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Research

Prenatal opioid exposure and subsequent risk of neuropsychiatric disorders in children: nationwide birth cohort study in South Korea

BMJ 2024; 385 doi: https://doi.org/10.1136/bmj-2023-077664 (Published 24 April 2024) Cite this as: BMJ 2024;385:e077664

Linked Editorial

Reducing the risks of prenatal opioid exposure in children
  1. Jiseung Kang, postdoctoral researcher1 2 3,
  2. Hyeon Jin Kim, senior data scientist and co-principal investigator4 5,
  3. Tae Kim, professor1,
  4. Hyeri Lee, doctoral student4 5,
  5. Minji Kim, doctoral student4 5,
  6. Seung Won Lee, professor6,
  7. Min Seo Kim, postdoctoral researcher7,
  8. Ai Koyanagi, professor8,
  9. Lee Smith, professor9,
  10. Guillaume Fond, professor10,
  11. Laurent Boyer, professor10,
  12. Masoud Rahmati, professor10 11 12,
  13. Guillermo F López Sánchez, professor13,
  14. Elena Dragioti, professor14 15,
  15. Samuele Cortese, professor16 17 18 19 20,
  16. Jae Il Shin, professor21 22,
  17. Dong Keon Yon, professor and principal investigator4 5 23,
  18. Marco Solmi, professor24 25 26 27
  1. 1Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea
  2. 2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
  3. 3Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
  4. 4Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea
  5. 5Department of Regulatory Science, Kyung Hee University, Seoul, South Korea
  6. 6Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, South Korea
  7. 7Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  8. 8Research and Development Unit, Parc Sanitari Sant Joan de Deu, Barcelona, Spain
  9. 9Centre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge, UK
  10. 10Research Centre on Health Services and Quality of Life, Aix Marseille University, Marseille, France
  11. 11Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran
  12. 12Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran
  13. 13Division of Preventive Medicine and Public Health, Department of Public Health Sciences, School of Medicine, University of Murcia, Murcia, Spain
  14. 14Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
  15. 15Research Laboratory Psychology of Patients, Families and Health Professionals, Department of Nursing, School of Health Sciences, University of Ioannina, Ioannina, Greece
  16. 16Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
  17. 17Clinical and Experimental Sciences (Central Nervous System and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK
  18. 18Solent NHS Trust, Southampton, UK
  19. 19Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York City, NY, USA
  20. 20DiMePRe-J-Department of Precision and Regenerative Medicine-Jonic Area, University of Bari “Aldo Moro,” Bari, Italy
  21. 21Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea
  22. 22Severance Underwood Meta-Research Center, Institute of Convergence Science, Yonsei University, Seoul, South Korea
  23. 23Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, South Korea
  24. 24On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, ON, Canada
  25. 25Clinical Epidemiology Program, Ottawa Hospital Research Institute, University of Ottawa, ON, Canada
  26. 26Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
  27. 27Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada
  1. Correspondence to: Dong Keon Yon yonkkang{at}gmail.com
  • Accepted 5 March 2024

Summary

Objective To investigate the potential association between prenatal opioid exposure and the risk of neuropsychiatric disorders in children.

Design Nationwide birth cohort study.

Setting From 1 January 2009 to 31 December 2020, birth cohort data of pregnant women in South Korea linked to their liveborn infants from the National Health Insurance Service of South Korea were collected.

Participants All 3 251 594 infants (paired mothers, n=2 369 322; age 32.1 years (standard deviation 4.2)) in South Korea from the start of 2010 to the end of 2017, with follow-up from the date of birth until the date of death or 31 December 2020, were included.

Main outcome measures Diagnosis of neuropsychiatric disorders in liveborn infants with mental and behaviour disorders (International Classification of Diseases 10th edition codes F00-99). Follow-up continued until the first diagnosis of neuropsychiatric disorder, 31 December 2020 (end of the study period), or the date of death, whichever occurred first. Eight cohorts were created: three cohorts (full unmatched, propensity score matched, and child screening cohorts) were formed, all of which were paired with sibling comparison cohorts, in addition to two more propensity score groups. Multiple subgroup analyses were performed.

