BACKGROUND:

Health administrative data offer a vital source of data on maternal prenatal opioid exposure (POE). The impact of different methods to estimate POE, especially combining maternal and newborn records, is not known.

METHODS:

This population-based cross-sectional study included 454 746 hospital births with linked administrative data in Ontario, Canada, in 2014–2017. POE ascertainment included 3 sources: (1) prenatal opioid prescriptions, (2) maternal opioid-related hospital records, and (3) newborn hospital records with neonatal abstinence syndrome (NAS). Positive percent agreement was calculated comparing cases identified by source, and a comprehensive method was developed combining all 3 sources. We replicated common definitions of POE and NAS from existing literature and compared both number of cases ascertained and maternal socio-demographics and medical history using the comprehensive method.

RESULTS:

Using all 3 data sources, there were 9624 cases with POE (21.2 per 1000 births). Among these, positive percent agreement (95% confidence interval) was 79.0% (78.2–79.8) for prenatal opioid prescriptions, 19.0% (18.2–19.8) for maternal opioid-related hospital records, and 44.7% (43.7–45.7) for newborn NAS. Compared with other definitions, our comprehensive method identified up to 523% additional cases. Contrasting ascertainment with maternal opioid-related hospital records, newborn NAS, and prenatal opioid prescriptions respective rates of maternal low income were 57%, 48%, and 39%; mental health hospitalization history was 33%, 28%, and 17%; and infant discharge to social services was 8%, 13%, and 5%.

CONCLUSIONS:

Combining prenatal opioid prescriptions and maternal and newborn opioid-related hospital codes improves identification of a broader population of mothers and infants with POE.

What’s Known on This Subject:

Opioid use in pregnancy is a major public health concern in North America. Health administrative data play a role in analyzing long-term health effects of prenatal opioid exposure (POE). Current methods of identifying exposure vary with important implications for findings.

What This Study Adds:

Data availability and linkage have an important impact on POE estimation. Opioid-related hospitalization data alone underestimates POE by almost 50% and results in a socially and medically higher-risk group of mothers than with the addition of pregnancy prescription data.

Opioid use in pregnancy is a major public health concern in North America.14  Women who use opioids during pregnancy are more likely to have social, economic, and environmental disadvantage and concurrent mental illness, polysubstance use, and chronic medical conditions that can compound the risk of drug effects.59  Opioid use during pregnancy is associated with increased health care costs1,4  and adverse maternal and neonatal outcomes1017 ; however, long-term child and maternal health effects are not well understood and have been identified as research priorities.18,19 

Public health surveillance and epidemiological research are needed to monitor opioid use in pregnancy and study long-term health outcomes in children to inform preventive interventions and support healthy child development.20,21  Health administrative data are attractive in availability and population-based nature; however, they pose measurement challenges. For example, jurisdictional differences exist in definitions of opioid use in pregnancy and neonatal abstinence syndrome (NAS), often used as a proxy for neonatal opioid withdrawal syndrome, on the basis of data availability, and ability to link across data sources, health care episodes, and mother–newborn dyads.20,21  Limitations are also introduced with study populations restricted to recipients of publicly funded health care benefits that typically serve people with lower incomes, such as Medicaid programs in the United States or public prescription drug benefits in Ontario.1,11  Various measures have been used to estimate prenatal opioid exposure (POE), defined in this study as maternal administration of opioids and/or fetal exposure to opioids in pregnancy (Supplemental Table 5), including NAS. NAS is a postnatal withdrawal condition that commonly follows intrauterine exposure to opioids. Although NAS is the focus of an important growing body of evidence, it is also used as an indirect marker of maternal opioid use.16  NAS is identified by using International Classification of Diseases (ICD) codes from newborn hospitalization records; however, ICD diagnostic codes vary by surveillance system and study.22 

To date, no studies have quantified the impact of different methods of measuring opioid use in pregnancy on POE estimation or explored maternal characteristics in relation to POE definitions. We are in a unique position in Ontario, Canada, with a universal publicly funded health care system for all legal residents and access to rich linked population-based health administrative data, including all prescription opioid use, hospital care for mother-newborn dyads, and other socio-demographics. The objectives with this study were to describe differences in the ascertainment of births with POE and maternal characteristics by different methods among all hospital births in Ontario from 2014 to 2017. Study findings can inform the design of rigorous longitudinal research using health administrative data to study the effects and mechanisms of POE, including postnatal exposures, on child health and development.

In this population-based cross-sectional study, we used linked health and demographic administrative data obtained from ICES. ICES is an independent, nonprofit research institute whose legal status under privacy law allows it to collect and analyze health and demographic data, without consent, for health system evaluation. Data sets were linked by using unique encoded identifiers. Study data sets are detailed in Supplemental Table 6 and described elsewhere.2326  Ethics approval was granted from the University of Toronto and Hospital for Sick Children research ethics boards. We followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 27  and Reporting of Studies Conducted Using Observational Routinely-Collected Data (RECORD)28  reporting guidelines.

We included all hospitalizations for a livebirth or stillbirth among women aged 12 to 50 years, in Ontario, Canada, in 2014–2017. Ontario has an estimated population of 14 million29  and ∼140 000 births annually, 97% of which occur in a hospital.30  Women were included who had continuous eligibility for Ontario’s public health insurance during pregnancy and <100 days of ineligibility in the 2 years preconception.31  Ineligibility could arise from relocation or recent immigration to Ontario. Included were stillbirths starting at 20 weeks' gestation32  and livebirths between 23 and 42 weeks' gestation.33  To restrict our cohort to clinically meaningful opioid use, we excluded women with 1 to 10 cumulative days of opioid analgesic use during pregnancy and those with opioids prescribed only for cough. The 10-day threshold corresponded to the 75th percentile of the distribution of opioid analgesic use in pregnancy among the study cohort and was made by expert opinion through consensus among a pediatrician (A.G.), high-risk pregnancy internist (J.G.R.), and expert in pharmaceutical use (T.G.). Infants with iatrogenic NAS were identified by using International Classification of Diseases, 10th Revision (ICD-10) P96.2 (withdrawal symptoms from therapeutic use of drugs in newborn), in addition to previously published methods,34  and excluded.

