term. Children born extremely preterm received the most medications; however, even those born at moderate or late gestational ages had higher use than those who were born at full term. The increased medication needs in young school age children included most therapeutic classifications of medications. Although a number of these medications were attributable to the respiratory complications of Medication Utilization at School Age for Children Born Preterm
asthma and CLD, children born preterm had needs that extended beyond respiratory-related medications. Even among children with a diagnosis of asthma, children born preterm averaged more medications than children born at full term. The need for asthma medications in early childhood by those born preterm has been the one area of medication use that has well documented for the preterm population. A recent systematic review and meta-analysis found preterm birth was associated with an increased risk of wheezing disorders in childhood, with those born at <32 weeks at greatest risk; however, moderately premature children also have been documented to have increased needs for respiratory medications in early childhood.3,7,15 Expanding on this, we explored whether the increased need for medication at school age was related to a diagnosis of CLD or asthma, or if simply being born preterm played a role in our results. We found that approximately 50% of the prematurity association with medication use in early childhood was related to a history of CLD, as well as asthma independent of having the diagnosis of CLD. Regardless of a history of CLD and asthma, preterm birth independently increased the receipt of medications in the majority of classifications. We found similarities in the types of medications prescribed to both children born preterm and children born at full term, although children born preterm were more likely to receive medications for issues related to gastrointestinal, central nervous system, cardiovascular, psychiatric, sleep, and nutritional needs. This finding is most likely reflective of the medical challenges children born preterm continue to face in early childhood and suggests an 3
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additional burden for children born preterm related to medication use at school age. We found that male children were more likely to receive prescriptions and those with Hispanic and other non-Hispanic ethnicities received fewer prescriptions. These findings are similar to a study of national pediatric prescriptions in which males were more likely to receive prescriptions from 6 to 12 years of age, mainly owing to a higher rate of chronic medications; and non-white and Hispanic children were less like to receive prescriptions.16 This racial/ethnic disparity in pediatric prescriptions has been documented for medications such as antibiotics, yet the reasons for this are not well-understood. Racial-ethic differences in parental expectation, implicit bias, access to care, and differences in a provider’s likelihood to treat are but a few potential drivers.17-21 We found that children with Medicaid insurance were more likely to receive prescriptions. Because children with asthma are more likely to be covered through Medicaid than those without asthma and children born preterm with CLD or asthma were more likely to receive prescriptions in our study, this may have influenced this finding.22 Because our focus was on medications used by children born preterm in the community setting as documented in the ambulatory electronic record, a limitation of our study is that our findings do not capture medications children may have received in other clinical settings such as urgent/ emergent care centers or inpatient settings or prescribed by providers outside of the system. In addition, we excluded those with significant non-prematurity-related neonatal conditions such as congenital anomalies to focus on the risk prematurity alone confers. Owing to these exclusions, our findings may underestimate the actual medication use of our cohort. Our cohort was limited to 1 large pediatric network and therefore may not be generalizable to other practice settings. However, this site has >30 urban, suburban, and rural sites in 2 states, providing a large diversity of patients to study. Our study showed that children born preterm continued to have higher medication use at 5-8 years of age than children born at full term. The range of medications, including most therapeutic classifications, suggests a diversity of prematurity-related needs that continue to challenge children born preterm in childhood and suggest a continuum of increased medication needs throughout their lifespan. n
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Submitted for publication Aug 6, 2019; last revision received Oct 30, 2019; accepted Nov 6, 2019. Reprint requests: Scott A. Lorch, MD, MSCE, The Children’s Hospital of Philadelphia, Division of Neonatology, 3401 Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected]
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Data Statement
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Data sharing statement available at www.jpeds.com.
