Intrauterine Substance Exposure and the Risk for Subsequent Physical Abuse Hospitalizations

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Intrauterine Substance Exposure and the Risk for Subsequent Physical Abuse Hospitalizations Henry T. Puls MD , James D. Anderst MD, MSCI , Karen Farst MD, MPH , Matthew Hall PhD PII: DOI: Reference:

S1876-2859(20)30056-5 https://doi.org/10.1016/j.acap.2020.02.002 ACAP 1479

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Academic Pediatrics

Received date: Accepted date:

20 September 2019 1 February 2020

Please cite this article as: Henry T. Puls MD , James D. Anderst MD, MSCI , Karen Farst MD, MPH , Matthew Hall PhD , Intrauterine Substance Exposure and the Risk for Subsequent Physical Abuse Hospitalizations, Academic Pediatrics (2020), doi: https://doi.org/10.1016/j.acap.2020.02.002

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Intrauterine Substance Exposure and the Risk for Subsequent Physical Abuse Hospitalizations Henry T. Puls, MD,a James D. Anderst, MD, MSCI,b Karen Farst, MD, MPH,c Matthew Hall, PhD,a,d Affiliations: Divisions of aHospital Medicine and bChild Adversity and Resilience, Department of Pediatrics, Children’s Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; Section for Children at Risk, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; dChildren’s Hospital Association; Lenexa, Kansas Corresponding Author: Henry T. Puls MD, Division of Hospital Medicine, Children’s Mercy Hospitals, 2401 Gillham Road, Kansas City, MO 64108, [email protected], Phone 816-302-3262, Fax 816-302-9729. Keywords: neonatal abstinence syndrome; narcotic; opiate; cocaine; alcohol; child physical abuse; abusive head trauma Word Counts: abstract= 250; main text= 3098 Abbreviations: substance exposed infants (SEI); neonatal abstinence syndrome (NAS); adjusted relative risks (aRR); confidence intervals (CI); Nationwide Readmissions Databases (NRD); International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) Funding source: This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors. Financial disclosure: Authors do not have financial relationships to report. Conflict of Interest: The authors have no conflicts of interest relevant to this article to disclose. Contributor Statements: Dr. Puls conceptualized and participated in the study design, interpretation of data, and was the primary author of the manuscript. Drs. Anderst and Farst participated in the study design and interpretation of data. Dr. Hall participated in the study design, and acquisition, analysis and interpretation of data. All authors provided critical revision of the manuscript and approved the final version.

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ABSTRACT: Objectives: To describe the relative risk for a physical abuse hospitalization among substance exposed infants (SEI) with and without neonatal abstinence syndrome (NAS).

Methods: We created a nationally representative U.S. birth cohort using the 2013 and 2014 Nationwide Readmissions Databases. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify newborns, predictor variables, and subsequent hospitalizations for physical abuse within 6 months of discharge from newborns’ birth hospitalization. Predictor variables included newborn demographics, prematurity or low birth weight, and intrauterine substance exposure: non-SEI, SEI without NAS, and SEI with NAS. Multiple logistic regression calculated adjusted relative risks (aRR) and 95% confidence intervals (CI). A sub-analysis of newborns with narcotic exposure was performed.

Results: There were 3,740,582 newborns in the cohort; of which 13,024 (0.4%) were SEI without NAS and 20,196 (0.5%) SEI with NAS. Overall, 1,247 (0.03%) newborns were subsequently hospitalized for physical abuse within 6 months. Compared to non-SEI, SEI with NAS (aRR: 3.84 [95% CI: 2.79-5.28]) were at increased risk for having a subsequent hospitalization for physical abuse, but SEI without NAS were not. A similar pattern was observed among narcotic-exposed infants; infants with NAS due to narcotics were at increased risk, but narcotic-exposed infants without NAS were not.

Conclusions: Our results suggest that newborns diagnosed with NAS are at increased risk of physical abuse during early infancy, above that of substance-exposed infants without NAS.