Results Of the 3 128 571 infants included (from 2 299 664 mothers), we identified 2 912 559 (51.3% male, 48.7% female) infants with no prenatal opioid exposure and 216 012 (51.2% male, 48.8% female) infants with prenatal opioid exposure. The risk of neuropsychiatric disorders in the child with prenatal opioid exposure was 1.07 (95% confidence interval 1.05 to 1.10) for fully adjusted hazard ratio in the matched cohort, but no significant association was noted in the sibling comparison cohort (hazard ratio 1.00 (0.93 to 1.07)). Prenatal opioid exposure during the first trimester (1.11 (1.07 to 1.15)), higher opioid doses (1.15 (1.09 to 1.21)), and long term opioid use of 60 days or more (1.95 (1.24 to 3.06)) were associated with an increased risk of neuropsychiatric disorders in the child. Prenatal opioid exposure modestly increased the risk of severe neuropsychiatric disorders (1.30 (1.15 to 1.46)), mood disorders, attention deficit hyperactivity disorder, and intellectual disability in the child.

Conclusions Opioid use during pregnancy was not associated with a substantial increase in the risk of neuropsychiatric disorders in the offspring. A slightly increased risk of neuropsychiatric disorders was observed, but this should not be considered clinically meaningful given the observational nature of the study, and limited to high opioid dose, more than one opioid used, longer duration of exposure, opioid exposure during early pregnancy, and only to some neuropsychiatric disorders.

Introduction

The global opioid crisis has generated widespread attention because of its extensive effect on public health. While many women are generally cautious about medication intake during pregnancy,1 the need for pain management in some instances has led to an observable reliance on analgesics, including opioids.23 Besides analgesic treatment, pregnant women mainly used opioid as an antitussive treatment for coughs during pregnancy.4 The prevalence of opioid use during pregnancy in cohort studies of Medicaid beneficiaries in the United States and pregnancy cohort studies in Quebec is approximately 5%.56 Pregnant women often encounter specific physiological changes, such as increased ligamentous laxity, abnormal pain, and weight gain.7 These changes can induce or exacerbate various painful conditions, often necessitating the guidance of opioids as analgesics.8

While considerable attention has been directed towards the direct effect of opioid use on individuals using the drug, an increasing concern arises regarding the indirect effects on their offspring. Prenatal and early life exposure to various substances has been associated with long term neuropsychiatric and developmental outcomes in the child. For instance, prenatal exposure to alcohol, tobacco, and some medications has been associated with an array of developmental, cognitive, and behavioural deficits in the child.910 The effect of opioid exposure during the prenatal period is a topic of substantial importance but requires more in-depth examination.

Various neuropsychiatric disorders begin in childhood and result in established neuropsychiatric disorders later in life.11 Opioid exposure during the prenatal and infancy periods might be an emerging risk factor for neuropsychiatric outcomes. While previous studies reported that exposure to opioids during the prenatal period is associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder, alcohol misuse, and depression,1213 others suggest that exposure to opioids during pregnancy may not be deleterious to early childhood neurobehavioural development.1415 Given the potential confounding factors and limited cohort size in earlier research,16 a more precise investigation with a large scale birth cohort is warranted. Thus, we aimed to examine the association between maternal opioid exposure and the subsequent risk of neuropsychiatric disorders in children using a nationwide, population based, large scale birth cohort in South Korea. We also aimed to investigate the specific neuropsychiatric disorders potentially associated with fetal exposure to opioids.

Methods

Data source

This large scale nationwide cohort study was conducted using data from the National Health Insurance Service (NHIS) of South Korea,17 which covers 98% of the South Korean population. Data, including baseline demographic details of individuals, outpatient and inpatient medical records, general health screening, and mortality information were collected through a universal health coverage system that provides comprehensive insurance services.18 This study followed The Reporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement (table S1).

In this study, we focused on children born between 1 January 2010 and 31 December 2017. These children were subsequently paired with their mothers using the unique family insurance identification numbers allocated to every individual in the NHIS data (fig 1, figure S1-S4).1719 The Korean government anonymised all patient related data, including personal identification numbers, to enhance confidentiality. While direct identification of individuals was not possible due to the removal of names, all other pertinent data remained intact and accessible for our analyses. The research protocol was approved by the institutional review board of Kyung Hee University (KHUH 2022-06-042) and the NHIS (NHIS-2023-1-168). We conducted this study using de-identified administrative data. No consent was required for this type of study.20

Fig 1
Fig 1

Disposition and study subjects (full version). Cohort 1 involved infants born between 2010 and 2017. Cohort 2 paired the exposed and unexposed groups in a 1:5 ratio using propensity score. Cohort 3 included children from the National Health Screening Program for Infants and Children at six months after birth. Cohort 4 included infants born between 2010 and 2015 with the exposed and unexposed groups matched in a 1:5 ratio. Cohort 5 was where children who received at least one diagnosis based on the outcome criteria were matched in a 1:5 ratio between exposed and unexposed groups. Cohort 6 was a sibling comparison cohort derived from the full unmatched cohort. Cohort 7 was sibling comparison cohort derived from the 1:5 matched cohort A. Cohort 8 was sibling comparison cohort derived from the child screening cohort