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References
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1. Wade KC, Lorch SA, Bakewell-Sachs S, Medoff-Cooper B, Silber JH, Escobar GJ. Pediatric care for preterm infants after NICU discharge: 4
high number of office visits and prescription medications. J Perinatol 2008;28:696-701. Westrupp EM, Lucas N, Mensah FK, Gold L, Wake M, Nicholson JM. Community-based healthcare costs for children born low birthweight, preterm and/or small for gestational age: data from the Longitudinal Study of Australian Children. Child Care Health Dev 2014;40:259-66. Vrijlandt EJ, Kerstjens JM, Duiverman EJ, Bos AF, Reijneveld SA. Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term. Am J Respir Crit Care Med 2013;187:1234-40. Cuevas KD, Silver DR, Brooten D, Youngblut JM, Bobo CM. The cost of prematurity: hospital charges at birth and frequency of rehospitalizations and acute care visits over the first year of life: a comparison by gestational age and birth weight. Am J Nurs 2005;105:56-64. Houweling LM, Bezemer ID, Penning-van Beest FJ, Meijer WM, van Lingen RA, Herings RM. First year of life medication use and hospital admission rates: premature compared with term infants. J Pediatr 2013;163:61-6.e1. Crump C, Winkleby MA, Sundquist J, Sundquist K. Risk of asthma in young adults who were born preterm: a Swedish national cohort study. Pediatrics 2011;127:e913-20. Haataja P, Korhonen P, Ojala R, Hirvonen M, Paassilta M, Gissler M, et al. Asthma and atopic dermatitis in children born moderately and late preterm. Eur J Pediatr 2016;175:799-808. Castro-Rodriguez JA, Forno E, Rodriguez-Martinez CE, Celedon JC. Risk and protective factors for childhood asthma: what is the evidence? J Allergy Clin Immunol Pract 2016;4:1111-22. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830-8. Crump C, Winkleby MA, Sundquist J, Sundquist K. Gestational age at birth and risk of gastric acid-related disorders in young adulthood. Ann Epidemiol 2012;22:233-8. Crump C, Winkleby MA, Sundquist K, Sundquist J. Risk of diabetes among young adults born preterm in Sweden. Diabetes Care 2011;34: 1109-13. Crump C, Winkleby MA, Sundquist K, Sundquist J. Preterm birth and psychiatric medication prescription in young adulthood: a Swedish national cohort study. Int J Epidemiol 2010;39:1522-30. Crump C, Sundquist K, Winkleby MA, Sundquist J. Preterm birth and risk of epilepsy in Swedish adults. Neurology 2011;77:1376-82. Kluwer W. Medi-Span Generic Product Identifier (GPI) 2018. www. wolterskluwercdi.com/drug-data/gpi/. Accessed October 30, 2019. Been JV, Lugtenberg MJ, Smets E, van Schayck CP, Kramer BW, Mommers M, et al. Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis. PLoS Med 2014;11:e1001596. Qato DM, Alexander GC, Guadamuz JS, Lindau ST. Prescription medication use among children and adolescents in the United States. Pediatrics 2018;142:e20181042. Gerber JS, Prasad PA, Localio AR, Fiks AG, Grundmeier RW, Bell LM, et al. Racial differences in antibiotic prescribing by primary care pediatricians. Pediatrics 2013;131:677-84. Goyal MK, Johnson TJ, Chamberlain JM, Casper TC, Simmons T, Alessandrini EA, et al. Racial and ethnic differences in antibiotic use for viral illness in emergency departments. Pediatrics 2017;140:e20170203. Mangione-Smith R, Elliott MN, Stivers T, McDonald L, Heritage J, McGlynn EA. Racial/ethnic variation in parent expectations for antibiotics: implications for public health campaigns. Pediatrics 2004;113: e385-94. Blair IV, Steiner JF, Fairclough DL, Hanratty R, Price DW, Hirsh HK, et al. Clinicians’ implicit ethnic/racial bias and perceptions of care among Black and Latino patients. Ann Fam Med 2013;11:43-52. Flores G , Committee On Pediatric Research. Technical report–racial and ethnic disparities in the health and health care of children. Pediatrics 2010;125:e979-1020. CDC. Health. Care Coverage among Children 2016. www.cdc.gov/ asthma/asthma_stats/Health_Care_Coverage_among_Children.htm. Accessed October 30, 2019.
