In Utero Exposure to Maternal Injury and the Associated Risk of Cerebral Palsy

Asma Ahmed; Laura C Rosella; Maryam Oskoui; Tristan Watson; Seungmi Yang

doi:10.1001/jamapediatrics.2022.4535

. 2022 Nov 28;177(1):53–61. doi: 10.1001/jamapediatrics.2022.4535

In Utero Exposure to Maternal Injury and the Associated Risk of Cerebral Palsy

Asma Ahmed ^1,^2,^✉, Laura C Rosella ^3,^4,^5,⁶, Maryam Oskoui ^7,^8,⁹, Tristan Watson ^3,⁴, Seungmi Yang ¹

¹Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

²Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

³Dalla Lana School of Public Health, Division of Epidemiology, University of Toronto, Toronto, Ontario, Canada

⁴ICES, Toronto, Ontario, Canada

⁵Institute for Better Health, Trillium Health Partners, Mississauga, Ontario, Canada

⁶Temerty Faculty of Medicine, Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada

⁷McGill University Health Center Research Institute, Child Health and Human Development Program, Centre for Outcomes Research and Evaluation, Montreal, Quebec, Canada

⁸Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

⁹Department of Neurology & Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

Accepted for Publication: August 24, 2022.

Published Online: November 28, 2022. doi:10.1001/jamapediatrics.2022.4535

^✉

Corresponding Author: Asma Ahmed, MD, PhD, MPH, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, 686 Bay St, Toronto, ON M5G0A4, Canada (asma.ahmed@sickkids.ca).

Author Contributions: Dr Ahmed had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ahmed, Rosella, Oskoui, Yang.

Acquisition, analysis, or interpretation of data: Ahmed, Rosella, Oskoui, Watson.

Drafting of the manuscript: Ahmed.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ahmed, Rosella, Yang.

Obtained funding: Ahmed, Yang.

Administrative, technical, or material support: Ahmed, Rosella, Watson.

Supervision: Oskoui, Yang.

Conflict of Interest Disclosures: Dr Ahmed reported receiving research funding from the Santé-Québec Doctoral Training Award during the conduct of the study. Dr Yang reported receiving grants from Santé-Québec research funds during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported in part by research funds from Santé-Québec (checheur-boursier junior 1 career award [Dr Yang] and doctoral training award to [Dr Ahmed]); ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Parts of this study material are based on data and information compiled and provided by MOMBABY (Mother-Baby Database), CIHI-DAD (The Canadian Institute for Health Information Discharge Abstract Database), OHIP (The Ontario Health Insurance Plan), RPDB (Registered Persons Database), Census data, ON-Marg (Ontario Marginalization Index), and ODB (Ontario Drug Benefit Claims). 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. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions, and statements expressed in the material are those of the author(s), and not necessarily those of CIHI.

Additional Contributions: We thank IQVIA Solutions Canada Inc for use of their Drug Information File.

Additional Information: Data for this study were obtained from ICES, an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement. While data sharing agreements prohibit ICES from making the data set publicly available, access can be granted to those who meet their criteria for access to confidential data, available at https://www.ices.on.ca/. Requests to access ICES data for research purposes may be submitted to ICES’ Data and Analytic Services (visit https://www.ices.on.ca/DAS for further information). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

^✉

Corresponding author.

PMCID: PMC9706397 PMID: 36441546

This cohort study investigates the association between maternal exposure to injury during pregnancy and the risk of cerebral palsy in offspring.

Key Points

Question

What is the association between maternal exposure to unintentional injury during pregnancy and the risk of cerebral palsy (CP) in offspring?

Findings

In this population-based cohort study of 2 110 177 births, maternal unintentional injury during pregnancy was associated with an increased risk of CP in children, particularly among those who were exposed to maternal injuries that resulted in hospitalization and those who were delivered shortly after the injury.

Meaning

Children exposed in utero to maternal unintentional injury, particularly with greater severity, might benefit from better monitoring for neurodevelopmental development.

Abstract

Importance

Although maternal unintentional injury during pregnancy has shown negative impacts on the mother and fetus, the evidence on its long-term associations with children’s neurodevelopment is limited.

Objective

To examine the association between maternal unintentional injury and cerebral palsy (CP) in offspring.

Design, Setting, and Participants

This was a population-based, longitudinal, cohort study of all in-hospital live births born between April 1, 2002, and March 31, 2017, in a publicly funded health care system setting of Ontario, Canada. Infants born more than 20 weeks’ gestation were included and followed up until March 31, 2018. Excluded from the analysis were stillbirths, infants with missing or invalid records, and births with missing or invalid birth characteristics. Data were analyzed from March 1 to June 30, 2021.

