Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies

Abstract

To investigate the association between labor epidural analgesia exposure and the risk of autism spectrum disorder in offspring, this meta-analysis reviewed relevant literature from Medline, Cochrane Library, Google Scholar, and EMBASE databases from inception to May 2022 to evaluate the overall adjusted risk of autism spectrum disorder in offspring (primary outcome) and adjusted risks of autism spectrum disorder focusing on sibling-matched data, children who were delivered vaginally, and duration of labor epidural analgesia exposure (secondary outcomes). Pooled results of seven eligible observational studies involving 4,021,406 children revealed slightly higher risks of autism spectrum disorder in children with labor epidural analgesia exposure than those without (hazard ratio = 1.11, 95% confidence interval: 1.06–1.16, I² = 67%, seven studies, level of evidence: very low). Consistent findings were found in subgroup analysis focusing on sibling data (hazard ratio: 1.10, 95% confidence interval: 1.02–1.18, I² = 0%, five studies) and children delivered vaginally (hazard ratio: 1.11, 95% confidence interval: 1.06–1.17, I² = 64%, seven studies). The tendency of an increased risk of autism spectrum disorder in children exposed to labor epidural analgesia <4 h was not observed in those exposed to labor epidural analgesia >8 h (two studies). Although our results demonstrated a slightly increased risk of autism spectrum disorder in offspring with previous labor epidural analgesia exposure, the small effect size and lack of cumulative dose–response effect precluded tangible evidence supporting the association.

Lay abstract

A previous meta-analysis has demonstrated a superior analgesic efficacy of epidural analgesia (e.g. labor epidural analgesia) in comparison with non-epidural approaches. The widely accepted safety of labor epidural analgesia also endorses its current popularity in obstetric practice. However, the results of a recent large-scale longitudinal study that demonstrated a significant increase in risk of autism spectrum disorder in offspring from mothers with labor epidural analgesia exposure have raised some concerns over the safety of its use. The current meta-analysis aimed at examining the strength of evidence regarding this issue based on updated clinical data. Through systematically reviewing seven eligible observational studies involving 4,021,406 children from electronic databases, our results showed a slight but statistically significant increase in risk of autism spectrum disorder in children with exposure to labor epidural analgesia compared with those without. The finding was consistent in subgroup analysis focusing on siblings and children delivered vaginally. Nevertheless, despite the tendency of an increased risk of autism spectrum disorder in children exposed to labor epidural analgesia <4 h, this effect was not observed in those exposed to labor epidural analgesia >8 h (data from two studies). In conclusion, the level of evidence linking labor epidural analgesia to autism spectrum disorder development in offspring was very low based on the latest data because of the small effect size and the finding of a lack of cumulative dose–response effect in the current analysis. Further studies are warranted to provide an insight into this issue.

Keywords

autism spectrum disorder labor epidural analgesia meta-analysis offspring

Introduction

The majority of parturients reported intense labor pain that could not be inadequately controlled (Dickinson et al., 2003; Ranta et al., 1996). A previous meta-analysis has demonstrated more satisfactory relief of labor pain among women receiving neuraxial analgesia (e.g. labor epidural analgesia (LEA)) compared to those undergoing non-epidural approaches (Anim-Somuah et al., 2018). In addition, because LEA is widely believed to be a safe procedure (Halliday et al., 2022) without significant impact on the risk of cesarean section (CS) and neonatal status (e.g. low Apgar scores) (Anim-Somuah et al., 2018), LEA has gained wide acceptance in obstetric practice and is currently being used in up to 57%–80% of parturients (Harkins et al., 2010; Le Ray et al., 2008; Wang et al., 2018). However, a recent retrospective longitudinal database study on 147,895 children demonstrated a 37% increased risk of autism spectrum disorder (ASD) in offspring with previous LEA exposure compared to those without (Qiu et al., 2020), raising a safety concern over the peripartum use of LEA. On the other hand, other large-scale observational studies with (Hanley et al., 2021; Mikkelsen et al., 2021; Wall-Wieler et al., 2021) or without (Straub et al., 2021) sibling-matched analysis did not demonstrate a significant association between LEA exposure and ASD development in offspring (Hanley et al., 2021; Mikkelsen et al., 2021; Straub et al., 2021; Wall-Wieler et al., 2021). Although the previously reported correlation (Qiu et al., 2020) may be partly attributed to methodological limitations, heterogeneous population characteristics, and underdetermined confounders (e.g. genetic and environmental factors) (A. J. Butwick et al., 2022; A. J. Butwick & Wall-Wieler, 2021; McKeen & Zaphiratos, 2021; Saito et al., 2021), a possible link could not be ruled out. Through systematically reviewing the updated clinical data, the current meta-analysis aimed at addressing the possible relationship between LEA exposure and risk of ASD to guide clinical practice.