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BRIEF REPORTS
Table II. Univariate analysis of therapeutic classifications prescribed between 5-8 years of age to children born preterm as compared with children born full term Classifications Analgesic Anti-infective Antineoplastic Cardiovascular Central nervous system Endocrine/metabolic Gastrointestinal Genitourinary Hematologic Miscellaneous Neuromuscular Nutritional Respiratory Topical
Rate Ratio, 95% CI
P value
1.45 (0.88-2.41) 1.09 (1.05-1.12) 1.56 (0.89-2.71) 1.58 (1.27-1.98) 1.33 (1.25-1.41) 1.41 (1.32-1.50) 1.57 (1.46-1.68) 2.28 (1.66-3.14) 1.14 (0.86-1.52) 2.34 (1.60-3.41) 2.03 (1.75-2.36) 1.07 (1.01-1.13) 1.48 (1.44-1.51) 1.13 (1.09-1.17)
.14 <.0001 .12 .0001 <.0001 <.0001 <.0001 <.0001 .36 <.0001 <.0001 .02 <.0001 <.0001
Medication Utilization at School Age for Children Born Preterm
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Table III. Top 3 most common medications prescribed to preterm and children born at full term per therapeutic classification Classifications Analgesics Preterm Full term Anti-infectives Preterm Full term Antineoplastic Preterm Full term Cardiovascular Preterm Full term Central Nervous System Preterm Full term Endocrine/metabolic Preterm Full term Gastrointestinal Preterm Full term Genitourinary Preterm Full term Hematologic Preterm Full term Miscellaneous Preterm Full term Neuromuscular Preterm Full term Nutritional Preterm Full term Respiratory Preterm Full term Topical Preterm Full term
Most common
Less common
Least common
Naproxen Naproxen
Magic mouthwash Rizatriptan benzoate
Meloxicam Magic mouthwash
Amoxicillin Amoxicillin
Azithromycin Azithromycin
Amoxicillin-potassium clavulanate Amoxicillin-potassium clavulanate
Temozolomide Hydroxyurea
Irinotecan HCl Leuprolide acetate
Leuprolide acetate Procarbazine HCl
Guanfacine HCl Guanfacine HCl
Clonidine HCl Clonidine HCl
Enalapril maleate Amlodipine besylate
Methylphenidate HCl Methylphenidate HCl
Amphetamine-dextroamphetamine Amphetamine-dextroamphetamine
Dexmethylphenidate HCl Dexmethylphenidate HCl
Prednisolone sodium phosphate Prednisolone sodium phosphate
Prednisolone Prednisolone
Prednisone Prednisone
Polyethylene glycol Polyethylene glycol
Lansoprazole Ranitidine HCl
Ranitidine HCl Lansoprazole
Oxybutynin chloride Oxybutynin chloride
Estrogens, conjugated Estrogens, conjugated
Nitrofurantoin Nitrofurantoin
Folic acid Folic acid
Ferrous sulfate Ferrous sulfate
Pegfilgrastim Aminocarproic acid
Melatonin Melatonin
Azathioprine Mycophenolate mofetil
Deferasirox
Levetiracetam Oxcarbazepine
Oxcarbazepine Levetiracetam
Diazepam Lamotrigine
Pediatric multivitamins-Fl Pediatric multivitamins-Fl
Sodium fluoride Sodium fluoride
Multivitamin Multivitamin
Albuterol sulfate Albuterol sulfate
Fluticasone propionate HFA Fluticasone propionate HFA
Cetirizine HCl Cetirizine HCl
Hydrocortisone Hydrocortisone
Polymyxin B-trimethoprim Mupirocin
Ofloxacin Ofloxacin
HCI, hydrochloric acid.
Table IV. Multivariate analysis of predictors to medication prescription between 5 and 8 years of age SES and CLD Variables Preterm birth Race/ethnicity White Non-Hispanic Black Non-Hispanic Other Non-Hispanic Hispanic Insurance Private Medicaid Self-pay Male sex CLD Asthma
SES and asthma
SES, CLD, and asthma
RR (95% CI)
P value
RR (95% CI)
P value
RR (95% CI)
P value
1.17 (1.1-1.24)
<.0001
1.1 (1.04-1.16)
.0004
1.07 (1.01-1.13)
.017
* 1.11 (1.02-1.21) 0.88 (0.83-0.94) 0.93 (0.81-1.07)
*
* 1.01 (0.93-1.09) 0.88 (0.83-0.93) 0.88 (0.79-0.99)
*
.90 <.0001 .03
* 1.56 (1.48-1.65) 1.2 (0.97-1.48) 1.17 (1.13-1.21) 1.8 (1.49-2.16)
* <.0001 .086 <.0001 <.0001
* 1.43 (1.36-1.51) 1.07 (0.95-1.2) 1.05 (1.02-1.08) 1.45 (1.2-1.74) 2.8 (2.56-3.05)
* <.0001 .27 <.01 <.001 <.0001
.02 <.001 .33
* 1.01 (0.93-1.09) 0.88 (0.83-0.93) 0.88 (0.78-0.99)
*
* 1.44 (1.36-1.51) 1.07 (0.95-1.2) 1.05 (1.02-1.08)
* <.0001 .27 .003
2.81 (2.57-3.06)
<.0001
.89 <.0001 .03
SES, socioeconomic status. *Reference Group
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P
remature birth is associated with increased health service use after discharge from the neonatal intensive care unit.1-4 In the first year after birth, infants born prematurely have been shown to have high medication needs. In a study of 892 infants born at £32 weeks of gestation, 43% filled a prescription in the first year, with an average of 5.5 prescriptions per year (including antibiotics, respiratory medications, diuretics, gastric acid suppression and prokinetic medications, and central nervous system stimulants). Infants born preterm are twice as likely to receive a respiratory medication than infants born full term in the first year and in early childhood.3,5-9 Although medication needs for children born preterm during infancy and their need for asthma medication during childhood have been described, there is a gap in the literature regarding other medication needs for children born preterm. As adults, those who were born preterm have been shown to have an increased need for asthma, gastric acid suppression, diabetes, antipsychotic, antidepressant, hypnotic/sedative, and antiepileptic medications compared with those born at term.6,10-13 What is unclear from the literature is if the increased need for medication that children born preterm experience in the first year of life continues throughout their lifespan or if there is improvement after the neonatal period with resurgence of medication needs in adulthood. The purpose of this study was to explore medication use for children between 5 and 8 years of age born preterm compared with children born at full term in the community setting, and to assess influencing factors.