Exposures

Maternal unintentional injury during pregnancy ascertained based on inpatient or emergency department diagnoses.

Main Outcomes and Measures

CP diagnosis between birth and the end of follow-up in 2018 with the CP case definition of a single inpatient or 2 or more outpatient diagnoses at least 2 weeks apart between birth and age 16 years.

Results

Of 2 110 177 children included in this study (mean [SD] gestational age, 38.8 [1.9] weeks; 1 082 520 male [51.3%]), 81 281 (3.9%) were exposed in utero to maternal unintentional injury. During a median (IQR) follow-up time of 8 (4-12) years, 5317 children (0.3%) were diagnosed with CP (292 CP cases [5.5%] were exposed to maternal unintentional injury). The mean incidence rates of CP were 4.36 and 2.93 per 10 000 child-years in the exposed and the unexposed group, respectively. Children exposed to maternal unintentional injury had a modest increase in the risk of CP, compared with those unexposed (hazard ratio [HR], 1.33; 95% CI, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics. Severe injuries that resulted in hospitalization and delivery within 1 week from the injury conferred higher risks of CP (adjusted HR, 2.18; 95% CI, 1.29-3.68 and adjusted HR, 3.40; 95% CI, 1.93-6.00, respectively). Results were robust in multiple bias analyses.

Conclusions and Relevance

In this Canadian population-based birth cohort study, in utero exposure to maternal unintentional injury was associated with an increased risk of CP, with a higher risk with more severe injuries. These findings fill an important gap in knowledge on the potential role of maternal injury on children’s neurodevelopment outcomes. Public health professionals and stakeholders should be aware of these potential long-term consequences on offspring when designing programs and providing recommendations about safety during pregnancy. Early monitoring and developmental assessment of children exposed to maternal injury might be warranted.

Introduction

Injuries affect approximately 6% to 8% of pregnant women.^1,2 Most injuries are unintentional, with motor vehicle crashes and falls being the 2 most common (88%-92%).^1,2,3 Injuries are the leading cause of nonobstetrical maternal mortality during pregnancy and are associated with complications in both the mother and the baby.^3,4,5 Maternal complications after injuries include uterine rupture, preterm delivery, and placental abruption.^3,4,5 Maternal injuries are also linked to numerous fetal and neonatal complications, such as fetal asphyxia.^3,5

Although maternal and fetal complications have been reported after minor injuries, studies have shown that more severe injuries carry higher risks.^3,6 For example, researchers have found that 1 in 3 pregnant women hospitalized for injury would deliver during her hospitalization, and they have worse maternal and fetal outcomes than women who deliver after being discharged.^3,7

Despite the common occurrence of unintentional injury during pregnancy, studies of its associations with an offspring’s neurodevelopment are scarce. Few case series have reported an increased risk of poor neurodevelopmental outcomes after the in utero exposure to injury.^8,9,10 To date, only 1 population-based study has examined associations between maternal motor vehicle crashes and cerebral palsy (CP) and showed an associated increase in the risk of CP in children born preterm.¹¹

In a large population-based cohort from the general population, therefore, we aimed to examine the association between unintentional injuries during pregnancy and CP risk in offspring and explore the role of severity of the injury on the risk of CP.

Methods

Study Population

We created a retrospective birth cohort by linking several individual- and area-level administrative data sets at ICES (formerly known as Institute for Clinical Evaluative Sciences), which houses and maintains databases with health and demographic information of all users of the publicly funded provincial health care system in Ontario, Canada.^12,13 The data sets were linked using unique encoded identifiers and analyzed at ICES. Eligible infant-mother dyads were identified from the Mother-Baby Database that deterministically links mother and delivery records with greater than 98% linkage rate (eTable 1 in the Supplement contains details of data sources). We included all infants born more than 20 weeks’ gestation in Ontario hospitals between April 1, 2002, and March 31, 2017, and followed up until March 31, 2018. We excluded stillbirths, missing or invalid records, and births with missing or invalid birth characteristics.¹⁴ Data regarding participant race and ethnicity were not available for this study because administrative data at ICES do not collect these data. We received ethics approval from the institutional review board of the Faculty of Medicine and Health Sciences at McGill University, with a waiver of informed consent because deidentified data were used. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.¹⁵