Materials and methods

This study was conducted based on the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and registered on PROSPERO (CRD42022336136).

Data sources and searches

The four major databases including MEDLINE, Embase, Google Scholar, and Cochrane Library were searched using a combination of relevant keywords and MeSH terms. The literature search was conducted from inception to 30 May 2022 without restrictions regarding language, publication years, and sample size. The reference lists of the retrieved articles were further examined to identify potentially eligible studies.

The search strategies for three of the databases (i.e. MEDLINE, Embase, and Cochrane Library) are shown in Supplemental Table 1. With respect to Google Scholar, we adopted a hand-search strategy to identify the related studies, followed by using a forward snowballing strategy to retrieve all potentially eligible articles as previously described (Greenhalgh & Peacock, 2005; Vassar et al., 2016).

Inclusion and exclusion criteria

Studies that met the following criteria were considered eligible: (a) Population: children who were delivered vaginally or via CS; (b) Exposure: children exposed to LEA for peripartum pain relief (LEA group), irrespective of the exposure duration. Studies in which LEA was used during labor and subsequently for pain relief following CS were also included; (c) Outcome: the risk of ASD was available. The identification of children diagnosed with ASD was based on the criteria used in each study. Two reviewers independently screened the eligibility of the retrieved studies. Any discrepancy in opinion regarding study selection was settled through discussion with a third reviewer until a consensus was reached. Articles published as non-original studies (e.g. reviews), non-human investigations, studies without a suitable control group (i.e. children not exposed to LEA), and those reporting effect sizes in formats unsuitable for statistical analysis were excluded.

Study screening and data extraction

Each of the two independent reviewers adopted a two-step process for determining the eligibility of the acquired articles, including the screening of titles and/or abstracts followed by a full-text review. Two authors independently extracted data, and conflicts were resolved by consultation with a third author. For each study, we collected data pertaining to the first author’s last name, year of publication, country, study design, name of study/database, follow-up duration, and total number of children with and without LEA exposure.

Risk of bias assessment and certainty assessment

As described in our previous investigation (Gómez et al., 2021), the quality of the included studies was evaluated by two independent authors using the Newcastle–Ottawa Scale (NOS) that comprises three categories with a total of eight items, including four items in the Selection category, one item in the Comparability category, and three items in the Outcome category. A maximum of one star can be given to each item within the Selection and Outcome categories, while a maximum of two stars can be assigned to each item in the Comparability category. Therefore, a maximum of nine stars can be given to each study. Studies awarded with more than seven stars were considered to have a low risk of bias. Any discrepancy in opinion was settled through arbitration involving a third author.

The same two authors independently graded the certainty of evidence regarding the outcomes (i.e. high, moderate, low, and very low) based on the probabilities of publication bias, study limitations, effect consistency, indirectness, and imprecision as mentioned in the Grading of Recommendations Assessments, Development, and Evaluation (GRADE). Conflicts regarding certainty ratings were resolved through discussion.

Statistical analysis

All statistical analyses of this study were conducted with the Cochrane Review Manager (RevMan 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). If a study provided several adjusted hazard ratios (HRs) based on different models, the fully adjusted models (or highest-level adjusted estimates) were selected as the corresponding effect size estimates. The random-effects meta-analysis model was used to combine the results of the included studies (Hung et al., 2022). The pooled results are expressed as HR with 95% confidence intervals (CIs). Between-study heterogeneity was assessed with I² statistics, while publication bias was evaluated with funnel plots and Egger’s test. The effect of the outcome of each study on the overall results was determined by sensitivity analysis (Hung et al., 2021). Subgroup analyses based on sibling-matched data, the duration of LEA exposure (i.e. <4 h, 4–8 h, >8 h), and a potential overlap of study population were performed. For two or more studies that reported findings on potentially the same or overlapping population, the one with the largest sample size was selected for subgroup analysis to exclude the bias from a doubled weight for analysis. Moreover, because a previous meta-analysis has reported a possible increased odds of ASD in children delivered by CS (Curran, O’Neill, et al., 2015), we also focused on the subgroup of children who were delivered vaginally to minimize the risk of bias. Statistical significance was set at the 5% level, and all tests were two-tailed.