A comprehensive measure of POE was developed by using 3 ascertainment methods including prenatal prescription opioid data, maternal opioid-related hospital records, and newborn hospital records with NAS (Supplemental Table 6). First, prenatal prescription opioid use during pregnancy was identified and categorized as opioid analgesics for pain and opioid agonist therapy (OAT) for opioid use disorder (OUD). Second, we identified maternal opioid-related hospital records (hospitalizations and emergency department [ED] visits) during pregnancy using ICD-10 diagnostic codes for mental and behavioral disorders due to opioid use, opioid poisoning, or opioid-related adverse drug reactions. Last, as in previous work, POE was identified among neonates in the newborn birth episode or infant hospital readmission during the first 14 days of life by using ICD-10 diagnostic codes for NAS P96.1 (withdrawal from maternal drugs of addiction) or P04.4 (infant affected by maternal drugs of addiction).16,35  The use and validity of ICD-10 codes to identify NAS was previously described.16 

To compare and contextualize the measure of POE developed herein, we replicated existing measures of maternal opioid use and NAS, as described in studies with administrative data (Supplemental Table 5). Existing measures included types of prenatal prescription opioid use, OUD ascertained from maternal hospital records, and NAS from newborn hospital records.

Additional variables characterized women by ascertainment method, many used and validated elsewhere (Supplemental Table 6). Socio-demographic variables were maternal age at first36  and current birth, area-level low income (quintile 1),37  rural residence (<10 000 inhabitants), immigrant status, and previous livebirths. Indicators of maternal social risk were receiving medical care while in the criminal justice system, health care related to violence or homelessness, receipt of social assistance for prescriptions, and newborn apprehension at birth hospitalization.38  Maternal substance use included hospital care related to tobacco, alcohol, opioid, or nonopioid and/or multidrug use. Mental health and addiction-related hospital care included any ED visit or hospitalization.39  Preconception morbidity included chronic pain conditions (low back, joint, migraine or headache, rheumatoid arthritis,40  fibromyalgia, joint pain, chronic pancreatitis, peripheral neuropathy, sickle cell disease and renal calculus),11,41  and common chronic conditions from validated registries (diabetes,42,43  hypertension,43,44  asthma45 ). Johns Hopkins ACG System Aggregated Diagnosis Groups (v10) scores of 10+ were used to describe significant medical comorbidities. Measures of appropriate access to care included ultrasound by 20 weeks38  and first trimester prenatal care by a physician. We describe common delivery and newborn characteristics to allow comparisons with other jurisdictions.

Data Analyses

We calculated positive percent agreement (PPA), analogous to sensitivity in the absence of a gold standard, and 95% confidence intervals (CIs), to measure agreement between conventionally used definitions of POE and the comprehensive method for identifying POE developed herein, using all 3 linked data sources combined. At study outset, it was understood the latter would serve as an imperfect reference standard.

Baseline characteristics by POE were described by using means or frequencies and compared by using standardized differences, where a difference >0.10 is considered clinically meaningful.46 

We then replicated and contrasted conventional definitions of different types of maternal opioid use and NAS with our comprehensive measure of POE and estimated the additional cases of POE identified by our approach (Supplemental Table 5). To be consistent with other definitions of prescription opioid use, we removed our previous exclusion of prenatal exposure to 1 to 10 days of opioid analgesics.11,47,48  Analyses were performed by using SAS software, version 9.4 (SAS Institute Inc, Cary, NC).

There were 471 798 Ontario hospital livebirths or stillbirths between 2014 and 2017. We excluded 17 004 births with prenatal exposure of 1 to 10 days of opioid analgesics only, or opioids for cough only (3.6%) (Supplemental Fig 2). We identified 115 newborns with potential iatrogenic NAS. Using linked hospital records and prescription opioid data, we found evidence of POE in 67 births identified with iatrogenic NAS. Forty-eight newborns with no history of maternal opioid use who met the criteria for iatrogenic NAS were excluded. The final cohort comprised 454 746 births: 9624 with, and 445 122 without, POE.

Compared with mothers without POE, those with exposure were more likely to be disadvantaged, with notable disparities in demographic and social factors, hospital care for mental illness and medical morbidities, and neonatal health outcomes (Table 1).

TABLE 1

Maternal and Newborn Characteristics Among 454 746 Births in Ontario, Canada, 2014–2017, by Maternal POE Status