Methods A retrospective cohort was constructed from the electronic health record of 1 large 34-site pediatric network with 6 urban and 28 suburban/rural sites. The cohort included infants born between 2005 and 2008 with a documented gestational age between 23 and 44 weeks who presented for primary care by 6 months of corrected age and had ³1 primary care visit after 7 years chronological age (n = 22 525). Of those, 94% had >2 visits during the study period. Most children (75%) were seen in the suburban/rural primary sites. Infants with complex congenital heart disease, genetic syndromes,
CLD IRR
Chronic lung disease Incident rate ratio
metabolic disorders, and major birth defects were excluded because medication use may have been related to their coexisting medical conditions (n = 1392). The final cohort included 21 133 infants. This study was approved by the Institutional Review Board at The Children’s Hospital of Philadelphia. All medications in the ambulatory electronic record prescribed between 5 and 8 years of age were reviewed based on documentation by providers during ambulatory health care encounters using the EPIC Hyperspace system. Therapeutic classifications were used for analysis and were predefined in the electronic record based on Medispan’s hierarchical therapeutic classification system.14 Because the focus of this study was to explore community medication use, the following routes of administration were excluded: epidural and, intravenous. For similar reasons, diagnostic products, general anesthetics, local anesthetics, hypnotics, neuromuscular blocking agents, skeletal muscle relaxants, inotropic agents, narcotic analgesics, and vaccines were excluded. Acetaminophen and ibuprofen were excluded owing to the frequent prescription of these medications on an asneeded basis. We included prescriptions for all other overthe-counter medications. Medications administered in a primary care provider’s office, other than those excluded, were included. Historical medications, which constituted <5% of all medications, were excluded as it was unclear when these were prescribed or if the medication was still in active use. Demographic factors included gestational age, ethnicity, race, and sex. Insurance type was divided into 3 exclusive categories: any office visit without insurance during the study period of 5-8 years of age; any use of Federal Medicaid insurance without being uninsured during the study period; and sole use of private insurance during the study period. Potential confounding medical factors included chronic lung disease (CLD) and asthma as defined
From the 1Department of Pediatrics, 2Center for Perinatal and Pediatric Health Disparities Research, The Children’s Hospital of Philadelphia; 3The University of Pennsylvania School of Medicine; and 4Senior Scholar, Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA Supported by an National Institutes of Health grant (R01 HD057168). The authors declare no conflicts of interest. Portions of this study were presented as a poster at the Pediatric Academic Society annual meeting, May 5-8, 2018, Toronto, Canada. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.015
1
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by International Classification of Diseases, 9th and 10th edition, codes.
Volume -
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children born at full term (Table I; P < .0001). There was a trend toward fewer yearly prescriptions over time from 5 to 8 years for children born preterm and those born at full term; however, children born preterm were more likely to receive prescriptions for all years compared with children born at full term (Table I). Children born extremely preterm with a gestational age between 23 and 28 weeks averaged the most prescriptions, whereas those born at moderate and late preterm averaged more medications than those who were born at full term (Figure). Children with asthma or CLD averaged more medications between 5 and 8 years of age (12.8 13.7 medications; median, 9; IQR, 4-17), than those without asthma or CLD (4.3 5.5; median, 3; IQR, 1-6). Children born preterm with asthma or CLD averaged 14.1 14.9 prescriptions (median,9; IQR, 5-19) compared with 12.6 13.4 prescriptions (median, 9; IQR, 4-16) for children born at full term with asthma or CLD.
Statistical Analyses Descriptive analysis included the c2 and Kruskal-Wallis tests. The ratios of prescriptions by therapeutic classification were calculated using Poisson regression for those who were born preterm (33-36, 29-32, and 23-28 weeks) compared with those who were born at full term (³37 weeks) gestation. Multivariate Poisson regression identified the independent association of gestational age on the rate of prescription use after adjusting for socioeconomic status and medical factors listed above, through calculation of an incident rate ratio (IRR). These analyses were performed for all medications and by therapeutic classification after the calculation of standard errors accounting for clustering of patients at the site of primary care. We found no difference in the results when clustering on primary care site vs using fixed or random effects.