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These results should improve the identification of higher-risk infants who may benefit from more rigorous safety planning and follow-up care.

What’s New: We provide new information on the association between intrauterine substance exposure, uniquely stratified by neonatal abstinence syndrome, and infants’ risk for physical abuse. Abstinence syndrome was a risk factor for physical abuse, above that of substance exposure without abstinence syndrome.

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INTRODUCTION: Newborn infants have increasingly been exposed in utero to licit and illicit substances. The Substance Abuse and Mental Health Services Administration reported that 1.4% of pregnant U.S.

women abused prescription opiates and 0.6% used cocaine, heroin, hallucinogens, or methamphetamines in 2017.1 An estimated 2% of Medicaid-enrolled women in Pennsylvania received medication-assisted treatment for opiate use disorder during pregnancy.2 Not surprisingly, rates of neonatal abstinence syndrome (NAS) have increased. 3,4 NAS is a clinical diagnosis resulting from the abrupt cessation of fetal exposure to substances with the potential for physiologic dependence.5 NAS is most often secondary to narcotics/opiates (also known as neonatal opioid withdrawal syndrome), but NAS has also been associated with antidepressant medications, benzodiazepines, amphetamines, and inhalants.5

Substance use disorders are characterized by physiologic tolerance and withdrawal, cycles of recovery and relapse, as well as social/interpersonal/legal problems and neglect of major responsibilities.6 Pregnancy and the postpartum period can be particularly challenging times for women with substance use disorders, impacting both their well-being and their fetus.7-9 Intrauterine substance exposure and NAS have been associated with higher rates of prematurity and low birth weight as well as significant burdens and economic costs for the health care and child welfare systems.3,4,10,11 Substance exposed infants (SEI) represent populations at greater risk for child abuse and neglect in general (henceforth maltreatment),12 but their risk for physical abuse, specifically, is less clear. 13-16 A better delineation of which SEI are at the greatest risk for physical abuse may better inform prevention and safety planning by the health care and child protection systems.

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Using a nationally representative U.S. birth cohort, we sought to describe the relative risk of a hospitalization for physical abuse during early infancy among SEI with and without NAS. We hypothesized that SEI with NAS would represent a population with higher levels of risk for physical abuse compared to non-SEI and SEI without NAS. Given the scope of the opioid public health crisis in the U.S.,17 we also performed a sub-analysis of narcotic-exposed newborns with and without NAS.

METHODS This was a retrospective nationally representative birth cohort study. Data from the 2013 and 2014 Nationwide Readmissions Databases (NRD) were used to identify newborns, classify their intrauterine substance exposure and NAS status, and then track them for a physical abuse hospitalization. The NRD is part of the Healthcare Cost and Utilization Project’s family of nationwide databases and provides weighted estimates of hospital discharges to allow U.S. national-level readmission analyses for all payers and the uninsured. The NRD contains deidentified International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9CM) discharge codes and patient demographics. Linkage numbers allow tracking of patients for readmissions across hospitals within a state, but only within a single database year. This study was deemed exempt from institutional board review, due to non-human subjects determination by the Office of Research Integrity at Children’s Mercy Kansas City.

Study Population

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The birth cohort was identified using ICD-9-CM codes for all liveborn infants who are consuming health care, including simple hospital occupancy (V30-V39). Newborns with inhospital mortality during their birth hospitalization were excluded. Since patients cannot be tracked between NRD database years, inclusion in the birth cohort was limited to January 1 st through June 30th for each database year. The second 6 months of each database year served as the window for the outcome. Essentially, this created a 12-month birth cohort and allowed all newborns to have a uniform 6-month follow-up period. Weighted counts of newborns, reflective of the total U.S. population, were used in all analyses.