CharacteristicOverall Cohort by Maternal Prenatal Opioid UseStandardized Differencea
Exposed, n = 9624Unexposed, n = 445 122
Of the mother    
 Demographics around the current pregnancy    
  Maternal age at first delivery, y, mean (SD) 24.0 (6.0) 28.1 (5.5) 0.70 
  Maternal age at current birth, y, mean (SD) 29.3 (5.6) 30.8 (5.3) 0.27 
  3+ previous livebirths 1858 (19.3) 29 038 (6.5) 0.39 
  Area-level low-income quintile 3959 (41.1) 94 701 (21.3) 0.44 
  Rural residence 1983 (20.6) 45 284 (10.2) 0.29 
  Immigrant to Canada 662 (6.9) 114 137 (25.6) 0.53 
   Refugee immigrant 166 (25.1) 17 688 (15.5) 0.24 
Social variables within 2 y preconception, up to birth    
 Social assistance recipient 5071 (52.7) 40 941 (9.2) 1.07 
 Homelessnessd 198 (2.1) 550 (0.1) 0.19 
 Involvement in the criminal justice systemd 587 (6.1) 6161 (1.4) 0.25 
 Violence-related health care event 589 (6.1) 3308 (0.7) 0.30 
Prepregnancy morbidity within 2 y preconception    
 High medical comorbidities 3047 (31.7) 47 892 (10.8) 0.53 
 Pain condition (low back pain, migraine, chronic painb2537 (26.4) 43 391 (9.7) 0.44 
 Prepregnancy diabetes 404 (4.2) 13 437 (3.0) 0.06 
 Chronic hypertension 434 (4.5) 13 164 (3.0) 0.08 
 Asthma within 5 y preconception 189 (2.0) 5746 (1.3) 0.05 
 Any mental health or addiction hospitalization or ED visit 1678 (17.4) 11 910 (2.7) 0.51 
Care-related variables in the index pregnancy    
 No fetal ultrasound at 18–20 wk gestation 1387 (14.4) 32 147 (7.2) 0.23 
 No prenatal care visit in the first trimester 783 (8.1) 32 496 (7.3) 0.03 
 Multifetal pregnancy 196 (2.0) 8125 (1.8) 0.02 
 Caesarian birth 3200 (33.3) 130 602 (29.3) 0.08 
 Assisted vaginal delivery 685 (7.1) 48 105 (10.8) 0.13 
 Stillbirth 78 (0.8) 2389 (0.5) 0.03 
Of the newbornc    
 Female sex 4293 (45.0) 211 843 (47.8) 0.06 
 Gestational age at birth, wk    
  23–31 184 (1.9) 4080 (0.9) 0.08 
  32–36 1360 (14.2) 26 361 (6.0) 0.28 
  37–42 8002 (83.8) 412 292 (93.1) 0.29 
 Small for gestational age birth weight <10th percentile 1461 (15.3) 42 060 (9.5) 0.18 
 Small for gestational age birth weight <5th percentile 765 (8.0) 19 283 (4.4) 0.15 
 NICU admission 4005 (42.0) 52 409 (11.8) 0.72 
 Length of stay in the birth hospitalization, d, mean (SD) 9.4 (14.2) 3.8 (8.5) 0.48 
 Infant discharged to social services at birth 629 (6.6) 1272 (0.3) 0.35 
CharacteristicOverall Cohort by Maternal Prenatal Opioid UseStandardized Differencea
Exposed, n = 9624Unexposed, n = 445 122
Of the mother    
 Demographics around the current pregnancy    
  Maternal age at first delivery, y, mean (SD) 24.0 (6.0) 28.1 (5.5) 0.70 
  Maternal age at current birth, y, mean (SD) 29.3 (5.6) 30.8 (5.3) 0.27 
  3+ previous livebirths 1858 (19.3) 29 038 (6.5) 0.39 
  Area-level low-income quintile 3959 (41.1) 94 701 (21.3) 0.44 
  Rural residence 1983 (20.6) 45 284 (10.2) 0.29 
  Immigrant to Canada 662 (6.9) 114 137 (25.6) 0.53 
   Refugee immigrant 166 (25.1) 17 688 (15.5) 0.24 
Social variables within 2 y preconception, up to birth    
 Social assistance recipient 5071 (52.7) 40 941 (9.2) 1.07 
 Homelessnessd 198 (2.1) 550 (0.1) 0.19 
 Involvement in the criminal justice systemd 587 (6.1) 6161 (1.4) 0.25 
 Violence-related health care event 589 (6.1) 3308 (0.7) 0.30 
Prepregnancy morbidity within 2 y preconception    
 High medical comorbidities 3047 (31.7) 47 892 (10.8) 0.53 
 Pain condition (low back pain, migraine, chronic painb2537 (26.4) 43 391 (9.7) 0.44 
 Prepregnancy diabetes 404 (4.2) 13 437 (3.0) 0.06 
 Chronic hypertension 434 (4.5) 13 164 (3.0) 0.08 
 Asthma within 5 y preconception 189 (2.0) 5746 (1.3) 0.05 
 Any mental health or addiction hospitalization or ED visit 1678 (17.4) 11 910 (2.7) 0.51 
Care-related variables in the index pregnancy    
 No fetal ultrasound at 18–20 wk gestation 1387 (14.4) 32 147 (7.2) 0.23 
 No prenatal care visit in the first trimester 783 (8.1) 32 496 (7.3) 0.03 
 Multifetal pregnancy 196 (2.0) 8125 (1.8) 0.02 
 Caesarian birth 3200 (33.3) 130 602 (29.3) 0.08 
 Assisted vaginal delivery 685 (7.1) 48 105 (10.8) 0.13 
 Stillbirth 78 (0.8) 2389 (0.5) 0.03 
Of the newbornc    
 Female sex 4293 (45.0) 211 843 (47.8) 0.06 
 Gestational age at birth, wk    
  23–31 184 (1.9) 4080 (0.9) 0.08 
  32–36 1360 (14.2) 26 361 (6.0) 0.28 
  37–42 8002 (83.8) 412 292 (93.1) 0.29 
 Small for gestational age birth weight <10th percentile 1461 (15.3) 42 060 (9.5) 0.18 
 Small for gestational age birth weight <5th percentile 765 (8.0) 19 283 (4.4) 0.15 
 NICU admission 4005 (42.0) 52 409 (11.8) 0.72 
 Length of stay in the birth hospitalization, d, mean (SD) 9.4 (14.2) 3.8 (8.5) 0.48 
 Infant discharged to social services at birth 629 (6.6) 1272 (0.3) 0.35 

All data are presented as a number (%) unless otherwise indicated.

a

Standardized differences >0.10 denotes meaningful imbalance in the characteristic between the 2 groups.

b

Chronic pain conditions include rheumatoid arthritis, fibromyalgia, joint pain, chronic pancreatitis, peripheral neuropathy, sickle cell disease, and renal calculi.

c

Comprises 9546 newborns in the exposed group and 442 733 newborns in the unexposed group. Missing data for infant sex: exposed: n = 495 (5.2%), unexposed: n = 7479 (1.7%)

d

As noted on health care records, may not be comprehensive.