Univariate Results by Therapeutic Classification Preterm children were more likely than children born at full term to receive medications from 11 of 14 therapeutic classifications (Table II; available at www.jpeds.com). Of the 3 most commonly prescribed medications in each therapeutic classification, the top 2 medications were the same for both preterm and children born at full term in most classifications except in 2 situations: for gastrointestinal medications, children born preterm were more likely to receive a proton pump inhibitor and children born at full term an histamine-2 receptor antagonist; whereas for neuromuscular medications, children born preterm were
Results The cohort included 18 698 children (88.48%) born at full term and 2435 children (11.52%) born preterm. Children born preterm were more likely to be black, non-Hispanic, receive Medicaid, and were more likely to have asthma and CLD compared with those who were born at full term (Table I). Overall 87.86% of the cohort received a prescription between 5 and 8 years of age. Children born preterm were prescribed medications more frequently than
Table I. Demographics Variables
Total
Number (%) Gestational age, wk 33-36 29-32 23-28 Race/ethnicity White Non-Hispanic 11 168 (52.85%) Black Non-Hispanic 6260 (29.62%) Other Non-Hispanic 2573 (12.18%) Hispanic 1132 (5.36%) Insurance Private 12 451 (58.92%) Medicaid 7182 (33.98%) Self-pay 1500 (7.1%) Male sex 10 662 (50.45%) Asthma 7126 (33.72%) CLD 141 (0.67%) Number of children receiving prescriptions 5-8 years Total 18 567 (87.86%) 5-6 years 14 232 (67.34%) 6-7 years 13 511 (63.93%) 7-8 years 12 627 (59.75%) Average number of prescriptions by age (mean SD) 5-8 years Total 7.22 9.97 5-6 years 2.55 3.95 6-7 years 2.45 4.01 7-8 years 2.22 3.86 2
Full term
95% CI
18 698 (88.48)
Preterm
95% CI
P value
2435 (11.52)
– – –
1845 (75.77%) 404 (16.59%) 186 (7.64%) <.0001
10 046 (53.73%) 5336 (28.54%) 2324 (12.43%) 992 (5.31%)
(53.01-54.44) (27.89-29.19) (11.96-12.91) (4.99-5.64)
1122 (46.08%) 924 (37.95%) 249 (10.23%) 140 (5.75%)
(44.11-48.06) (36.04-39.89) (9.08-11.49) (4.89-6.75)
11 205 (59.93%) 6175 (33.02%) 1318 (7.05%) 9450 (50.54%) 6070 (32.46%) 10 (0.05%)
(59.22-60.63) (32.35-33.70) (6.69-7.42) (49.82-51.26) (37.80-33.14) (0.02-0.01)
1246 (51.17%) 1007 (41.36%) 182 (7.47%) 1212 (49.77%) 1056 (43.37%) 131 (5.38%)
(49.18-53.15) (39.41-43.32) (6.49-8.59) (47.79-51.76) (41.41-45.35) (4.55-6.35)
.477 <.0001 <.0001
16 388 (87.65%) 12 496 (66.83%) 11 862 (63.44%) 11 083 (59.27%)
(87.17-88.11) (66.15-67.50) (62.75-64.13) (58.57-59.98)
2179 (89.49%) 1736 (71.29%) 1649 (67.72%) 1544 (63.41%)
(88.20-90.64) (69.46-73.06) (65.84-69.55) (61.48-65.30)
.0089 <.0001 <.0001 <.0001
(6.85-7.13) (2.42-2.52) (2.32-2.43) (2.10-2.20)
8.99 12.27 3.15 5.03 3.05 4.55 2.78 4.57
(8.50-9.47) (2.95-3.35) (2.86-3.24) (2.60-2.97)
<.0001 <.0001 <.0001 <.0001
<.0001
6.99 9.61 2.47 3.78 2.37 3.89 2.15 3.75
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Figure. Average number of prescriptions by demographic factors.
more likely to receive levetiracetam and children born at full term were more likely to receive oxcarbazepine (Table III; available at www.jpeds.com). Multivariate Results Controlling for socioeconomic status and CLD, prematurity was a significant predictor for medications at 5-8 years of age compared with children born at full term (IRR, 1.17; 95% CI, 1.1-1.24). When asthma was added into the model, prematurity remained a significant predictor for medications (IRR, 1.07; 95% CI, 1.01-1.13) (Table IV; available at www.jpeds. com). Children with asthma (IRR, 2.8; 95% CI, 2.56-3.05), CLD (IRR, 1.45; 95% CI, 1.2-1.74), Medicaid (IRR, 1.43; 95% CI, 1.36-1.51), and male sex (IRR, 1.05; 95% CI, 1.021.08) were more likely to receive prescriptions. Compared with non-Hispanic white infants, those who were Hispanic (IRR, 0.88; CI, 0.79-0.99) and other non-Hispanic (IRR, 0.88; CI, 0.83-0.93) were less likely to received prescriptions.