Exposure and Outcome

Maternal unintentional injury during pregnancy was classified by any inpatient (from the Canadian Institute for Health Information-Discharge Abstract Database [CIHI-DAD]) or emergency department (from the National Ambulatory Care Reporting System [NACRS] database) diagnosis of unintentional injury during the index pregnancy, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes (V01–X59).¹⁶ Further details are described in eTable 2 in the Supplement. We excluded intentional injuries (eg, suicidal attempts, domestic violence) as their associations may reflect different processes of high levels of maternal stress, mental health disorders, or other psychosocial factors from those due to unintentional injuries.¹⁷

The severity of the identified injury was stratified into 2 categories: injuries treated in the emergency department with no in-hospital admission as the nonsevere injury, and injuries treated as an inpatient as the severe injury. We also classified injuries according to the frequency of exposure to injury (1 or ≥2), the timing of delivery relative to the injury (delivered within 7 days or >7 days of injury), and the timing of the injury (the first, second, and third trimester).

A diagnosis of CP in children between birth and the age of up to 16 years was based on (1) a single inpatient hospitalization diagnosis from CIHI-DAD (ICD-10 code: G80), or (2) 2 or more outpatient diagnoses, at least 2 weeks apart (International Statistical Classification of Diseases and Related Health Problems, Ninth Revision, code: 343), on physician billings claims (eTable 2 in the Supplement).^11,12

Covariates

We identified several sociodemographic and clinical factors that are potentially associated with both exposure and outcome based on the literature.^6,18,19 These factors included maternal age (<20, 20-24, 25-29, 30-34, 35-39, or ≥40 years), parity (0, 1, 2, 3, or ≥4 previous live births), maternal eligibility for the provincial drug benefits available for individuals with financial needs due to unemployment or disability²⁰ as a proxy for individual-level low socioeconomic status, the start of prenatal care (delayed if the first visit >13 weeks’ gestation),²¹ rural residence,²² and area-based socioeconomic characteristics (neighborhood income and the 4 Ontario marginalization indices, namely residential instability, material deprivation, economic dependency, and ethnic concentration) (eMethods in the Supplement).²³ We further included maternal diagnoses of substance (including smoking, alcohol, and drug) use disorder and obesity before or during pregnancy (eTable 2 in the Supplement). We also included birth year to account for temporal changes in rates of exposure and outcome during the study period.

Statistical Analysis

We estimated incidence rates of CP by exposure to maternal unintentional injury and crude and adjusted hazard ratios (HRs) using Cox proportional hazards models with age as the time scale. We followed up each child from birth to the time of CP diagnosis, death, or the end of follow-up on March 31, 2018, whichever came first. Adjusted analyses included the a priori determined potential confounders in the following sequence: model 1 adjusting for birth year, model 2 adjusting for birth year and maternal sociodemographic characteristics (age, parity, and socioeconomic indicators), and model 3 adjusting for all covariates in model 2 plus maternal substance use disorder or obesity and delayed onset of prenatal care. We accounted for nonlinear associations between birth year and the outcome, using restricted cubic splines^24,25 with 3 knots at years 2003, 2010, and 2016. We found no evidence of a violation of the proportional hazards assumption (tested graphically and statistically by the scaled Schoenfeld residuals for nonzero slope and the χ² test of proportional hazards assumption) for all variables except for birth year. We, therefore, allowed the baseline hazard to vary by birth year (stratified Cox model)²⁶ because models with birth year as time-varying covariates did not converge. Robust (sandwich) variance estimates were used in all models to account for correlation due to clustering of siblings within mothers (n = 1 021 086 siblings born to 450 929 mothers). All statistical tests were 2-sided, and the threshold for significance was P < .05. All statistical analyses were conducted using Stata, version 16.1 (StataCorp). Data were analyzed from March 1 to June 30, 2021.

Quantitative Bias Analysis

We conducted multiple probabilistic bias analyses (record-level correction) to examine the robustness of our estimates against potential misclassification and confounding biases.^27,28 We first assessed impacts of outcome misclassification using sensitivity and specificity values of diagnostic codes of CP obtained from the literature²⁹ (eMethods in the Supplement). We also evaluated the impact of unmeasured confounding by maternal individual-level socioeconomic factors by simulating a dichotomous variable (U) representing low maternal education (university graduate or not).^2,30 We conducted additional quantitative bias analyses to quantify the potential impact of residual confounding by maternal lifestyle factors (ie, capturing smoking, alcohol, or drug use beyond clinical diagnoses) on observed associations.^2,5,31,32,33 We also corrected for outcome misclassification and unmeasured confounding simultaneously, together with measured confounders, in the fully adjusted model (eMethods in the Supplement).