Using all 3 linked data sources (prenatal prescription opioid data, maternal opioid-related hospital records, and newborn hospital records with NAS), we identified 9624 births with POE (21.2 per 1000 births). Compared with ascertainment of POE by using all 3 data sources, PPA was highest with prenatal prescription opioid data alone (79.0%, 95% CI: 78.2–79.8), followed by newborn hospital records with NAS alone (44.7%, 95% CI: 43.7–45.7) and maternal opioid-related hospital records alone (19.0%, 95% CI: 18.2–19.8) (Fig 1).

FIGURE 1

PPA in the ascertainment of births with maternal POE comparing different ascertainment methods by data source to an comprehensive method by using all 3 data sources (N = 9624). Included are hospital births in Ontario, Canada, 2014–2017. Hospital data include ED visits, hospitalizations, and hospitalizations to dedicated mental health beds. Prescription data includes opioid analgesics for pain and methadone and buprenorphine for opioid agonist therapy. Women with <11 cumulative days of opioid analgesic use or use of opioids for cough during pregnancy and no other history of opioid use or NAS were excluded from the analysis. ED visits and hospitalizations are mutually exclusive.

FIGURE 1

PPA in the ascertainment of births with maternal POE comparing different ascertainment methods by data source to an comprehensive method by using all 3 data sources (N = 9624). Included are hospital births in Ontario, Canada, 2014–2017. Hospital data include ED visits, hospitalizations, and hospitalizations to dedicated mental health beds. Prescription data includes opioid analgesics for pain and methadone and buprenorphine for opioid agonist therapy. Women with <11 cumulative days of opioid analgesic use or use of opioids for cough during pregnancy and no other history of opioid use or NAS were excluded from the analysis. ED visits and hospitalizations are mutually exclusive.

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Ascertainment of POE varied by data linkage of mothers and newborns and across health records. For example, maternal opioid-related hospital records during pregnancy were used to identify 1825 births with POE (4.0 per 1000). Newborn hospital records with NAS increased the estimate of POE to 5024 births (11.0 per 1000). Further addition of prenatal opioid prescriptions notably increased case ascertainment to 9624 births (21.2 per 1000).

Table 2 further illustrates how POE estimates vary by method and provides additional numbers of cases identified by using our comprehensive method. The largest difference was with maternal opioid-related hospital records alone. Compared with opioid-related hospital care captured at the birth hospitalization (1584 births [3.5 per 1000]), our comprehensive method identified an additional 8040 cases (Table 2). The smallest gain was in comparison with prenatal prescription opioid data alone (7605 births [16.7 per 1000]) wherein the comprehensive method identified an additional 2019 births.

TABLE 2

Comparison of the Number of Cases and Rates of POE According to Different Measures and Data Sources Used to Determine POE

MeasureDefinitionNumber of POE CasesPOE Rate per 1000 BirthsAdditional Number of Cases Identified by Using the Comprehensive Method Developed in the Current Study (n = 9624)
Any POE Any prescription opioid during pregnancy or opioid-related hospital care during pregnancy or NAS at birth 9624 21.2 — 
Any maternal prenatal opioid prescription Any prescription dispensed for 11+ days of an opioid analgesic or methadone or buprenorphine for OAT 7605 16.7 2019 
Any maternal prenatal OAT prescription 1+ prescription for methadone or buprenorphine for OAT 3354 7.4 6270 
Any maternal prenatal analgesic prescription (11+ days) 11+ cumulative days supplied of opioid analgesics for pain 4409 9.7 5215 
Maternal opioid-related hospital records, pregnancy Any opioid-related hospital care between conception and discharge from delivery hospitalization 1825 4.0 7799 
Maternal opioid-related hospital records, delivery hospitalization Any opioid-related hospital care at the delivery hospitalization 1584 3.5 8040 
Infant hospital records with NAS ICD-10 codes P96.1 (withdrawal from maternal drugs of addiction) or P04.4 (infant affected by maternal drugs of addiction) 4303 9.5 5321 
MeasureDefinitionNumber of POE CasesPOE Rate per 1000 BirthsAdditional Number of Cases Identified by Using the Comprehensive Method Developed in the Current Study (n = 9624)
Any POE Any prescription opioid during pregnancy or opioid-related hospital care during pregnancy or NAS at birth 9624 21.2 — 
Any maternal prenatal opioid prescription Any prescription dispensed for 11+ days of an opioid analgesic or methadone or buprenorphine for OAT 7605 16.7 2019 
Any maternal prenatal OAT prescription 1+ prescription for methadone or buprenorphine for OAT 3354 7.4 6270 
Any maternal prenatal analgesic prescription (11+ days) 11+ cumulative days supplied of opioid analgesics for pain 4409 9.7 5215 
Maternal opioid-related hospital records, pregnancy Any opioid-related hospital care between conception and discharge from delivery hospitalization 1825 4.0 7799 
Maternal opioid-related hospital records, delivery hospitalization Any opioid-related hospital care at the delivery hospitalization 1584 3.5 8040 
Infant hospital records with NAS ICD-10 codes P96.1 (withdrawal from maternal drugs of addiction) or P04.4 (infant affected by maternal drugs of addiction) 4303 9.5 5321 

Also shown is the additional number of cases of POE identified by using the comprehensive method developed in the current study, presented in the last column. Based on all hospital stillbirths and livebirths between 2014 and 2017, N = 454 746; Ontario, Canada. Additional cases ascertained with a comprehensive method of identifying POE (“any POE”) were calculated by using a reference of 9624 births (21.2 per 1000 births), ascertained by using linked maternal prescription opioid data, maternal hospital records, and newborn hospital records. Data Sources: Narcotic Monitoring System, Discharge Abstract Database, National Ambulatory Care Reporting System, Ontario Mental Health Reporting System. —, not applicable.