Predictor Variables All data for the predictor variables were collected from the birth hospitalizations. The primary predictor variable was newborns’ category of intrauterine substance exposure: non-SEI, SEI without NAS, and SEI with NAS. SEI without NAS were defined as those newborns with an ICD-9-CM code for intrauterine exposure to: drugs not elsewhere classified (760.70), alcohol/fetal alcohol syndrome (760.71), narcotics (760.72), hallucinogenic agents (760.73), or cocaine (760.75). ICD-9-CM codes identifying iatrogenic intrauterine drug exposures (e.g., antiepileptics) were not included. SEI with NAS were defined as those newborns with the ICD-9CM code for drug withdrawal syndrome (779.5). SEI with NAS could also have an ICD-9-CM code for a specific substance exposure, but this was not required to qualify as a case of NAS. This method of identifying SEI with NAS has been shown to be highly accurate (88% sensitivity, 97% specificity, 91% positive predictive value, and 95% negative predictive value).18,19 Other predictor variables included: newborns’ sex and insurance payer type, the median household income for newborns’ ZIP code of residence, the urban-rural category of newborns’ county of

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residence, whether newborns’ were premature or low birth weight, and length of stay for the birth hospitalizations. Urban-rural categories included: 1) dense central metropolitan (counties containing the majority of a metropolitan statistical area with a population >1 million), 2) fringe or small metropolitan (counties in metropolitan statistical areas with populations <1 million), 3) micropolitan (counties outside metropolitan statistical areas containing a town with a population 10,000-49,999), and 4) rural (counties with towns with 0-9,999 persons).20 These predictor variables were obtained from NRD demographic fields or identified using previously described ICD-9-CM codes.13

Outcome Variable All newborns were tracked for 6 months after discharge from their birth hospitalization for any hospitalization for physical abuse. Abuse hospitalizations were identified using a previously validated coding scheme where hospitalizations qualified as cases of physical abuse if they had an ICD-9-CM code for abuse, shaken infant syndrome, or assault and an ICD-9-CM code for an injury, retinal hemorrhages or anoxic brain injury.21,22 For those infants who were subsequently hospitalized for physical abuse, we reported the frequencies of their different types of abusive injuries.

Statistical Analysis Frequencies of abuse hospitalizations among the birth cohort were calculated. Chi-square tests were used in bivariate analyses. Multiple logistic regression modeling calculated the adjusted odds for any abuse hospitalization which were then converted to adjusted relative risk (aRR) ratios with 95% confidence intervals (CI) given the extremely rare nature of abuse

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hospitalizations.23 Given that opiates are the most common cause of NAS and an area currently receiving considerable attention from a public health standpoint, we performed a sub-analysis of infants with documented narcotics exposures, again using multiple logistic regression modeling to calculate aRR and 95% CI. For infants to be included in this sub-analysis they had to have received a code for narcotics exposure (760.72). This sub-analysis did not enable comparison of risk between substances; rather it tested our hypothesis that NAS confers greater risk for physical abuse above simple substance exposure specifically among infants with documented narcotics exposure. Non-SEI served as the control group for both the main analysis and the sub-analysis of infants with documented narcotics exposure. Only covariates with a P value <0.1 in bivariate analyses were used as covariates in the regression modeling. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Inc, Cary, NC) with a P value < 0.05 being considered statistically significant.

RESULTS: There were 3,740,582 newborns included in the birth cohort, with 33,220 (0.9%) having had intrauterine substance exposure. Of these SEI, 13,024 (39.2%) did not have NAS and 20,196 (60.8%) did have NAS. Overall, 45.8% of newborns had public insurance, 52.1% lived in dense central metropolitan counties, 9.4% were preterm or low birth weight, and 87.8% of their birth hospitalizations were 1-3 days in duration (Table 1). There were 1247 (0.03%) newborns who were subsequently hospitalized for physical abuse within 6 months of being discharged from their birth hospitalization.

Exposure to Individual Substances

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For the 13,024 SEI without NAS, 59.3% were coded for narcotics, 16.5% for cocaine, 10.4% for a hallucinogenic, 3.7% for alcohol, and 13.9% received a code for drugs not elsewhere classified (total >100% given that the groups were not mutually exclusive). Of the 20,196 SEI with NAS, the majority (84.4%) were not coded for a specific substance exposure; 13.3% were coded for narcotics, 1.6% cocaine, and <1% each for a hallucinogenic and alcohol.