Study design and participants

All infants born in South Korean during the study period were included. The cohort comprised 3 251 594 children and 2 369 322 paired mothers. Using unique identification numbers, we paired children with their corresponding mothers (figure S4).21 The data from 1 January 2009 to 31 December 2020 were included to ensure follow-up of all medical records within this timeframe. The exclusion criteria applied to the initial cohort are as follows (tables S2 and S3): participants with inadequate information on socioeconomic status (excluded n=66); missing birth dates (excluded n=76 028); children diagnosed with immune mechanism disorders (excluded n=936), cystic fibrosis (excluded n=18), chronic kidney disease (excluded n=388), β thalassemia or sickle cell disorders (excluded n=27), malignancy (excluded n=4116), teratogenic/genetic syndromes, microdeletions, chromosomal abnormalities, and malformation syndromes (excluded n=8015), or neuropsychiatric disorders within six months after birth (excluded n=6871); children of mothers diagnosed with cancer before delivery (excluded n=26 620); and mothers whose offspring were already excluded (excluded n=69 646). The final cohort comprised 3 128 571 children and 2 299 664 mothers.

Exposures

Opioid exposure was defined on the basis of mothers receiving two or more opioid prescriptions within each trimester, following the exposure criteria as per previous studies.52223 Table S4 and figure S5 list the specific opioids included. Based on this definition, the extent of prenatal opioid exposure was classified into three categories. Firstly, based on trimesters of pregnancy, the four groups were defined as opioid use in the first, second, and third trimesters, and more than one trimester. Secondly, total opioid intake was calculated based on morphine milligram equivalents,523 and mothers were categorised into non-user, user of low dose, and user of high dose by using the 75th percentile as the cutoff (25.5 morphine milligram equivalents). Thirdly, mothers were grouped according to the number of opioid prescriptions received (0-1, 2, or ≥3) and exposure duration (<30, 30-59, or ≥60 days) over the whole pregnancy. Additionally, we listed maternal health conditions among pregnant women with opioid prescriptions (table S5).

Outcomes

The primary outcome of the study was the onset of neuropsychiatric disorders in children, defined as having received at least two diagnoses of F00-99 codes as per the International Classification of Diseases, 10th edition (ICD-10) (table S2 and S6). In the context of psychiatric diagnoses in South Korea, predominantly psychiatrists, and to a lesser extent, paediatricians, are authorised to diagnose psychiatric conditions and assign the F-code in ICD-10 codes (table S6). Among the identified cases, infants with psychotic features were categorised as having severe neuropsychiatric disorders, whereas the other cases were classified as common neuropsychiatric disorders (table S2).24 The specific diagnoses for children with neuropsychiatric disorders were categorised as follows (table S7): alcohol or drug misuse; mood disorders, excluding those with psychotic symptoms; anxiety and stress-related disorders; eating disorders; compulsive disorders; attention deficit hyperactivity disorder; autism spectrum disorder; and intellectual disability.

Covariates

We considered these covariates related to mothers: maternal age at delivery (<20, 20-24, 25-29, 30-34, or ≥35 years), region of residence (rural or urban),25 household income level (first to fourth quartiles), parity (one or ≥two children), maternal mental illness (no mental illness, common, or severe), severe maternal morbidity score (0, 1, or ≥2),26 delivery type (vaginal delivery or caesarean section), opioid prescription history, hospital admission (0, 1, or ≥2), and outpatient visit (0, 1, or ≥2) in the year before pregnancy, use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen during pregnancy, and history of maternal neuropsychiatric conditions (alcohol or drug misuse, mood disorders except those with psychotic symptoms, anxiety and stress-related disorders, sleep disorders, epilepsy, and other neuropsychiatry disorders). We considered the following covariates for infants: sex, birth season (spring (March to May), summer (June to August), autumn (September to November), and winter (December to February)), year of delivery (2010-12, 2013-15, or 2016-17), preterm birth (≤36 weeks), low birth weight (≤2499 g), and breastfeeding history. All variables were obtained from eligibility data, claim codes, and child health examination data provided by the NHIS.