Table 3 describes measurement implications of more restrictive measures of maternal opioid use and NAS, in previous studies, compared with a more comprehensive measure of POE. After replicating existing definitions with data from Ontario, estimates of maternal opioid use ranged from 3.4 to 47.1 per 1000 births. We identified an additional 1811 to 8079 cases using our method. Studies designed to capture maternal OUD from maternal hospital records identified the fewest cases. Variations in OUD definitions by ICD code (OUD and poisoning) and timing (pregnancy and delivery) had a minor impact on ascertainment (Table 3).

TABLE 3

Comparison of Number of Cases and Rates of Maternal POE by Conventional Measures From Existing Studies Using Administrative Data and Additional Gains Using a Comprehensive Method

Existing StudiesAdditional Number of Cases Identified by Using the Comprehensive Method Developed in the Current Study (N = 9624)
Study (Country)MeasureData SourcePOE RatePOE Rate per 1000 Births Estimated by Using Our Current Study Cohort
Haight et al3  2018 (United States) Maternal OUD at delivery hospitalization Maternal hospital records 6.5 per 1000 delivery hospitalizations 3.4 per 1000 (n = 1545) 8079 
Kozhimannil et al49  2019 (United States) Maternal OUD (dependence or poisoning) at delivery hospitalization and no adverse effects to therapeutic opioids Maternal hospital records 3.6–8.9 per 1000 deliveries depending on urban or rural residence and hospital type 3.4 per 1000 (n = 1550) 8074 
Krans et al50  2019 (United States) Maternal OUD in pregnancy (conception to birth) Maternal hospital records 35.5 per 1000 livebirths 3.5 per 1000 (n = 1613) 8011 
Patrick et al11  2015 (United States) Any prescription opioid dispensed in pregnancy Outpatient prescription claims 279.9 per 1000 pregnant women 47.1 per 1000 (n = 22 103) 1811a 
Sujan et al47  2019 (Sweden) Any prescription opioid analgesic dispensed in pregnancy (excluding exposure to OAT) Prescribed Drug Register 44.4 per 1000 births 40.0 per 1000 (n = 18 749) 5165a 
Falk et al48  2017 (Canada) Any prescription opioid analgesic dispensed in pregnancy Drug Program Information Network 76.5 per 1000 pregnancies 40.8 per 1000 (n = 19 141) 4773a 
Filteau et al4  2018 (Canada) NAS Newborn hospital records 6.4 per 1000 livebirths 7.2 per 1000 (n = 3239) 6385 
Existing StudiesAdditional Number of Cases Identified by Using the Comprehensive Method Developed in the Current Study (N = 9624)
Study (Country)MeasureData SourcePOE RatePOE Rate per 1000 Births Estimated by Using Our Current Study Cohort
Haight et al3  2018 (United States) Maternal OUD at delivery hospitalization Maternal hospital records 6.5 per 1000 delivery hospitalizations 3.4 per 1000 (n = 1545) 8079 
Kozhimannil et al49  2019 (United States) Maternal OUD (dependence or poisoning) at delivery hospitalization and no adverse effects to therapeutic opioids Maternal hospital records 3.6–8.9 per 1000 deliveries depending on urban or rural residence and hospital type 3.4 per 1000 (n = 1550) 8074 
Krans et al50  2019 (United States) Maternal OUD in pregnancy (conception to birth) Maternal hospital records 35.5 per 1000 livebirths 3.5 per 1000 (n = 1613) 8011 
Patrick et al11  2015 (United States) Any prescription opioid dispensed in pregnancy Outpatient prescription claims 279.9 per 1000 pregnant women 47.1 per 1000 (n = 22 103) 1811a 
Sujan et al47  2019 (Sweden) Any prescription opioid analgesic dispensed in pregnancy (excluding exposure to OAT) Prescribed Drug Register 44.4 per 1000 births 40.0 per 1000 (n = 18 749) 5165a 
Falk et al48  2017 (Canada) Any prescription opioid analgesic dispensed in pregnancy Drug Program Information Network 76.5 per 1000 pregnancies 40.8 per 1000 (n = 19 141) 4773a 
Filteau et al4  2018 (Canada) NAS Newborn hospital records 6.4 per 1000 livebirths 7.2 per 1000 (n = 3239) 6385 

Additional cases ascertained by an optimized method of identifying POE and were calculated by using a reference of 9624 births (21.2 per 1000 births) ascertained by using linked maternal prescription opioid data, maternal hospital records, and newborn hospital records unless otherwise specified.

a

Additional cases ascertained were calculated without restriction of short-term analgesic use (1–10 d) by using a reference of 23 914 births with POE (51.0 per 1000 births).

Mothers with POE ascertained through maternal and newborn opioid-related hospital records generally displayed higher levels of disadvantage than those identified through prenatal prescription opioid data (Table 4). Both groups had notably higher rates of maternal polysubstance use, mental health care, and markers of social instability. Mothers identified through maternal opioid-related hospital records were more likely to reside in rural and low-income areas, have a higher parity, and have a history of mental health hospital care compared with those ascertained through newborn hospital records with NAS and prenatal prescription opioid data. Prescription opioids were dispensed to 68.8% of mothers identified through maternal opioid-related hospital records and 61.5% of mothers identified through newborn hospital records with NAS, and OAT use was more common in both groups compared with those ascertained through prenatal prescription opioid data.