Differences Between Non-SEI, SEI without NAS, and SEI with NAS SEI with NAS (0.2%, 95% CI: 0.1-0.3%) and SEI without NAS (0.08%, 95% CI: 0.03-0.13%) were more often hospitalized for physical abuse compared to non-SEI (0.03%, 95% CI: 0.030.03%; p<0.001; Figure 1). SEI with and without NAS were more often insured by a public payer and premature or low birth weight compared to non-SEI (p<0.001 for both). There were statistically significant differences between the substance exposure groups in sex, median household income for ZIP code, and the urban-rural category of their county of residence, but these were small in magnitude. The median length of stay for the birth hospitalizations was significantly longer among SEI with NAS (12 days [interquartile range: 5, 22]) compared to SEI without NAS (3 days [interquartile range: 2, 6]) and non-SEI (2 days [interquartile range: 2, 3]; p<0.001).

Multiple Logistic Regression Modeling Compared to the 3,707,362 non-SEI, SEI with NAS were at increased risk for a subsequent physical abuse hospitalization (aRR: 3.84 [95% CI: 2.79-5.28]), but SEI without NAS were not (Table 2). Male infants (aRR 1.21 [95% CI: 1.08, 1.35]), infants with public insurance (aRR

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3.17 [95% CI: 2.75, 3.66]), and infants born premature or low birth weight (aRR 2.22 [95% CI: 1.93, 2.55]) were independently at increased risk for a physical abuse hospitalization.

Sub-Analysis of Narcotic-Exposed Infants There were 10,407 newborns with documented narcotics exposure; of which 74.2% did not have NAS and 25.8% did have NAS. Compared to the 3,707,362 non-SEI, only narcotic-exposed infants with NAS were more frequently hospitalized for physical abuse (0.4%, 95% CI: 0.2-0.6% vs. 0.03%, 95% CI: 0.03-0.03%; p<0.001; Figure 1). In adjusted analyses, narcotics-exposed infants without NAS were not at increased risk for a physical abuse hospitalization, but narcotics-exposed infants with NAS were at increased risk (aRR: 7.55 [95% CI: 4.14-13.77]). The associations between the other predictor variables and the risk for physical abuse hospitalizations among narcotics-exposed infants was otherwise essentially identical to that observed among the full birth cohort (Table 2).

Injuries at the Subsequent Physical Abuse Hospitalizations For the 1,247 newborns subsequently hospitalized for physical abuse, they were diagnosed with traumatic brain injuries (50.4%), fractures (49.8%), skin injuries (28.1%), abdominal injuries (1.8%), burns (1.4%), and other injuries (5.7%) (total >100% given that the groups were not mutually exclusive).

DISCUSSION: Using a nationally representative birth cohort of 3.7 million newborns, we examined the relative risk of a hospitalization for physical abuse during early infancy among SEI with and without

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NAS. In bivariate analysis, we found that both SEI with and without NAS were more frequently hospitalized for physical abuse during early infancy compared to non-SEI. In adjusted analyses, SEI with NAS remained at increased risk for physical abuse. Somewhat surprisingly however, we found that SEI without NAS were not at increased risk after adjustment. When examining only infants with documented narcotics exposure, a similar pattern of adjusted risk was observed. Again, compared to non-SEI, narcotic-exposed infants with NAS were at elevated risk for physical abuse, but infants with narcotic exposures without NAS were not. Collectively, these results indicate that NAS may be an indicator of risk for future physical abuse, above that of simple intrauterine substance exposure without symptoms of withdrawal. These results should prove useful for identifying which newborns may be at the greatest risk for physical abuse and aid in the development of safe discharge plans for newborns.