Cohorts

We used eight cohorts to comprehensively understand the association between maternal opioid prescriptions and risk of neuropsychiatric disorders in their child as follows: (1) a full unmatched cohort involving infants born between 2010 and 2017 (cohort 1 in fig 1 and table S8); (2) propensity score matched cohort A, derived from the full unmatched cohort, pairing the exposed and unexposed groups in a 1:5 ratio using propensity score (cohort 2 in fig 1 and table S8); (3) the child screening cohort, based on the full unmatched cohort, consisted of children from the National Health Screening Program for Infants and Children at six months after birth (cohort 3 in fig 1 and table S8); (4) propensity score matched cohort B consisting of infants born between 2010 and 2015, with the exposed and unexposed groups matched in a 1:5 ratio (cohort 4 in fig 1 and table S8); (5) propensity score matched cohort C including infants born between 2010 and 2017, forming a cohort where children who received at least one diagnosis based on the outcome criteria are matched in a 1:5 ratio between exposed and unexposed groups (cohort 5 in fig 1 and table S8); and (6) three sibling cohorts each specifically including sibling pairs with differing exposure statuses: sibling cohort A is formed from the full unmatched cohort (cohort 6 in fig 1 and table S8), sibling cohort B is derived from the propensity score matched cohort A (cohort 7 in fig 1 and table S8), and sibling cohort C is based on the child screening cohort (cohort 8 in fig1 and table S8).

Propensity score matched cohort

To mitigate potential confounding and to balance demographic covariates between the groups exposed to opioids and groups not exposed, we created a propensity score matched cohort informed by opioid exposure.27 Propensity score was derived using a univariate logistic regression model, incorporating variables such as maternal age at delivery, region of residence, household income level, parity, maternal mental illness, severe maternal morbidity score, hospital admission, and outpatient visit in the year before pregnancy and history of maternal neuropsychiatric conditions (alcohol or drug misuse, mood disorders except those with psychotic symptoms, anxiety and stress related disorders, sleep disorders, epilepsy, and other neuropsychiatry disorders). Individuals were matched in 1:5 ratio matching between the opioid exposed (matched n=215 958) and unexposed (matched n=1 075 454) groups within the entire cohort. Using the greedy nearest-neighbor algorithm, we randomly matched the two groups based on propensity score values within the specified caliper (0.001), ensuring minimal differences. The appropriateness of propensity score matched was evaluated using standardised mean differences. We considered no substantial imbalance between the two groups when the standardised mean difference was less than 0.1 (figure S6 and S7).27

Child screening cohort

A previous birth cohort study reported significant benefits of breastfeeding on subsequent hospital admissions for infection, gastrointestinal tract, respiratory, genitourinary tract, and oral cavity in children.28 To minimise unmeasured confounding factors, we formed a cohort of children who received the National Health Screening Program for infants and children at six months after birth, enabling us to obtain information on their breastfeeding history (table S9). Individuals with missing breastfeeding data despite having undergone screening were excluded from this cohort. A total of 1 377 246 children were included in the screening cohort (table S10).

Sibling comparison cohort

Sibling comparison analysis provides a suitable approach to counter potential biases arising from unmeasured confounding factors, such as genetics, lifestyle, and environmental influences.29 In all cohorts (full unmatched, propensity score matched, and child screening cohorts), we established sibling comparison cohorts for sibling pairs with different exposure statuses. Pairs of only children or siblings sharing uniform opioid exposure or no exposure were systematically excluded.

Other analyses

To enhance our findings, we conducted additional analyses using different follow-up duration and criteria for outcome. We first further investigated the prolonged effects of maternal opioid prescriptions by utilising 1:5 propensity score matched cohort B of children, born between 2010 and 2015 (figure S3, S7, and table S11). Then, to ascertain the robustness of our findings, we reanalysed using a 1:5 propensity score matched cohort C, defining the outcome by at least one diagnosis.

Statistical analysis

Across all cohort analyses, the primary exposure was prenatal opioid exposure, and the primary outcome was the onset of neuropsychiatric disorders in children. We designated each childbirth date as the index date. Follow-up continued until the first diagnosis of neuropsychiatric disorder, 31 December 2020 (end of the study period), or the date of death, whichever occurred first.