Discussion In this study using ambulatory records, children born preterm were more likely to receive medication prescriptions in the community setting between 5 and 8 years of age than children born at full term. Children born extremely preterm received the most medications; however, even those born at moderate or late gestational ages had higher use than those who were born at full term. The increased medication needs in young school age children included most therapeutic classifications of medications. Although a number of these medications were attributable to the respiratory complications of Medication Utilization at School Age for Children Born Preterm
asthma and CLD, children born preterm had needs that extended beyond respiratory-related medications. Even among children with a diagnosis of asthma, children born preterm averaged more medications than children born at full term. The need for asthma medications in early childhood by those born preterm has been the one area of medication use that has well documented for the preterm population. A recent systematic review and meta-analysis found preterm birth was associated with an increased risk of wheezing disorders in childhood, with those born at <32 weeks at greatest risk; however, moderately premature children also have been documented to have increased needs for respiratory medications in early childhood.3,7,15 Expanding on this, we explored whether the increased need for medication at school age was related to a diagnosis of CLD or asthma, or if simply being born preterm played a role in our results. We found that approximately 50% of the prematurity association with medication use in early childhood was related to a history of CLD, as well as asthma independent of having the diagnosis of CLD. Regardless of a history of CLD and asthma, preterm birth independently increased the receipt of medications in the majority of classifications. We found similarities in the types of medications prescribed to both children born preterm and children born at full term, although children born preterm were more likely to receive medications for issues related to gastrointestinal, central nervous system, cardiovascular, psychiatric, sleep, and nutritional needs. This finding is most likely reflective of the medical challenges children born preterm continue to face in early childhood and suggests an 3
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additional burden for children born preterm related to medication use at school age. We found that male children were more likely to receive prescriptions and those with Hispanic and other non-Hispanic ethnicities received fewer prescriptions. These findings are similar to a study of national pediatric prescriptions in which males were more likely to receive prescriptions from 6 to 12 years of age, mainly owing to a higher rate of chronic medications; and non-white and Hispanic children were less like to receive prescriptions.16 This racial/ethnic disparity in pediatric prescriptions has been documented for medications such as antibiotics, yet the reasons for this are not well-understood. Racial-ethic differences in parental expectation, implicit bias, access to care, and differences in a provider’s likelihood to treat are but a few potential drivers.17-21 We found that children with Medicaid insurance were more likely to receive prescriptions. Because children with asthma are more likely to be covered through Medicaid than those without asthma and children born preterm with CLD or asthma were more likely to receive prescriptions in our study, this may have influenced this finding.22 Because our focus was on medications used by children born preterm in the community setting as documented in the ambulatory electronic record, a limitation of our study is that our findings do not capture medications children may have received in other clinical settings such as urgent/ emergent care centers or inpatient settings or prescribed by providers outside of the system. In addition, we excluded those with significant non-prematurity-related neonatal conditions such as congenital anomalies to focus on the risk prematurity alone confers. Owing to these exclusions, our findings may underestimate the actual medication use of our cohort. Our cohort was limited to 1 large pediatric network and therefore may not be generalizable to other practice settings. However, this site has >30 urban, suburban, and rural sites in 2 states, providing a large diversity of patients to study. Our study showed that children born preterm continued to have higher medication use at 5-8 years of age than children born at full term. The range of medications, including most therapeutic classifications, suggests a diversity of prematurity-related needs that continue to challenge children born preterm in childhood and suggest a continuum of increased medication needs throughout their lifespan. n
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Submitted for publication Aug 6, 2019; last revision received Oct 30, 2019; accepted Nov 6, 2019. Reprint requests: Scott A. Lorch, MD, MSCE, The Children’s Hospital of Philadelphia, Division of Neonatology, 3401 Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected]
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Data Statement
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Data sharing statement available at www.jpeds.com.