Secondary Analyses

To examine if the risk of CP varies by injury mechanism, we estimated the associations by different categories: transport-related injuries, falls, injuries related to mechanical forces, and other unintentional injuries. Time-to-event analyses may reflect the age of diagnosis rather than the onset of CP and may be influenced by factors that affect how soon a child is diagnosed with CP. Thus, we reexamined associations between maternal unintentional injury and CP using Poisson regression with follow-up time as the offset variable and log-binomial regressions. Children born preterm are at increased risk of CP³⁴ and have a shorter duration for the in utero exposure to maternal injury than those born at term; thus, the association using the anytime in pregnancy definitions may be underestimated. We thus reestimated associations separately for preterm and term births to examine whether associations varied by preterm birth status.

Results

Of 2 227 286 identified births, 2 110 177 live births (mean [SD] gestational age, 38.8 [1.9] weeks; 1 082 520 male [51.3%]; 1 027 657 female [48.7%]) were included in the study (eFigure 1 in the Supplement). Of those, 81 281 children were exposed in utero to maternal unintentional injury. Young mothers (<20 years, 5546 [6.8%] vs 60 818 [3.0%]), mothers with substance use disorder (2658 [3.3%] vs 28 134 [1.4%]), recipients of provincial drug benefits (11 921 [16.1%] vs 164 474 [8.1%]), and those living in rural areas (13 088 [16.9%] vs 198 683 [9.8%]) or neighborhoods with low ethnic diversity (least marginalized, 14 132 [17.4%] vs 248 452 [12.3%]), high material deprivation (most marginalized, 21 284 [26.2%] vs 425 446 [21.0%]), or high economic dependency (most marginalized, 13 187 [16.2%] vs 259 645 [12.8%]) were more likely to experience unintentional injury during pregnancy (Table 1). The most common mechanisms of injury were falls, transport-related injuries, and injuries related to mechanical forces such as being struck by an object or another person (eTable 3 in the Supplement). As shown in Table 2, 8.1% of exposed women (6578 of 81 281) experienced more than 1 injury during pregnancy, and a minority were hospitalized after the injury (2.7% [2158 of 81 281]) or delivered the baby within a week of injury (1.6% [1323 of 81 281]). The prevalence of live births exposed to unintentional injury has remained stable during the study period at approximately 4%, except for 2002 births (approximately 2.5%) (eFigure 2 in the Supplement), reflecting the incomplete ascertainment of maternal injury for those born in 2002 as we only used NACRS and CIHI-DAD data from April 2002 onward.

Table 1. Maternal Characteristics by Exposure to Maternal Unintentional Injury During Pregnancy in Children Born in Ontario, Canada, in 2002-2017 (N = 2 110 177).