Hazard ratios with 95% confidence intervals (CIs) using Cox proportional hazards model for estimation. Additionally, to control for the influence of potential confounders and to strengthen the validity of the results, two adjusted models were developed using the following variables. Firstly, for the adjusted model, maternal age at delivery years, infant’s sex, region of residence, household income level, birth season, parity, maternal mental illness, severe maternal morbidity score, and hospital outpatient visit as well as hospital admission contact in a year before pregnancy were used. And secondly, for the fully adjusted model, covariates of the adjusted model were used in addition to history of maternal neuropsychiatric conditions (alcohol or drug misuse, mood disorders except those with psychotic symptoms, anxiety and stress related disorders, sleep disorders, epilepsy, and other neuropsychiatry disorders), and use of NSAIDs as well as acetaminophen during pregnancy. We further adjusted for breastfeeding history in the child screening cohort. To reduce unpredictable biases and reverse causality, we conducted a stratification analysis using variables. A dose dependent analysis was conducted to elucidate the association between opioid use and onset of neuropsychiatric disorders. Furthermore, we explored a potential association between specific factors (maternal health condition, opioid prescription a year before pregnancy, and delivery type) and opioid prescriptions during pregnancy by a multiplicative interaction analysis. We used Cox models that included multiplicative interaction terms between opioid prescriptions during pregnancy and each factor (tables S12-14).30 All statistical inferences were considered significant at a two sided Pvalue of less than 0.05. Statistical analyses were performed using SAS (version 9.4; SAS Institute Inc, Cary, NC, USA).

Patient and public involvement

The Korean government anonymised all patient related data, including personal identification numbers, to enhance confidentiality. While direct identification of individuals was rendered impossible due to the removal of names, all other pertinent data remained intact and accessible for our analyses. Due to the database containing data for the national population, access was limited to participating researchers only for security and confidentiality purposes. The research questions and outcome measures were independently determined without the involvement of the children or their parents. The study design and implementation were conducted without consultation. In South Korea, no framework for the management of patient and public involvement has been established. However, the results of the study will be officially registered and released to NHIS (the official institutions of the Korean government) and we plan to disseminate the results of this study to all study participants and wider relevant communities on request.

Results

Of 2 299 664 mothers included in the study, 3 128 571 infants were linked and we identified 93.1% (n=2 912 559) infants with no prenatal opioid exposure (51.3% male, 48.7% female) and 6.9% (n=216 012) infants with prenatal opioid exposure (51.2% male, 48.8% female) in the full matched cohort within follow-up periods from 1 January 2009 to 31 December 2020 (fig 1; table 1).

Table 1

Baseline characteristics of study subjects from 2010 to 2017

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After 1:5 propensity score matching, the standardised mean difference values were less than 0.1, indicating no major imbalances in the general characteristics. The association between maternal exposure to opioids and neuropsychiatric outcomes in the offspring from the subgroup analysis is indicated as crude and adjusted hazard ratio in table 2 and table S15. Prenatal exposure to opioids was associated with an increased risk of neuropsychiatric disorders (fully adjusted hazard ratio 1.07 (95% CI 1.05 to 1.10), table 2). In particular, exposure to opioids during the first trimester showed an increased risk of neuropsychiatric disorders in the offspring compared with the offspring who was not exposed (1.11 (1.07 to 1.15)). Risk of neuropsychiatric disorders in the offspring increased in a dose-dependent manner with opioid doses (low dose 1.06 (1.03 to 1.09); high dose, 1.15 (1.09 to 1.21)). Compared with infants who were not exposed, the risk of neuropsychiatric disorders in infants who were exposed showed increasing trends depending on the days of opioid prescriptions (1-29 days of opioid prescriptions, 1.07 (1.04 to 1.10); 30-59 days, 1.34 (1.12 to 1.62); ≥60 days, 1.95 (1.24 to 3.06)). In addition, similar trends were reported in further analysis by using different timeframes of infants born between 2010 to 2015 and different outcome criteria with one or more instances of diagnosis (tables S16 and S17). We performed stratification analysis in the 1:5 propensity score matched cohort A (table 3). The subsequent risk of neuropsychiatric disorders with maternal opioid use was significantly associated with caesarean sections in comparison to vaginal deliveries (P value for interaction=0.009; ratio of hazard ratio 1.08 (95% CI 1.03 to 1.14); table S14).