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References
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1. Wade KC, Lorch SA, Bakewell-Sachs S, Medoff-Cooper B, Silber JH, Escobar GJ. Pediatric care for preterm infants after NICU discharge: 4
high number of office visits and prescription medications. J Perinatol 2008;28:696-701. Westrupp EM, Lucas N, Mensah FK, Gold L, Wake M, Nicholson JM. Community-based healthcare costs for children born low birthweight, preterm and/or small for gestational age: data from the Longitudinal Study of Australian Children. Child Care Health Dev 2014;40:259-66. Vrijlandt EJ, Kerstjens JM, Duiverman EJ, Bos AF, Reijneveld SA. Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term. Am J Respir Crit Care Med 2013;187:1234-40. Cuevas KD, Silver DR, Brooten D, Youngblut JM, Bobo CM. The cost of prematurity: hospital charges at birth and frequency of rehospitalizations and acute care visits over the first year of life: a comparison by gestational age and birth weight. Am J Nurs 2005;105:56-64. Houweling LM, Bezemer ID, Penning-van Beest FJ, Meijer WM, van Lingen RA, Herings RM. First year of life medication use and hospital admission rates: premature compared with term infants. J Pediatr 2013;163:61-6.e1. Crump C, Winkleby MA, Sundquist J, Sundquist K. Risk of asthma in young adults who were born preterm: a Swedish national cohort study. Pediatrics 2011;127:e913-20. Haataja P, Korhonen P, Ojala R, Hirvonen M, Paassilta M, Gissler M, et al. Asthma and atopic dermatitis in children born moderately and late preterm. Eur J Pediatr 2016;175:799-808. Castro-Rodriguez JA, Forno E, Rodriguez-Martinez CE, Celedon JC. Risk and protective factors for childhood asthma: what is the evidence? J Allergy Clin Immunol Pract 2016;4:1111-22. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830-8. Crump C, Winkleby MA, Sundquist J, Sundquist K. Gestational age at birth and risk of gastric acid-related disorders in young adulthood. Ann Epidemiol 2012;22:233-8. Crump C, Winkleby MA, Sundquist K, Sundquist J. Risk of diabetes among young adults born preterm in Sweden. Diabetes Care 2011;34: 1109-13. Crump C, Winkleby MA, Sundquist K, Sundquist J. Preterm birth and psychiatric medication prescription in young adulthood: a Swedish national cohort study. Int J Epidemiol 2010;39:1522-30. Crump C, Sundquist K, Winkleby MA, Sundquist J. Preterm birth and risk of epilepsy in Swedish adults. Neurology 2011;77:1376-82. Kluwer W. Medi-Span Generic Product Identifier (GPI) 2018. www. wolterskluwercdi.com/drug-data/gpi/. Accessed October 30, 2019. Been JV, Lugtenberg MJ, Smets E, van Schayck CP, Kramer BW, Mommers M, et al. Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis. PLoS Med 2014;11:e1001596. Qato DM, Alexander GC, Guadamuz JS, Lindau ST. Prescription medication use among children and adolescents in the United States. Pediatrics 2018;142:e20181042. Gerber JS, Prasad PA, Localio AR, Fiks AG, Grundmeier RW, Bell LM, et al. Racial differences in antibiotic prescribing by primary care pediatricians. Pediatrics 2013;131:677-84. Goyal MK, Johnson TJ, Chamberlain JM, Casper TC, Simmons T, Alessandrini EA, et al. Racial and ethnic differences in antibiotic use for viral illness in emergency departments. Pediatrics 2017;140:e20170203. Mangione-Smith R, Elliott MN, Stivers T, McDonald L, Heritage J, McGlynn EA. Racial/ethnic variation in parent expectations for antibiotics: implications for public health campaigns. Pediatrics 2004;113: e385-94. Blair IV, Steiner JF, Fairclough DL, Hanratty R, Price DW, Hirsh HK, et al. Clinicians’ implicit ethnic/racial bias and perceptions of care among Black and Latino patients. Ann Fam Med 2013;11:43-52. Flores G , Committee On Pediatric Research. Technical report–racial and ethnic disparities in the health and health care of children. Pediatrics 2010;125:e979-1020. CDC. Health. Care Coverage among Children 2016. www.cdc.gov/ asthma/asthma_stats/Health_Care_Coverage_among_Children.htm. Accessed October 30, 2019.