Results

Literature search

Figure 1 shows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. Initially, the search yielded a total of 207 records, of which 36 were removed owing to duplication and an additional 160 were excluded following title/abstract screening. Of the 11 articles eligible for full-text screening, 4 were excluded for various reasons (Figure 1). Finally, seven studies were included for quantitative analysis in the current study (Hanley et al., 2021; Mikkelsen et al., 2021; Murphy et al., 2022; Qiu et al., 2020; Ren et al., 2022; Straub et al., 2021; Wall-Wieler et al., 2021). The baseline characteristics of the seven studies are summarized in Table 1. Overall, we included seven studies comprising a total of 4,021,406 children, with the proportion of girls being 48.6%–49.8%. There were 1,894,266 and 2,127,140 children in the LEA and non-LEA groups, respectively. Six out of the seven studies reported the incidence of ASD ranging from 1.2% to 1.8% (Hanley et al., 2021; Mikkelsen et al., 2021; Murphy et al., 2022; Qiu et al., 2020; Ren et al., 2022; Wall-Wieler et al., 2021), while the other study mentioned the cumulative incidence of ASD by the age of 10 years (range: 1.19%–1.93%) (Straub et al., 2021). Four studies focused on the association of LEA exposure with ASD in children who were delivered vaginally (Hanley et al., 2021; Murphy et al., 2022; Qiu et al., 2020; Wall-Wieler et al., 2021), while the other three studies also analyzed those undergoing vaginal delivery and CS (Mikkelsen et al., 2021; Ren et al., 2022; Straub et al., 2021). For one cohort study that presented data based on two types of insurance (i.e. public vs private) (Straub et al., 2021), we considered the data to be from two separate sources on performing our analysis. All studies were published from 2020 to 2022 and conducted in three countries including the United States (n = 2) (Qiu et al., 2020; Straub et al., 2021), Denmark (n = 2) (Mikkelsen et al., 2021; Ren et al., 2022), and Canada (n = 3) (Hanley et al., 2021; Murphy et al., 2022; Wall-Wieler et al., 2021). Quality assessment showed a good quality in all of the included studies (Supplemental Table 2).

Figure 1.

PRISMA flow diagram of study selection for the current meta-analysis.

Table 1.

Characteristics of the included studies (n = 7).

Study	Period	Maternal age (years)	Type of delivery	Girl (%)	N of children	N of siblings	LEA (N)	Non-LEA (N)	ASD (n/%)	GA (weeks)	Follow-up (years)	Country
Hanley et al. (2021)	2000–2014	29.9 vs 30.1	VD	49.8	388,254	233,482	111,480	276,774	5192 (1.3%)	39.2 vs 39.2	9.05	BC, Canada
Mikkelsen et al. (2021)	2006–2013	30 vs 31.1	VD, CS	48.7	479,178	59,154	92,900	386,278	6428 (1.3%)	40 vs 39.9	7	Denmark
Murphy et al. (2022)	2006–2014	29.7	VD	49.3	650,373	82,610	418,761	231,612	7546 (1.8%)	39.1	9.7	Ontario, Canada
Qiu et al. (2020)	2008–2015	29.8 vs 30.6	VD	49.7	147,895	NA	109,719	38,176	2524 (1.7%)	38.9 vs 38.7	NA	United States
Ren et al. (2022)	2005–2016	29 vs 30	VD, CS	48.6	624,952	80,862	116,296	508,656	7671 (1.2%)	89.8% vs 89.4%^a	7.2	Denmark
Straub (2021)	2005–2014^b	23.9 vs 24.8	VD, CS	NA	910,696	NA	484,752	425,944	1.93% vs 1.64%^c	91.7% vs 90.4%^a	NA^d	United States
Straub (2021)	2005–2015^e	31.5 vs 31.8	VD, CS	NA	696,883	NA	513,347	183,536	1.33% vs 1.19%^c	93.9% vs 92.8%^a	NA^d	United States
Wall-Wieler et al. (2021)	2005–2016	28.2	VD	49.1	123,175	80,459	47,011	76,164	2257 (1.8%)	39.3 vs 39.3	7.9	Manitoba, Canada

ASD: autism spectrum disorder; LEA: labor epidural analgesia; GA: gestational age; N: number; NA: not available; VD: vaginal delivery; CS: cesarean section; BC: British Columbia.

Proportion of parturient with gestational age ⩾37 weeks.

From public insurance.

Cumulative incidence of ASD by age 10 years.

Follow-up of children to age 10 years.

From private insurance.

Main results of the meta-analysis

Five studies had available information about the unadjusted HR on the association between LEA exposure and the risk of ASD (Hanley et al., 2021; Murphy et al., 2022; Ren et al., 2022; Straub et al., 2021; Wall-Wieler et al., 2021). Merged results showed a slightly higher risk of ASD in children born to mothers with LEA compared to those without maternal LEA exposure (HR: 1.24, 95% CI: 1.14–1.34, p < 0.00001, I² = 89%) (Figure 2(a)). Using the highest level of adjustment based on predefined variables from individual studies (Supplemental Table 3), merged results also revealed a slight increase in risk of ASD in children with previous maternal LEA exposure compared to those without (HR: 1.11, 95% CI: 1.06–1.16, p < 0.00001, I² = 67%) (Figure 2(b)).

Figure 2.

Association of labor epidural analgesia with risk of autism spectrum disorder in (a) unadjusted and (b) adjusted models.