Table 2

Hazard ratio models of the association between prenatal opioid exposure during pregnancy and neuropsychiatric disorders in children with the 1:5 propensity score matched cohort A from 2010 to 2017

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Table 3

Stratification analysis for hazard ratio models of the association between opioid exposure during pregnancy and neuropsychiatric disorders in children with the 1:5 propensity score matched cohort A from 2010 to 2017

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Table 4 and table S18 present the results of a dose-dependent subgroup analysis of the association between maternal opioid use during pregnancy and the risk of specific neuropsychiatric disorders in children from the full and 1:5 propensity score matched cohorts. Compared with infants who were not exposed to opioids, maternal opioid use significantly increased the risk of several neuropsychiatric diseases, including mood disorder (adjusted hazard ratio 1.15 (95% CI 1.04 to 1.26)), attention deficit hyperactivity disorder (1.12 (1.07 to 1.17)), and intellectual disability (1.30 (1.21 to 1.40)), but not risk of alcohol or drug misuse, anxiety and stress related disorders, eating disorders, compulsive disorders, and autism spectrum disorder. In particular, the risk of severe neuropsychiatric disorder in the infant (1.30 (1.15 to 1.46)) was higher than that of common neuropsychiatric disorders (1.07 (1.04 to 1.09)) among those who had maternal exposure to opioids.

Table 4

Adjusted hazard ratio models of the dose-dependence between prenatal opioid exposure during pregnancy and specific neuropsychiatric disorders in children within the 1:5 propensity score matched cohort A from 2010 to 2017

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Sibling analysis, which was performed to control for unmeasured familial confounders, showed no association between prenatal exposure to opioids and the risk of childhood neuropsychiatric disorders in the full unmatched, propensity score matched, and child screening cohorts (table 5). Similar associations were observed when performing the same analysis in the full unmatched (tables S19-22) and child screening cohorts stratified by breastfeeding history (table S23-26). No significant associations were noted between breastfeeding and subsequent risk for neuropsychiatric disorders (table S24).

Table 5

Crude and adjusted hazard ratio models of the association between opioid exposure during pregnancy and neuropsychiatric disorders in children with the sibling comparison cohort from full unmatched cohort, propensity score matched cohort A, and child screening cohort from 2010 to 2017

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Discussion

Findings and explanation

We investigated the effect of prenatal exposure to opioids on neuropsychiatric disorders in the child and obtained several key findings. Firstly, in this large scale nationwide cohort study that included 216 012 pregnancies that were exposed to opioids among 3 128 571 pregnancies overall, maternal opioid use was not associated with a substantially increased risk of neuropsychiatric disorders in the offspring. Although a statistically significant association (adjusted hazard ratio 1.06 (95% CI 1.04 to 1.09)) was observed between maternal opioid use and neuropsychiatric disorders in the offspring, the clinical significance of this finding is potentially limited due to the observational nature of the study. Similarly, the attenuated and null estimates observed in the sibling controlled analyses support the finding that prenatal opioid exposure was not associated with an increased risk of neuropsychiatric outcomes. Secondly, the timing of opioid exposure may have resulted in different outcomes. Using opioids during the first trimester showed a 11% increased risk of psychiatric disorders compared with no exposure. This specific effect of the first trimester suggests that the effect of opioid use on the fetus during the early neurodevelopmental phase is critical.3132 Thirdly, the risk of childhood neuropsychiatric disorders showed a dose-dependent association with maternal opioid dose and duration of opioid intake. The risk of neuropsychiatric disorders in the child increased with the number of opioid prescriptions and days of opioid prescriptions. In particular, long term prescriptions (≥60 days) were associated with a nearly doubled risk. Fourthly, offspring delivered via caesarean section had a significant risk of neuropsychiatric disorders in stratification analysis compared with vaginal delivery. Finally, compared with children who were not exposed to opioids, those who were exposed to prenatal opioids had a modestly increased risk of several neuropsychiatric disorders, including mood disorders, attention deficit hyperactivity disorder, and intellectual disability. However, no associated risk was found for alcohol or drug misuse, anxiety and stress related disorders, eating disorders, compulsive disorders, or autism spectrum disorder. Furthermore, prenatal opioid exposure was associated with a 16% increased risk of severe neuropsychiatric disorders, significantly higher than the 3% increased risk of common neuropsychiatric disorders.

Comparison with other studies

Previous studies explored the association between maternal opioid use and various health outcomes in the offspring52333; however, investigations specifically focusing on neuropsychiatric disorders are limited. A few studies reported no association between maternal opioid use and the risk of neuropsychiatric disorders in the offspring. However, these studies had limited cohort sizes (n=24 910) to generalise the results.16 Furthermore, they did not account for potential confounders, including maternal and childbirth related factors (eg, breastfeeding history). By contrast, our large scale nationwide cohort study, encompassing over 3.12 million pregnancies, offers a more sophisticated understanding supported by statistical analyses, thereby highlighting the nuanced association between prenatal opioid exposure and neuropsychiatric outcomes in the child.