Characteristics	Exposure to unintentional injury during pregnancy, No. (%)
Characteristics	No	Yes
No.	2 028 896	81 281
Maternal age, y
<20	60 818 (3.0)	5546 (6.8)
20-24	246 627 (12.2)	16 313 (20.1)
25-29	562 286 (27.7)	23 284 (28.7)
30-34	713 102 (35.2)	23 000 (28.3)
35-39	367 699 (18.1)	10 775 (13.3)
>40	78 364 (3.9)	2363 (2.9)
Parity
0	907 287 (44.7)	37 600 (46.3)
1	721 911 (35.6)	26 216 (32.3)
2	264 764 (13.1)	11 035 (13.6)
3	80 298 (4.0)	3758 (4.6)
>4	54 636 (2.7)	2672 (3.3)
Neighborhood income, quintile
1st (Highest)	336 246 (16.6)	11 075 (13.6)
2nd	419 902 (20.7)	15 324 (18.9)
3rd	413 458 (20.4)	16 162 (19.9)
4th	403 341 (19.9)	17 317 (21.3)
5th (Lowest)	448 642 (22.1)	21 049 (25.9)
Missing	7307 (0.4)	354 (0.4)
ON-Marg residential instability, quintile ^a
1st (Least marginalized)	402 937 (19.9)	12 472 (15.3)
2nd	401 903 (19.8)	15 158 (18.7)
3rd	358 897 (17.7)	15 258 (18.8)
4th	380 411 (18.8)	17 611 (21.7)
5th (Most marginalized)	450 431 (22.2)	18 968 (23.3)
Missing	34 317 (1.7)	1814 (2.2)
ON-Marg material deprivation, quintile
1st (Least marginalized)	488 055 (24.1)	14 637 (18.0)
2nd	368 920 (18.2)	13 395 (16.5)
3rd	360 808 (17.8)	14 467 (17.8)
4th	351 350 (17.3)	15 684 (19.3)
5th (Most marginalized)	425 446 (21.0)	21 284 (26.2)
Missing	34 317 (1.7)	1814 (2.2)
ON-Marg economic dependency quintile ^a
1st (Least marginalized)	616 554 (30.4)	20 536 (25.3)
2nd	458 002 (22.6)	16 532 (20.3)
3rd	358 264 (17.7)	15 105 (18.6)
4th	302 114 (14.9)	114 107 (17.6)
5th (Most marginalized)	259 645 (12.8)	13 187 (16.2)
Missing	34 317 (1.7)	1814 (2.2)
ON-Marg ethnic concentration, quintile ^a
1st (Least marginalized)	248 452 (12.3)	14 132 (17.4)
2nd	288 474 (14.2)	14 427 (17.8)
3rd	333 711 (16.5)	14 925 (18.4)
4th	440 666 (21.7)	15 999 (19.7)
5th (Most marginalized)	683 276 (33.7)	19 984 (24.6)
Missing	34 317 (1.7)	1814 (2.2)
Recipient of Ontario drug benefit
No	1 864 422 (91.9)	58 371 (83.9)
Yes	164 474 (8.1)	11 921 (16.1)
Living in rural area
No	1 829 459 (90.2)	68 193 (83.1)
Yes	198 683 (9.8)	13 088 (16.9)
Missing	754 (0)	41 (0.1)
Smoking, alcohol, or drug use disorder^a
No	2 000 762 (98.6)	78 623 (96.7)
Yes	28 134 (1.4)	2658 (3.3)
Obesity^a
No	1 983 282 (97.8)	78 700 (96.8)
Yes	45 614 (2.3)	2581 (3.2)
Start of prenatal care, wk
≤13	1 803 491 (88.9)	73 740 (90.7)
>13	225 405 (11.1)	7541 (9.3)
Cerebral palsy
No	2 023 871 (99.8)	80 989 (99.6)
Yes	5025 (0.3)	292 (0.4)

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Abbreviation: ON-Marg, Ontario Marginalization Index.

^{^a}

Maternal substance use disorder and obesity were based on inpatient or outpatient diagnoses before or during pregnancy (up to 660 days before the delivery date).

Table 2. Associations Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring.

Characteristic	No.	HR (95% CI)
Characteristic	No.	Crude	Model 1^a	Model 2^b	Model 3^c
Injury
No	2 028 896	1 [Reference]	1 [Reference]	1 [Reference]	1 [Reference]
Yes	81 281	1.46 (1.30-1.65)	1.45 (1.29-1.64)	1.35 (1.19-1.52)	1.33 (1.18-1.50)
Treatment of injury
No injury	2 028 896	1 [Reference]	1 [Reference]	1 [Reference]	1 [Reference]
Emergency department only	79 123	1.43 (1.27-1.62)	1.42 (1.26-1.61)	1.32 (1.17-1.49)	1.31 (1.15-1.48)
Hospitalization	2158	2.52 (1.49-4.26)	2.45 (1.45-4.14)	2.23 (1.32-3.78)	2.18 (1.29-3.68)
Frequency of injury
None	2 028 896	1 [Reference]	1 [Reference]	1 [Reference]	1 [Reference]
1	74 703	1.40 (1.24-1.59)	1.40 (1.23-1.59)	1.30 (1.15-1.48)	1.29 (1.14-1.47)
2 or more	6578	2.11 (1.51-2.96)	2.09 (1.48-2.93)	1.80 (1.28-2.54)	1.77 (1.26-2.48)
Timing of delivery relative to injury
None	2 028 896	1 [Reference]	1 [Reference]	1 [Reference]	1 [Reference]
Delivered >7 d after injury	79 958	1.42 (1.26-1.61)	1.42 (1.25-1.60)	1.31 (1.16-1.48)	1.30 (1.15-1.47)
Delivered ≤7 d after injury	1323	3.67 (2.08-6.47)	3.67 (2.08-6.46)	3.43 (1.94-6.04)	3.40 (1.93-6.00)
Timing of injury^d
None	2 028 896	1 [Reference]	1 [Reference]	1 [Reference]	1 [Reference]
1st Trimester (0-12 wk)	33 481	1.68 (1.42-1.99)	1.67 (1.41-1.98)	1.52 (1.28-1.80)	1.50 (1.26-1.78)
2nd Trimester (13-27 wk)	29 999	1.38 (1.13-1.68)	1.37 (1.13-1.67)	1.28 (1.05-1.56)	1.27 (1.04-1.55)
3rd Trimester (≥28 wk)	17 801	1.20 (0.91-1.57)	1.19 (0.91-1.56)	1.13 (0.86-1.48)	1.12 (0.86-1.47)

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Abbreviation: HR, hazard ratio.