Despite the realistic expectation that many SEI with NAS in our study would have received support services or even out-of-home placement, our results indicate that they were still at increased risk of being hospitalized for physical abuse, independent of prematurity and low birth weight and proxy measures for individual- and community-level poverty. These results appear to suggest that the existing systems of intervention for newborns with NAS in the U.S. are ineffective at reducing the risk for subsequent physical abuse to baseline levels. Our findings conflict with Uebel et al, who did not detect an increased risk for physical abuse among Australian newborns with NAS,16 but were similar to findings from a retrospective Washington state birth cohort study which showed that newborns with NAS were 4.5 times (95% CI: 1.2, 17.2) more likely to be hospitalized with abusive injuries or neglect compared to non-substance exposed infants in the first 5 years of life.24 Prindle et al did not report on physical abuse

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outcomes specifically, but among SEI in California they did identify that compared to SEI without NAS, newborns diagnosed with NAS had higher rates of subsequent substantiated maltreatment and receipt of out-of-home placement.12

Our results support our hypothesis that newborns with NAS would be at increased risk for abuse compared to non-SEI and SEI without NAS. This may be the case for a couple reasons. First, the heavier, more frequent, and third trimester substance use that increases newborns’ risk of developing NAS may directly contribute to or reflect impaired parental decision-making, or may correlate with impulsivity, violence, and other risk factors for abuse, such as mental illness.5,18 Alternatively, infant temperament related to withdrawals or impaired parent-newborn bonding during longer newborn hospitalizations may be possible mechanisms. Many hospitals have initiated practices and procedures (e.g., the Eat, Sleep, Console protocol) that have been shown to decrease newborns’ length-of-stay and need for pharmacologic treatment, but evidence for their impacts on maternal-infant bonding and reducing physical abuse are largely unknown. 25,26 Regardless, our results appear to indicate that compared to other newborns, including other SEI not diagnosed with NAS, newborns with NAS should demand greater maternal/family/foster parent support as well as stricter safety plans prior to being discharged home from their birth hospitalization.

The evidence is substantial and consistent that parental substance use, including maternal substance use during pregnancy, is associated with maltreatment.12,15,27-29 However, while we found that SEI without NAS were subsequently hospitalized for physical abuse more often compared to non-SEI, they were not at increased risk in adjusted analyses. Among studies likely

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powered to specifically detect physical abuse outcomes, our findings are in contrast with parental self-reporting of substance use and physical abuse behaviors but in agreement with a casecontrol study of abusive head trauma cases in New Zealand which found that SEI were not at increased risk for abusive head trauma after accounting for other confounding factors.14,15 These discrepancies may be a function of the different severities of physical abuse outcomes between studies; that is intrauterine substance exposure not resulting in NAS may increase the risk for neglect and less severe forms of physical abuse, as measured by parental self-report and reports to child protective services, but may not increase the risk for more severe cases of physical abuse, such as abusive head trauma or cases requiring hospitalization. Alternatively, given that there is a high degree of variability in newborn drug testing in clinical practice and our study likely under-identified SEI without NAS, our findings may be prone to selection bias.30 However, because drug testing is often risk-based, it may be reasonable to expect that our results would be more prone to amplify any association with abuse and not push our results towards the null. These findings, we believe, warrant further study.

Our sub-analysis comparing only those infants with documented narcotic exposures to non-SEI appeared to confirm the results of our main analysis. That is, infants born to mothers with narcotic use sufficient enough to cause NAS were at greater risk for physical abuse, above that of non-SEI and infants with documented narcotics exposures without NAS. While our sub-analysis of narcotic-exposed infants appears to suggest that their risk may be higher than all infants with NAS from any substance in our main analysis, we caution against this comparison due to the limitations of our data. Namely, that the vast majority of infants with NAS did not have a

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specific substance of exposure documented, indicating that many infants with true narcotic/opiate-related NAS in our main analysis were not included in the sub-analysis, creating the potential for misclassification bias. Despite these limitations, our sub-analysis also appears to support our hypothesis that NAS confers additional risk for physical abuse above that of intrauterine substance exposure not resulting in withdrawal.