Possible mechanisms

In this cohort study, prenatal opioid exposure was not associated with a substantial increase in the risk of neuropsychiatric disorders. The benefits of short term use of prescription opioids in attenuating acute pain without additional risk factors during pregnancy may surpass the potential risk of neuropsychiatric disorders because short term use of opioids during pregnancy seems to have a relatively low risk of neuropsychiatric outcomes. Previous studies showed that untreated pain during pregnancy may lead to a lower quality of life and limited productivity.34 When considering the risk to benefit ratio balance of prescribing opioids during pregnancy, relief of pain is crucial during pregnancy to manage maternal health and life; however, clinicians should consider avoiding opioid use under certain conditions, such as in the first trimester, for long term use, and at high dose use.

The increased risk of psychiatric disorders associated with first trimester opioid exposure suggests potential risk during the early neurodevelopmental phases. The early trimester is characterised by critical stages of neurogenesis, neuronal migration, and differentiation.3132 Opioids, acting on the central nervous system, might interfere with these processes and disrupt normal brain developmental patterns.35 In addition, the observed dose-response association between maternal opioid dosage and the incidence of neuropsychiatric disorders in the offspring indicates that prolonged and intense exposure might have cumulative heightened effects that are detrimental on fetal brain development. Higher doses and longer durations of opioid use could lead to more significant alterations in the neurochemical environment of the developing fetus, potentially altering neural pathways and synaptic functions.36

Children born via caesarean section display an increased risk of neuropsychiatric disorders.37 The increased risk might be attributed to several associated factors: the underlying maternal conditions necessitating a caesarean section that could influence fetal brain development; the absence of natural microbial exposure from the birth canal, affecting the gut microbiome of infants and potential brain interactions; altered hormonal responses compared with vaginal delivery, which can affect neonatal brain maturation; and differences in the immediate postnatal environment, such as exposure to anaesthetics, that could affect early neural patterns.3738 Therefore, combining the two adverse effects of caesarean section and maternal opioid use may synergistically increase the risk of neuropsychiatric disorders in offspring.38

Children with prenatal opioid exposure display an increased risk of specific neuropsychiatric disorders, suggesting that opioids may interfere with certain developmental processes in the fetal brain. Opioids can cross the placenta and blood–brain barrier and may influence the balance of neurotransmitters, which is crucial for developing and maintaining neural circuits.39 The increased risk of mood disorders, attention deficit hyperactivity disorder, and intellectual disabilities may result from opioids affecting the serotonin, dopamine, and norepinephrine pathways, which are primary neurotransmitters for mood regulation, attention, and cognition.39 The elucidated mechanisms presented in this study are speculative and require further validation. However, the significantly higher risk of severe neuropsychiatric disorders than that of common neuropsychiatric disorders implies the potential for opioids to disturb critical periods of neurodevelopment, leading to more critical neurobehavioural outcomes. Therefore, our findings suggest that clinicians should consider these potential risks when prescribing opioids during the first trimester, which is a crucial neurodevelopmental phase.

However, the overall population in our cohort study suggests no considerable association between maternal opioid use and neuropsychiatric disorders in the offspring. However, clinicians and patients should pay attention to opioid use in the first trimester or caesarean section, high dose, or long term intake.

Strengths and limitations of the study

This nationwide longitudinal study used validated diagnostic records and a large generalisable sample size, which minimised the risk of selection and recall biases (table S27). In addition, substantial individual-level healthcare data allowed us to characterise numerous potential confounders, including inpatient and outpatient medication exposure and medical conditions. The use of various study designs, including the full unmatched population based, propensity score matched, child screening, sibling comparison cohorts from the full unmatched, propensity score matched, and child screening cohorts, and multiple subgroup analyses, enhanced the results of our findings. Moreover, because opioids are available only as prescriptions in South Korea, exposure misclassification due to over-the-counter availability was unlikely.

Our study has several limitations. While prescriptions are recorded, they may not always reflect the actual consumption of the medication, leading to potential exposure misclassification. We can suggest an association but not explain the causal association owing to the observational nature of our study. Additionally, even with our sibling controlled analyses, potential confounding by unobserved non-shared familial factors exists.40 The method used to estimate the start of pregnancy, despite being previously validated, may retain the potential misclassification of the exposure window.40 We could not account for other potential risk factors for neuropsychiatric disorders, such as infection, epilepsy, fever, and vaccination. Because NSAIDs are not categorised as prescription drugs, an underestimation regarding their consumption is possible. However, considering the typically cautious approach of pregnant women towards medication intake without prescriptions, we decided to incorporate analyses related to NSAIDs as milder analgesics.141 Finally, the cohort was restricted to pregnancies that resulted in live births and excluded terminated pregnancies due to the absence of gestational age data for non-live births.