^{^a}

Model 1 included birth year. Birth year was modeled using restricted cubic splines with 3 knots at 2003, 2010, and 2016 years.

^{^b}

Model 2 included birth year maternal sociodemographic characteristics (age, parity, and socioeconomic indicators).

^{^c}

Model 3 included all covariates in model 2 plus clinically documented maternal substance use disorder and obesity.

^{^d}

Timing of injury was calculated based on the gestational age at the time of injury. Women exposed to more than 1 injury were classified according to the gestational age at the first injury.

The median (IQR) follow-up was 8 (4-12) years. During this time, 5317 children were diagnosed with CP; 292 of them were exposed to maternal unintentional injury (Table 1). The incidence rate was 2.99 (95% CI, 2.91-3.07) per 10 000 child-years. The Figure illustrates the Kaplan-Meier plot of crude cumulative incidence of CP by exposure status. Average annual CP incidence rates were 4.36 (95% CI, 3.89-4.89) and 2.93 (95% CI, 2.85-3.02) per 10 000 child-years in the exposed and unexposed to maternal injuries, respectively.

Figure. — The lines represent unadjusted cumulative incidence of CP, and the shaded areas represent 95% CIs.

Table 2 shows crude and adjusted associations of maternal unintentional injuries with CP. Children exposed to maternal unintentional injury had a higher risk of CP (HR, 1.46; 95% CI, 1.30-1.65); adjustment for sociodemographic factors and clinically documented maternal substance use disorder and obesity attenuated these associations (adjusted HR, 1.33; 95% CI, 1.18-1.50). Higher severity of injury may pose a higher risk of CP. For example, the adjusted HR for children exposed to injuries that resulted in maternal hospitalization was 2.18 (95% CI, 1.29-3.68; P = .06 for the Wald test of equality of coefficients); the corresponding figure for children exposed to more than 1 injury was 1.77 (95% CI, 1.26-2.48; P = .09). A higher risk of CP was also observed in children delivered shortly after the injury (adjusted HR, 3.40; 95% CI, 1.93-6.00; P < .001). Injuries that occurred earlier in pregnancy tended to show higher risks for CP than those exposed in the third trimester, although the coefficients across timing of injury categories were not statistically heterogeneous.

Results of quantitative bias analyses are presented in Table 3. Associations between maternal unintentional injury and CP slightly strengthened when we adjusted for the potential outcome misclassification (bias-adjusted HR, 1.54; 95% simulated CI, 1.35-1.76; accounting for systematic and random errors). Accounting for unmeasured confounding by maternal education did not influence our estimate, and adjusted estimates corrected simultaneously for outcome misclassification and unmeasured confounding were slightly stronger (HR, 1.40; 95% CI, 1.23-1.61) than the naive estimates. However, accounting for residual confounding by maternal lifestyle factors attenuated observed associations (HR, 1.15; 95% CI, 1.03-1.30) after accounting for unmeasured confounding and 1.30 (95% CI, 1.14-1.49) after further correction for outcome misclassification.

Table 3. Associations Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring Corrected for Outcome Misclassification and Unmeasured Confounding^a.

Crude analyses,^a HR (95% simulated interval)
Naive crude estimate^b	Corrected for outcome misclassification
1.46 (1.30-1.65)	1.54 (1.35-1.76)^c
Adjusted analyses ^d
Naive-adjusted estimate^e
1.33 (1.18-1.50)	1.30 (1.16-1.47)^c^,^f	1.40 (1.23-1.61)^c^,^g
1.33 (1.18-1.50)	1.15 (1.03-1.30)^c^,^h	1.30 (1.14-1.49)^c^,ⁱ

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^{^a}

Crude analyses only included maternal unintentional injury during pregnancy.

^{^b}

Naive crude estimates are crude estimates of the associations between maternal injury and CP calculated using Cox proportional hazards models.

^{^c}

Adjusted for both systematic and random errors.

^{^d}

Adjusted analyses included birth year, maternal sociodemographic characteristics (age, parity, and socioeconomic indicators), clinically documented substance use disorder, and obesity.