TABLE 4

Maternal Characteristics by Source of Maternal POE Data in Ontario. Included are all Hospital Births in Ontario, Canada, 2014 to 2017

CharacteristicPrenatal Prescription Opioid Data, n = 7605Hospital RecordsAll Sources of POE, n = 9624
Maternal Opioid-Related (Conception to Delivery), n = 1825Newborn Records with NAS (Birth Hospitalization), n = 4303
Percentage of all cases 79 19 45 100 
Maternal prescription opioid use in the current pregnancy     
 Any prescription opioid 7605 (100.0) 1255 (68.8) 2648 (61.5) 7605 (79.0) 
 Any opioid analgesic for pain, 11+ days 4409 (58.0) 171 (9.4) 475 (11.0) 4409 (45.8) 
 Any OAT 3354 (44.1) 1138 (62.4) 2276 (52.9) 3354 (34.9) 
  Methadone 2699 (35.5) 877 (48.1) 1926 (44.8) 2699 (28.0) 
  Buprenorphine 767 (10.1) 304 (16.7) 424 (9.9) 767 (8.0) 
Opioid-related hospital care in the current pregnancy     
 Hospital care (maternal and neonatal) 3005 (39.5) 1825 (100.0) 4303 (100.0) 5024 (52.2) 
 Maternal opioid-related care, pregnancy 1255 (16.5) 1825 (100.0) 1104 (25.7) 1825 (19.0) 
  Pregnancy excluding delivery record 264 (3.5) 399 (21.9) 229 (5.3) 399 (4.1) 
  Delivery record 1097 (14.4) 1584 (86.8) 971 (22.6) 1584 (16.5) 
 NAS 2648 (34.8) 1104 (60.5) 4303 (100.0) 4303 (44.7) 
  Withdrawal from maternal drugs of addiction 2234 (29.4) 898 (49.2) 3240 (75.3) 3240 (33.7) 
  Infant affected by maternal drugs of addiction 514 (6.8) 283 (15.5) 1234 (28.7) 1234 (12.8) 
 OUD (hospital) 1231 (16.2) 1735 (95.1) 1091 (25.4) 1735 (18.0) 
 OUD (hospital or prescription) 3463 (45.5) 1751 (95.9) 2544 (59.1) 3967 (41.2) 
Mental health and addiction-related hospital care within 2 y preconception, up to birth     
 Any opioid 1687 (22.2) 1825 (100.0) 1430 (33.2) 2320 (24.1) 
 Any tobacco 733 (9.6) 288 (15.8) 587 (13.6) 1018 (10.6) 
 Any alcohol 452 (5.9) 256 (14.0) 482 (11.2) 719 (7.5) 
 Any nonopioid or multidrug usea 919 (12.1) 394 (21.6) 1119 (26.0) 1437 (14.9) 
  Any cannabis 160 (2.1) 94 (5.2) 256 (5.9) 337 (3.5) 
  Any cocaine 199 (2.6) 123 (6.7) 277 (6.4) 342 (3.6) 
  Any multidrug use 618 (8.1) 210 (11.5) 682 (15.8) 854 (8.9) 
 Any mental health and addiction hospital care 1300 (17.1) 607 (33.3) 1213 (28.2) 1919 (19.9) 
Demographics around the current pregnancy     
 Maternal age at first delivery, y, mean (SD) 24.5 (6.1) 21.8 (4.9) 22.4 (5.3) 24.0 (6.0) 
 Maternal age at current birth, y, mean (SD) 30.0 (5.3) 27.8 (5.0) 27.9 (5.5) 29.3 (5.6) 
 Area-level low-income quintile 2948 (38.8) 1048 (57.4) 2065 (48.0) 3959 (41.4) 
 Rural residence 1332 (17.5) 759 (41.6) 982 (22.8) 1983 (20.6) 
 Immigrant to Canada 599 (7.9) 19 (1.0) 93 (2.2) 662 (6.9) 
 3+ previous livebirths 1412 (18.6) 523 (28.7) 920 (21.4) 1858 (19.3) 
Social variables within 2 y preconception, up to birth     
 Social assistance recipient 4115 (54.1) 1038 (56.9) 2908 (67.6) 5071 (52.7) 
 Homelessnessb 115 (1.5) 65 (3.6) 149 (3.5) 198 (2.1) 
 Involvement in the criminal justice systemb 425 (5.6) 176 (9.6) 414 (9.6) 587 (6.1) 
 Violence-related health care event 365 (4.8) 175 (9.6) 389 (9.0) 589 (6.1) 
 Infant discharged to social services at birth 340 (4.5) 153 (8.4) 559 (13.0) 629 (6.5) 
CharacteristicPrenatal Prescription Opioid Data, n = 7605Hospital RecordsAll Sources of POE, n = 9624
Maternal Opioid-Related (Conception to Delivery), n = 1825Newborn Records with NAS (Birth Hospitalization), n = 4303
Percentage of all cases 79 19 45 100 
Maternal prescription opioid use in the current pregnancy     
 Any prescription opioid 7605 (100.0) 1255 (68.8) 2648 (61.5) 7605 (79.0) 
 Any opioid analgesic for pain, 11+ days 4409 (58.0) 171 (9.4) 475 (11.0) 4409 (45.8) 
 Any OAT 3354 (44.1) 1138 (62.4) 2276 (52.9) 3354 (34.9) 
  Methadone 2699 (35.5) 877 (48.1) 1926 (44.8) 2699 (28.0) 
  Buprenorphine 767 (10.1) 304 (16.7) 424 (9.9) 767 (8.0) 
Opioid-related hospital care in the current pregnancy     
 Hospital care (maternal and neonatal) 3005 (39.5) 1825 (100.0) 4303 (100.0) 5024 (52.2) 
 Maternal opioid-related care, pregnancy 1255 (16.5) 1825 (100.0) 1104 (25.7) 1825 (19.0) 
  Pregnancy excluding delivery record 264 (3.5) 399 (21.9) 229 (5.3) 399 (4.1) 
  Delivery record 1097 (14.4) 1584 (86.8) 971 (22.6) 1584 (16.5) 
 NAS 2648 (34.8) 1104 (60.5) 4303 (100.0) 4303 (44.7) 
  Withdrawal from maternal drugs of addiction 2234 (29.4) 898 (49.2) 3240 (75.3) 3240 (33.7) 
  Infant affected by maternal drugs of addiction 514 (6.8) 283 (15.5) 1234 (28.7) 1234 (12.8) 
 OUD (hospital) 1231 (16.2) 1735 (95.1) 1091 (25.4) 1735 (18.0) 
 OUD (hospital or prescription) 3463 (45.5) 1751 (95.9) 2544 (59.1) 3967 (41.2) 
Mental health and addiction-related hospital care within 2 y preconception, up to birth     
 Any opioid 1687 (22.2) 1825 (100.0) 1430 (33.2) 2320 (24.1) 
 Any tobacco 733 (9.6) 288 (15.8) 587 (13.6) 1018 (10.6) 
 Any alcohol 452 (5.9) 256 (14.0) 482 (11.2) 719 (7.5) 
 Any nonopioid or multidrug usea 919 (12.1) 394 (21.6) 1119 (26.0) 1437 (14.9) 
  Any cannabis 160 (2.1) 94 (5.2) 256 (5.9) 337 (3.5) 
  Any cocaine 199 (2.6) 123 (6.7) 277 (6.4) 342 (3.6) 
  Any multidrug use 618 (8.1) 210 (11.5) 682 (15.8) 854 (8.9) 
 Any mental health and addiction hospital care 1300 (17.1) 607 (33.3) 1213 (28.2) 1919 (19.9) 
Demographics around the current pregnancy     
 Maternal age at first delivery, y, mean (SD) 24.5 (6.1) 21.8 (4.9) 22.4 (5.3) 24.0 (6.0) 
 Maternal age at current birth, y, mean (SD) 30.0 (5.3) 27.8 (5.0) 27.9 (5.5) 29.3 (5.6) 
 Area-level low-income quintile 2948 (38.8) 1048 (57.4) 2065 (48.0) 3959 (41.4) 
 Rural residence 1332 (17.5) 759 (41.6) 982 (22.8) 1983 (20.6) 
 Immigrant to Canada 599 (7.9) 19 (1.0) 93 (2.2) 662 (6.9) 
 3+ previous livebirths 1412 (18.6) 523 (28.7) 920 (21.4) 1858 (19.3) 
Social variables within 2 y preconception, up to birth     
 Social assistance recipient 4115 (54.1) 1038 (56.9) 2908 (67.6) 5071 (52.7) 
 Homelessnessb 115 (1.5) 65 (3.6) 149 (3.5) 198 (2.1) 
 Involvement in the criminal justice systemb 425 (5.6) 176 (9.6) 414 (9.6) 587 (6.1) 
 Violence-related health care event 365 (4.8) 175 (9.6) 389 (9.0) 589 (6.1) 
 Infant discharged to social services at birth 340 (4.5) 153 (8.4) 559 (13.0) 629 (6.5) 