Conclusion

In this nationwide birth cohort study, opioid use during pregnancy was not associated with a substantial increase in the risk of neuropsychiatric disorders in the child. Although a slightly increased risk was observed for neuropsychiatric disorders, given the observational nature of the study, these results should not be considered clinically meaningful. However, through several statistical analyses, we found that prenatal opioid exposure during the first trimester, higher doses, and long term opioid use were associated with an increased risk of psychiatric disorders in the child. Prenatal opioid exposure modestly increased the risk of severe neuropsychiatric disorders, mood disorders, attention deficit hyperactivity disorder, and intellectual disability in the child. However, in the context of opioids, excessive exposure, exposure during early pregnancy, and caesarean section may warrant caution owing to their potential associations with some brain developmental disorders in offspring.

What is already known on this topic

  • Previous studies have shown mixed findings on the association between maternal opioid use and various health outcomes in the offspring, with a limited focus on neuropsychiatric disorders

  • Large scale, population based birth cohort studies are needed to clarify the potential effect of prenatal opioid exposure on the risk of neuropsychiatric disorders in children

What this study adds

  • Opioid use during pregnancy was not associated with a substantial increase in the risk of neuropsychiatric disorders in the offspring, particularly in sibling controlled analyses

  • An increased risk of neuropsychiatric disorders was observed and limited to high opioid doses, more than one opioid, longer duration of exposure, opioid exposure during early pregnancy, and only to certain specific neuropsychiatric disorders

  • These results support cautious opioid prescribing during pregnancy, highlighting the importance of further research for more definitive guidelines

Ethics statements

Ethical approval

The Korean government anonymised all patient related data, including personal identification numbers, to enhance confidentiality. The research protocol was approved by the Institutional Review Board of Kyung Hee University (KHUH 2022-06-042) and the NHIS (NHIS-2023-1-168). We conducted this study using de-identified administrative data that were obtained without prior consent.

Data availability statement

Data are available on reasonable request. The study protocol and statistical code are available from DKY (yonkkang@gmail.com). The dataset is available from the National Health Insurance Service of Korea through a data use agreement.

Footnotes

  • Contributors: JK and HJK contributed equally to this work as first authors. JIS and DKY contributed equally. MS and DKY are senior authors. DKY is a principal investigator. HJK is a co-principal investigator. JK, HJK, JIS, and DKY developed the study concept and drafted analyses plan. HJK and DKY collected data. JK, HJK, and DKY conducted analysis and prepared results. JK and HJK wrote the first draft of the paper. JIS, DKY, and MS provided critical review. All authors provided input into interpretation of results and contents of the paper. DKY had full access to all of the data in the study and verified the data. HJK and DKY are responsible for the integrity of the data, accuracy of the data analysis, and decision to submit the manuscript, and act as guarantors. The corresponding author attests that all listed authors meet the authorship criteria and that no one meeting the criteria has been omitted.

  • Funding: This research was supported by a grant of the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT; RS-2023-00248157), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI; HE23C002800), and Ministry of Food and Drug Safety in 2024 (21153MFDS601). Samuele Cortese, NIHR Research Professor (NIHR303122) is funded by the NIHR for this research project. The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care. SC is also supported by NIHR grants NIHR203684, NIHR203035, NIHR130077, NIHR128472, RP-PG-0618-20003, and by grant 101095568-HORIZONHLTH- 2022-DISEASE-07-03 from the European Research Executive Agency. SC has declared reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health in relation to lectures delivered, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, and from Medicine and Healthcare Convention for educational activity on attention deficit hyperactivity disorder. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding for this research was provided by the National Research Foundation of Korea, the Korea Health Industry Development Institute, and the Ministry of Food and Drug Safety of the Republic of Korea; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. MS has received honoraria/been a consultant for Angelini, AbbVie, Lundbeck, Otsuka, unrelated to this work.

  • Transparency: The corresponding authors (JIS and DKY), senior author (MS), lead author (JK), and co-principal investigator (HJK) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: The results of the study will be officially registered and released to National Health Insurance Service of Korea and we plan to disseminate the results of this study to all study participants and wider relevant communities upon request.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

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This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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