^{^e}

Naive adjusted estimates are adjusted estimates of the associations between maternal injury and CP calculated using Cox proportional hazards models, adjusted for the confounders listed above.

^{^f}

Corrected for unmeasured confounding by maternal education.

^{^g}

Corrected for outcome misclassification and unmeasured confounding by maternal education.

^{^h}

Corrected for unmeasured confounding by maternal lifestyle factors.

^ⁱ

Corrected for outcome misclassification and unmeasured confounding by maternal lifestyle factors.

In our analysis stratified by the mechanism of the injury, the increased CP risk remained present for each type of injury, most notably transport-related injuries (eTable 4 in the Supplement). Crude and adjusted rate ratios from Poisson regression and risk ratios from log-binomial regression were similar to HRs presented in the main results (eTables 5 and 6 in the Supplement). When we separately analyzed preterm and term births, associations between maternal unintentional injury and CP in those born preterm were similar to the main results, while estimates for term-born children were slightly weaker (eTable 7 in the Supplement). Association with third trimester injury was more pronounced in children born at term or later.

Discussion

In this population-based cohort study of approximately 2 million births, results suggest that exposure to maternal unintentional injury was associated with an increased risk of CP in children. The associated risk of CP was higher among children exposed to maternal injuries that required hospital admission or resulted in delivery shortly after the injury, or those exposed to injuries multiple times.

Limited evidence exists on long-term associations of maternal unintentional injuries during pregnancy with the offspring’s neurodevelopment. Consistent with our findings, a few case reports have described poor neurodevelopment in children exposed in utero to injury.^8,9,10 Hayes and colleagues¹⁰ described 10 cases of CP after maternal trauma in pregnancy, reporting that all cases had uneventful deliveries at term with no sign of perinatal asphyxia but showed postnatal neuroimaging results consistent with prenatal brain damage. Another report based on 529 CP cases from the Australian CP Register found a 1.4-fold increase in CP risk in children of mothers exposed to injury requiring hospitalization, relative to those unexposed to injury.³⁵ However, their study included only 2 CP cases with maternal hospitalization due to injury. A Canadian population-based study has also found a small positive association between maternal motor vehicle crashes during pregnancy and CP but only among preterm-born children.¹¹ This study was also based on a small number of CP cases (18 children with CP in the exposed) and only considered injuries related to motor vehicle crashes.¹¹

Although we did not have direct information on injury severity, we have considered different characteristics related to the injury that may be linked to severity. Delivery within 7 days of injury, in particular, posed a high risk for CP, consistent with others who have observed worse maternal and fetal outcomes in women delivered during the same hospitalizations for injury.^3,7,16 We also found that injuries that resulted in hospitalization tended to show a higher risk of CP than injuries treated in the emergency department only. In the present study, approximately 8% of exposed women experienced more than 1 injury during pregnancy, and they showed slightly higher risks of CP in offspring than those exposed once. These results were consistent with Vladutiu et al³⁶ who found higher rates of adverse birth outcomes (eg, PTB and placental abruption) in those involved in multiple motor vehicle crashes during pregnancy than those exposed to a single crash.

Trimester-specific associations showed slightly higher risks of CP in children of women injured in the first and second trimester compared with the third trimester. However, third trimester associations would have been underestimated because children born less than 28 weeks have no opportunity to be classified as third trimester exposed but are at increased risk of CP.³⁴

As reported by others, falls and transport-related injuries (mostly motor vehicle crashes) were the 2 most common mechanisms of injury during pregnancy.^1,2,3 Although the association is unclear for falls, transport-related injuries posed an increase in the risk of CP after adjusting for factors commonly related to vehicle crashes (eg, young maternal age, low socioeconomic status).⁶ Motor vehicle crashes are associated with the highest rates of maternal mortality and morbidities and poor fetal outcome.^6,37 It is possible that injuries related to motor vehicle crashes are more severe (approximately 5% of patients with transport-related injuries in our study were hospitalized, compared with 2.7% for any injury) and may result in more damage to the placenta and fetus.