All data are presented as a number (%) unless otherwise indicated. Groups are not mutually exclusive. All sources of POE totals are highly driven by the births in the prescription opioid data group.

a

Any nonopioid or multidrug use includes cannabis, cocaine, stimulants, hallucinogens, sedative and hypnotic use, psychotropic drugs, volatile solvents, and multiple substances.

b

As noted on health care records, may not be comprehensive.

Prescription opioid exposure was notably higher among newborns diagnosed with ICD-10 P96.1 (withdrawal from maternal drugs of addiction) compared with P04.4 (infant affected by maternal drugs of addiction) (69.0% vs 41.7%, respectively) (Supplemental Table 7). Mothers of both had similar levels of socio-demographic disadvantage. Newborn characteristics between groups were largely similar, except for neonatal intensive care and hospital length of stay (Supplemental Table 7).

With this large population-based study, we add new and important information regarding the ascertainment of births with POE using health administrative data for public health surveillance and research. Use of 3 linked data sources (prenatal prescription opioid data, maternal opioid-related hospital records, and newborn hospital records with NAS) offered the most comprehensive approach to estimating POE (21.2 per 1000 births). When using different methods, estimates of POE ranged from 4.0 per 1000 births from maternal opioid-related hospital records alone, 9.5 per 1000 births from newborn hospital records with NAS alone, and 16.7 per 1000 births from prenatal prescription opioid data alone. Previously reported measures of prevalence of maternal opioid use and NAS ranged from 3.4 to 47.1 per 1000 births. Using a comprehensive approach to identify POE, we ascertained an additional 1811 to 8079 cases. Case ascertainment through maternal and newborn opioid-related hospital records identified high-risk mothers, indicating different ascertainment methods yield different study populations.