Although our study provides new information concerning the association between intrauterine substance exposure (uniquely stratified by NAS-status) and infants’ risk for physical abuse, there are at least 4 categories of limitations to take into consideration. First is that our data source lacks information on many of the psychosocial factors that confound infants’ risk for abuse, such as household composition, violence in the home, and mental illness among caregivers. Perhaps most salient to this study’s primary aim, we were not able to account for which newborns were reported to child protective services or received out-of-home placement during our study period. Second, there are limitations specifically related to our administrative data. ICD-9-CM discharge codes have good specificity (>90%) for the identification of hospitalizations for physical abuse, but their sensitivity (~75%) indicates that some abuse hospitalizations were likely missed. 22 Similarly, while ICD-9-CM codes are highly accurate for identifying infants with NAS, 18,19 prior validation studies were conducted in a single state, Tennessee, and potential coding variability elsewhere could have biased our sample. Codes for SEI without NAS have not been validated and our results suggest that we almost certainly did not identify all SEI without NAS. Additionally, the majority of infants with NAS did not receive a diagnosis for a specific substance of exposure, making it difficult for us to universally characterize our populations by substance type and possibly inflating the association between NAS due to narcotics and physical

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abuse seen in our sub-analysis. Third, we could not characterize the nature of infants’ narcoticexposures. That is, which exposures were due to illicit narcotic use, prescription opioid misuse, or which were from legitimate prescriptions for medical conditions or prescribed as medicationassisted treatment for opioid use disorder. Finally, data structure limited our window of tracking for physical abuse hospitalizations to 6 months. This may have biased our results if physical abuse had a seasonal pattern. Also, associations between SEI and NAS categories and physical abuse may differ if we were able to investigate a longer follow up period.

CONCLUSIONS: While concerns for neglect and ongoing parental substance use remain salient for all SEI, our results appear to indicate that newborns diagnosed with NAS are a population uniquely at risk for physical abuse, above that of SEI who are not diagnosed with withdrawal symptoms. These results should prove valuable for health care providers’ and child protection authorities’ efforts at identifying which SEI may benefit from more rigorous safety planning and follow up care. Further study is needed to determine how substance type, severity of maternal substance misuse/abuse, legality of maternal opioid use, maternal engagement in treatment, and substance use among other caregivers may change our findings.

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Figure 1. Unadjusted percent (95% confidence intervals) of newborns with a subsequent hospitalization for physical abuse within 6 months of being discharged from their birth hospitalization.

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Table 1. Characteristics of the Birth Cohort at the Time of Their Newborn Hospitalization. N (column % unless otherwise noted).a,b Substance Exposure Category Patient Characteristics Total (row %) Sex Male Insurance Payer Type Public Private Other Median household income for ZIP code of residence Lowest Below average Above average Highest

Overall

Non-SEI

SEI without NAS

SEI with NAS

3740582

3707362 (99.1)

13024 (0.4)

20196 (0.5)

1917493 (51.3)

1899611 (51.2)

6712 (51.5)

11170 (55.3)

1714906 (45.8) 1771891 (47.4) 253784 (6.8)

1688258 (45.5) 1767660 (47.7) 251444 (6.8)

10408 (79.9) 1434 (11) 1182 (9.1)

16241 (80.4) 2796 (13.8) 1159 (5.7)

875150 (23.7) 955552 (25.9) 1019462 (27.6) 843987 (22.8)

865958 (23.7) 946270 (25.8) 1010719 (27.6) 838523 (22.9)

4468 (34.8) 3900 (30.4) 3007 (23.4) 1451 (11.3)

4724 (23.8) 5383 (27.1) 5735 (28.9) 4013 (20.2)