Several complications of maternal injuries, such as placental abruptions, preterm birth (PTB), and fetal hypoxia, have been linked to an increased risk of CP.^{3,4,5,34,38,39} Diagnostic and treatment interventions for the mother, such as imaging or analgesics, may also negatively affect the developing fetus.^37,40 PTB is common after maternal injury,^5,7,16,41,42 but our data showed only a modest increase in the risk of PTB after maternal unintentional injury, possibly because we included all injuries (mild and severe) and could not differentiate between PTBs induced by the injury from those due to other causes. Our analyses stratified by PTB status showed that associations were present among children born preterm or at term; however, these results should be interpreted with caution as they are susceptible to collider-stratification bias, a phenomenon similar to the birth weight paradox.^43,44

Strengths and Limitations

This study had several strengths. Our study population consisted of a population-based cohort of almost all live births occurring in Ontario over a 16-year period, reducing potential selection bias and enhancing generalizability. The large sample also improved statistical precision and allowed for examining associations by more detailed characteristics of the injury.

Our results, however, should be interpreted in light of several limitations. Misclassification of exposure and outcome is plausible, however, it would more likely be nondifferential. Administrative databases lack a clear case definition for CP and only capture cases presented for medical care. However, CP diagnostic codes in administrative data in Canada have shown a sensitivity of 65.5% and a specificity of 99.9% in validation studies,²⁹ and we accounted for this potential misclassification in our bias analysis. Our CP case definition of at least 1 in-hospital diagnosis or 2 outpatient diagnoses would have further reduced misclassification. Underascertainment of CP may have also occurred due to the shorter follow-up time for those born in recent years, but almost 60% of CP cases were diagnosed before the age of 2 years in our data. Socioeconomic factors may affect the likelihood of accessing health care and getting a diagnosis of CP and are also associated with the exposure status, which may lead to differential outcome misclassification. However, our data included all births within a publicly funded health system that would reduce access barriers to health care in general. We also found no evidence of differences in the age of CP diagnosis by socioeconomic status or exposure status. We used injury codes developed by the international framework for injury surveillance by the Center for Disease Control and Prevention⁴⁵ that were extensively used in various populations, including in pregnant women.^11,16,46 Although we included injuries in pregnancy that sought medical attention only, leaving those with minor injuries out, we believe it would be small in proportion because pregnant women experiencing injuries would highly likely seek health care for maternal and fetal well-being.⁴⁷

We had information on neither individual-level maternal socioeconomic factors (eg, education, occupation) nor other lifestyle factors than clinically diagnosed substance disorders and obesity during pregnancy or the year before. Residual confounding by these factors is also a potential threat to the validity of our results; however, our quantitative bias analyses for unmeasured confounding only slightly attenuated observed associations. It is also plausible that potential confounders would differ according to injury mechanism (eg, body mass index for falls), but we were unable to correct for residual confounding specific to injury mechanism in our bias analysis due to lack of scientific evidence on the mechanism-specific associations. Although the association of maternal unintentional injury might vary across CP subtype,⁴⁸ we had no data on CP subtype and thus could not examine subtype-specific associations.

Conclusions

This research, the first and largest population-based cohort study, to our knowledge, suggests a role of maternal injury during pregnancy in fetal neurodevelopment by showing positive associations between in utero exposure to maternal unintentional injury and CP overall and across several classifications according to the injury frequency, severity, and mechanism. Future studies that directly measure the severity of injury are needed to further elucidate whether the risk of CP is linked to injury severity, as shown for other maternal and fetal outcomes.^3,7,37 Current guidelines for the management of injury in pregnant patients focus only on monitoring the fetal condition immediately after the injury with little attention to its long-term effects on offspring.^49,50 By providing evidence of potential long-term harmful associations of exposure to injuries during pregnancy, these results suggest that monitoring of children exposed to maternal injury in utero may contribute to early detection of adverse neurodevelopmental outcomes and thus to the provision of optimal management and needed support.

Supplement.

eMethods

eTable 1. Description of Different Data Sets at ICES and the Relevant Study Variables

eTable 2. Diagnostic Codes Used to Define Study Variables

eTable 3. Number of Children Exposed to Maternal Unintentional Injury According to the Mechanism of Injury

eTable 4. Hazard Ratios of the Association Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring According to the Mechanism of Injury

eTable 5. Rate Ratios for the Associations Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring, Calculated Using Poisson Regression Models

eTable 6. Risk Ratios for the Associations Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring, Calculated Using Log-Binomial Regression Models

eTable 7. Hazard Ratios of the Association Between Maternal Unintentional Injury During Pregnancy and Cerebral Palsy in Offspring Stratified by Preterm Birth

eFigure 1. Flowchart Illustrating the Formation of the Study Cohorts

eFigure 2. Crude Prevalence of Maternal Exposure to Unintentional Injury During Pregnancy by Year of Birth

Click here for additional data file.^{(294.1KB, pdf)}

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