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Table II. Univariate analysis of therapeutic classifications prescribed between 5-8 years of age to children born preterm as compared with children born full term Classifications Analgesic Anti-infective Antineoplastic Cardiovascular Central nervous system Endocrine/metabolic Gastrointestinal Genitourinary Hematologic Miscellaneous Neuromuscular Nutritional Respiratory Topical
Rate Ratio, 95% CI
P value
1.45 (0.88-2.41) 1.09 (1.05-1.12) 1.56 (0.89-2.71) 1.58 (1.27-1.98) 1.33 (1.25-1.41) 1.41 (1.32-1.50) 1.57 (1.46-1.68) 2.28 (1.66-3.14) 1.14 (0.86-1.52) 2.34 (1.60-3.41) 2.03 (1.75-2.36) 1.07 (1.01-1.13) 1.48 (1.44-1.51) 1.13 (1.09-1.17)
.14 <.0001 .12 .0001 <.0001 <.0001 <.0001 <.0001 .36 <.0001 <.0001 .02 <.0001 <.0001
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Table III. Top 3 most common medications prescribed to preterm and children born at full term per therapeutic classification Classifications Analgesics Preterm Full term Anti-infectives Preterm Full term Antineoplastic Preterm Full term Cardiovascular Preterm Full term Central Nervous System Preterm Full term Endocrine/metabolic Preterm Full term Gastrointestinal Preterm Full term Genitourinary Preterm Full term Hematologic Preterm Full term Miscellaneous Preterm Full term Neuromuscular Preterm Full term Nutritional Preterm Full term Respiratory Preterm Full term Topical Preterm Full term
Most common
Less common
Least common
Naproxen Naproxen
Magic mouthwash Rizatriptan benzoate
Meloxicam Magic mouthwash
Amoxicillin Amoxicillin
Azithromycin Azithromycin
Amoxicillin-potassium clavulanate Amoxicillin-potassium clavulanate
Temozolomide Hydroxyurea
Irinotecan HCl Leuprolide acetate
Leuprolide acetate Procarbazine HCl
Guanfacine HCl Guanfacine HCl
Clonidine HCl Clonidine HCl
Enalapril maleate Amlodipine besylate
Methylphenidate HCl Methylphenidate HCl
Amphetamine-dextroamphetamine Amphetamine-dextroamphetamine
Dexmethylphenidate HCl Dexmethylphenidate HCl
Prednisolone sodium phosphate Prednisolone sodium phosphate
Prednisolone Prednisolone
Prednisone Prednisone
Polyethylene glycol Polyethylene glycol
Lansoprazole Ranitidine HCl
Ranitidine HCl Lansoprazole
Oxybutynin chloride Oxybutynin chloride
Estrogens, conjugated Estrogens, conjugated
Nitrofurantoin Nitrofurantoin
Folic acid Folic acid
Ferrous sulfate Ferrous sulfate
Pegfilgrastim Aminocarproic acid
Melatonin Melatonin
Azathioprine Mycophenolate mofetil
Deferasirox
Levetiracetam Oxcarbazepine
Oxcarbazepine Levetiracetam
Diazepam Lamotrigine
Pediatric multivitamins-Fl Pediatric multivitamins-Fl
Sodium fluoride Sodium fluoride
Multivitamin Multivitamin
Albuterol sulfate Albuterol sulfate
Fluticasone propionate HFA Fluticasone propionate HFA
Cetirizine HCl Cetirizine HCl
Hydrocortisone Hydrocortisone
Polymyxin B-trimethoprim Mupirocin
Ofloxacin Ofloxacin
HCI, hydrochloric acid.
Table IV. Multivariate analysis of predictors to medication prescription between 5 and 8 years of age SES and CLD Variables Preterm birth Race/ethnicity White Non-Hispanic Black Non-Hispanic Other Non-Hispanic Hispanic Insurance Private Medicaid Self-pay Male sex CLD Asthma
SES and asthma
SES, CLD, and asthma
RR (95% CI)
P value
RR (95% CI)
P value
RR (95% CI)
P value
1.17 (1.1-1.24)
<.0001
1.1 (1.04-1.16)
.0004
1.07 (1.01-1.13)
.017
* 1.11 (1.02-1.21) 0.88 (0.83-0.94) 0.93 (0.81-1.07)
*
* 1.01 (0.93-1.09) 0.88 (0.83-0.93) 0.88 (0.79-0.99)
*
.90 <.0001 .03
* 1.56 (1.48-1.65) 1.2 (0.97-1.48) 1.17 (1.13-1.21) 1.8 (1.49-2.16)
* <.0001 .086 <.0001 <.0001
* 1.43 (1.36-1.51) 1.07 (0.95-1.2) 1.05 (1.02-1.08) 1.45 (1.2-1.74) 2.8 (2.56-3.05)
* <.0001 .27 <.01 <.001 <.0001
.02 <.001 .33
* 1.01 (0.93-1.09) 0.88 (0.83-0.93) 0.88 (0.78-0.99)
*
* 1.44 (1.36-1.51) 1.07 (0.95-1.2) 1.05 (1.02-1.08)
* <.0001 .27 .003
2.81 (2.57-3.06)
<.0001
.89 <.0001 .03
SES, socioeconomic status. *Reference Group
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