We compared differences in POE estimation by replicating existing methods of ascertaining types of maternal opioid use and NAS using our data. Although researchers in previous studies used more restrictive measures of POE, through choice or necessity, these comparisons are useful to contextualize differences in POE measures to understand if various cohorts represent different groups of women and describe differences in case capture. Our method was most similar to a cohort study of mother-infant dyads enrolled in Medicaid in Tennessee.11  In this sample, Patrick et al11  reported 279.9 per 1000 pregnant women filled 1 or more opioid prescriptions. Using Patrick et al’s11  method in Ontario, we estimated 22 103 births with POE (47.1 per 1000 births) compared with our method, which identified 23 914 births with POE (51.0 per 1000 births). Congruency between methods was due to the inclusion of prescription opioid analgesics and OAT, and the majority of cases derived from maternal prescription opioid records. Sole reliance on OUD codes in maternal hospital records resulted in a smaller cohort of higher-risk mothers. Haight et al3  presented the prevalence of maternal OUD at 6.5 per 1000 delivery hospitalizations in the United States. Using this method in Ontario, we estimated 1545 births (3.4 per 1000 births) compared with our estimate of 9624 births with POE (21.2 per 1000 births). We have shown a minority of cases are derived from maternal hospital records. In our cohort, case ascertainment based on maternal OUD in hospital records resulted in an underestimation of OUD and inclusion of a higher-risk study population. We identified mothers with OUD in 18% of births through maternal hospital records alone, compared with 41% using both maternal hospital records and prescription data. Finally, we have shown when NAS (ICD-10 P96.1) is used as a proxy for POE, POE is underestimated by 6385 births. Efforts were made to closely replicate definitions; however, there were not always corresponding conversion codes from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10, which may have resulted in minor differences in case ascertainment.

Findings have additional implications for defining NAS in surveillance and research. Our results suggest almost half of newborns with ICD-10 P04.4 are exposed to opioids, with notable prenatal polysubstance use, common among women with opioid dependence.51,52  Newborns with P96.1 or P04.4, regardless of withdrawal severity, are important to include in studies examining long-term effects of POE. Results suggest methods to exclude iatrogenic cases of NAS may be excluding births with POE,34  because 58% of potentially iatrogenic cases of NAS had evidence of POE.

This is the first study to explore a range of maternal demographic, social, and medical factors by data source. Using administrative data, we identified important differences in maternal characteristics by data source suggesting selection bias may occur in the design of observational studies. Births with POE ascertained through maternal and newborn opioid-related hospital records had higher-risk profiles versus those with prenatal prescription opioid data. This was evident for demographics, social risk factors, and mental health and addiction care. We did not differentiate between exposure to prescription opioid analgesics and OAT. There is inevitably within group heterogeneity as maternal characteristics differ by type of opioid. Group differences will be explored in subsequent work designed to develop maternal phenotypes by type of opioid(s) used during pregnancy. The decision to use a comprehensive measure of POE, as we developed, over more-specific measures of opioid type, OUD or NAS, will depend on the construct of interest. Findings are meant to aid researchers in their selection of measures and data sources while providing context to assess the potential for bias.

This descriptive study has several limitations. Information reported is limited to women who sought health care for themselves or newborns. Some cases may have been missed and constructs may have been underestimated, notably polysubstance use and social risk factors. Methods used represent progress in capturing the true universe of POE; however, misclassification may have been introduced in our approach. POE may be overestimated through inclusion of cases with NAS from intrauterine exposure to nonopioid substances.53  Cases may have been missed if illicit opioid use during pregnancy went unnoticed by health care practitioners or newborns were not in clinical withdrawal, resulting in underestimation of prevalence. The true universe of women who use opioids during pregnancy is not known. Thus, we could not evaluate our approach against a gold standard. Furthermore, because all conventional measures of POE were included in our overall definition of POE, we could not calculate negative percent agreement. We took an as-prescribed approach assuming women took the full course of medications prescribed. This may result in overestimation of POE; however, women with 1 to 10 days of opioid analgesic use were excluded, which mitigates this impact. Dose and timing were not considered in the exclusion of women with 1 to 10 days of opioid analgesic use; however, most women had 1 to 5 days of opioid analgesic use (60%), which is likely not clinically meaningful POE. Nevertheless, results from this study are widely generalizable. Findings are population-based and reflect women with hospital births who were eligible for Ontario’s universal health care system. Definitions in this study are easily replicable and can be applied to other settings with health administrative data.

This study demonstrates the importance of multiple linked health administrative databases to estimate the prevalence of POE and facilitate research of maternal and child health outcomes. Differences in data availability and linkage impact the number of cases and study population ascertained. Samples derived from different ascertainment methods may differ by important characteristics. Jurisdictions and public health researchers should be aware of potential biases and underestimation related to ascertainment method.

Parts of this material are based on data and information compiled and provided by MOH, Canadian Institute for Health Information, IMS Brogan Inc, and Immigration, Refugees and Citizenship Canada. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. We thank IMS Brogan Inc for use of their Drug Information Database. We thank Alison L Park, MSc (ICES) and Javaid Iqbal, MD (ICES) for their technical help with this study and Kinwah Fung, MSc (ICES) for her methodological guidance.

Ms Camden conceptualized and designed the study, conducted the analyses, drafted the initial manuscript, and revised the manuscript; Drs Guttmann, Ray, To, Gomes, and Bai conceptualized and designed the study and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health. This study also received funding from Canadian Institutes of Health Research Doctoral Award: Frederick Banting and Charles Best Canada Graduate Scholarship (A.C.).

CI

confidence interval

ED

emergency department

ICD

International Classification of Diseases

ICD-10

International Classification of Diseases, 10th Revision

ICD-9

International Classification of Diseases, Ninth Revision

NAS

neonatal abstinence syndrome

OAT

opioid agonist therapy

OUD

opioid use disorder

POE

prenatal opioid exposure

PPA

positive percent agreement

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data