Urban-rural category of newborns' county of residence 1931701 (52.1) 6202 (47.6) Dense central metropolitan 1949082 (52.1) 1239826 (33.4) 4731 (36.3) Fringe or small metropolitan 1250554 (33.4) 326797 (8.8) 1465 (11.3) Micropolitan 330137 (8.8) 209039 (5.6) 625 (4.8) Rural 210808 (5.6) 342155 (9.2) 4006 (30.8) Preterm or low birth weight 351544 (9.4) Length of stay (days) 3275872 (88.4) 6679 (51.3) 1-3 3285022 (87.8) 261523 (7.1) 3572 (27.4) 4-7 269654 (7.2) 169967 (4.6) 2773 (21.3) 8+ 185906 (5.0) Length of stay (days; median 2 [2, 3] 2 [2, 3] 3 [2, 6] [IQR])c Substance exposed infants (SEI); neonatal abstinence syndrome (NAS); interquartile range (IQR). a

Chi-square tests used unless otherwise noted.

b

All comparisons were significant at p<0.001.

c

Kruskal-Wallis test compared medians.

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11179 (55.4) 5998 (29.7) 1875 (9.3) 1144 (5.7) 5383 (26.7) 2471 (12.2) 4558 (22.6) 13166 (65.2) 12 [5, 22]

Table 2. Adjusted Relative Risk Ratios (95% Confidence Intervals) for Newborn Infants Having a Subsequent Hospitalizations for Physical Abuse within 6 Months of Being Discharged from Their Newborn Hospitalizations. a Newborn Populations Patient Characteristics

Full Birth Cohortb aRR (95% CI)

Narcotic Exposure Onlyc p

aRR (95% CI)

p

Drug exposure None SEI without NAS SEI with NAS

Reference 1.48 (0.81, 2.71) 3.84 (2.79, 5.28)

Reference 0.20 <0.001

0.90 (0.32, 2.50) 7.55 (4.14, 13.77)

0.84 <0.001

Sex Male Female Insurance Payer Type Public Private Other

1.21 (1.08, 1.35) Reference

0.001

1.22 (1.09, 1.37) Reference

0.001

3.17 (2.75, 3.66) Reference

<0.001

3.15 (2.73, 3.64) Reference

<0.001

1.69 (1.30, 2.20)

<0.001

1.72 (1.32, 2.24)

<0.001

1.31 (1.07, 1.60)

0.009 0.004 <0.001

1.37 (1.12, 1.68)

0.003 0.001 <0.001

0.95 (0.73, 1.22) 1.15 (0.89, 1.49) 1.36 (1.02, 1.82) Reference

0.67 0.28 0.03

1.02 (0.78, 1.33) 1.17 (0.90, 1.53) 1.46 (1.09, 1.96) Reference

0.90 0.24 0.01

2.22 (1.93, 2.55) Reference

<0.001

2.18 (1.89, 2.52) Reference

<0.001

Median household income for ZIP code of residence Lowest Below average Above average Highest

1.34 (1.10, 1.63) 1.50 (1.24, 1.82) Reference

1.40 (1.14, 1.72) 1.57 (1.29, 1.91) Reference

Urban-rural category of newborns' county of residenced Dense central metropolitan Fringe or small metropolitan Micropolitan Rural Preterm or low birth weight Yes No

Adjusted relative risk (aRR); confidence interval (CI); substance exposed infant (SEI); neonatal abstinence syndrome (NAS). a

All demographic and clinical variables with P< 0.1 in bivariate analyses were included in the models.

b

All 33,220 SEI with and without NAS were included with the 3,707,362 non-SEI serving as controls.

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c

Only the 10,407 newborns with a narcotics exposure, with or without NAS were included, with all 3,707,362 nonSEI serving as controls. The National Center for Health Statistics Urban-Rural Classification Scheme was used to categorize newborns’ county of residence and included: 1) dense central metropolitan (counties containing the majority of a metropolitan statistical area with a population >1 million), 2) fringe or small metropolitan (counties in metropolitan statistical areas with populations <1 million), 3) micropolitan (counties outside metropolitan statistical areas containing a town with a population 10,000-49,999), and 4) rural (counties with towns with 0-9,999 persons). d

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