Subgroup analysis focusing on children who were delivered vaginally showed a consistent finding (HR: 1.11, 95% CI: 1.06–1.17, p < 0.0001, I² = 64%) (Figure 3(a)) (Hanley et al., 2021; Mikkelsen et al., 2021; Murphy et al., 2022; Qiu et al., 2020; Ren et al., 2022; Straub et al., 2021; Wall-Wieler et al., 2021). In addition, sibling-matched analysis demonstrated that children with LEA exposure were associated with a slightly elevated risk of ASD compared to that in their siblings without exposure (HR: 1.1, 95% CI: 1.02–1.18, p = 0.008, I² = 0%) (Figure 3(b)) (Supplemental Table 4) (Hanley et al., 2021; Mikkelsen et al., 2021; Murphy et al., 2022; Ren et al., 2022; Wall-Wieler et al., 2021). Moreover, subgroup analysis based on country (i.e. Denmark, the United States, and Canada) by selecting the one with a larger sample size showed that children with LEA exposure were also associated with an elevated risk of ASD compared to those without exposure (HR: 1.11, 95% CI: 1.07–1.15, p < 0.00001, I² = 0%) (Figure 3(c)). The association of LEA exposure duration with the risk of ASD demonstrated a tendency of an increased risk of ASD in children with exposure to LEA <4 h (p = 0.05) (Figure 4(a) and (b)). However, this tendency disappeared in children with exposure to LEA >8 h (p = 0.35) (Figure 4(c)).

Figure 3.

Subgroup analysis based on (a) children who were delivered vaginally, (b) sibling-matched data, and (c) country of publication with the inclusion of studies with larger sample size.

Figure 4.

Association of labor epidural analgesia exposure with risk of autism spectrum disorder (a) <4 h, (b) 4–8 h, and (c) >8 h.

Publication bias, sensitivity analysis, and certainty of evidence

An inspection of the funnel plots of the included studies on the association between LEA exposure and the adjusted risk of ASD showed no significant publication bias (Egger’s test: p = 0.83) (Figure 5). The results for main outcome and subgroup analysis based on children who were delivered vaginally demonstrated stability on sensitivity analysis. However, the originally significant association between LEA exposure and the risk of ASD on sibling-matched subgroup analysis became non-significant when one study (Murphy et al., 2022) was removed on sensitivity analysis, indicating instability in this result. The quality of evidence for outcome measures according to the GRADE system was very low due to the retrospective study design, a high degree of inconsistency, and imprecision among the included studies.

Figure 5.

Publication bias for the association between labor epidural analgesia and the risk of autism spectrum disorder.

Discussion

Given that LEA has been widely accepted for pain relief in parturients and for improving the safety in those with a high risk of peripartum complications (e.g. preeclampsia) (Halliday et al., 2022), it is important to clarify whether the potential risk of LEA outweighs its reported benefits (Minnich et al., 1990; Rooth, 1982; Shnider et al., 1979). By incorporating the latest data, our results from over 4 million children indicated only a weak association between LEA exposure and the subsequent adjusted risk of ASD with a very low quality of evidence. Besides, although our subgroup analysis based on sibling-matched data and children who were delivered vaginally revealed similar findings, sensitivity analysis on the former showed a loss of significance in the association between LEA exposure and the risk of ASD by removing one study, suggesting weak evidence. Furthermore, taking into account the findings from subgroup analysis demonstrating that prolonged LEA exposure (>8 h) was not related to an increased risk of ASD, current evidence linking LEA to the risk of ASD remains weak.

ASD, which develops in early childhood around the age of 2–3 years, is a neurodevelopmental disorder characterized by rigid or repetitive behavior associated with social and communication difficulties (Gregory et al., 2013). The increasing prevalence of ASD over time (Autism and Developmental Disabilities Monitoring Network Surveillance Year 2002 Principal Investigators and Centers for Disease Control and Prevention, 2007; Maenner et al., 2020; Williams et al., 2006) may be attributed to changes in case definition and a heightened awareness of the condition (Fombonne, 2009; Williams et al., 2006). The etiology involves both genetic and environmental factors as well as their interactions (Bailey et al., 1995; Klauck, 2006). Despite the strong genetic predisposition as reflected by the increased prevalence in siblings (Ozonoff et al., 2011; Sandin et al., 2014), other risk factors also include unfavorable conditions associated with perinatal and neonatal health (e.g. abnormal presentation), a low birth weight, maternal diseases (e.g. preeclampsia or rheumatoid arthritis), and advanced parental age (Agrawal et al., 2018; Chiu et al., 2022; Dachew et al., 2018; Gardener et al., 2009; Hyman et al., 2020; Muhle et al., 2018; Song et al., 2022). Consistently, a previous meta-analysis of 40 heterogeneous observational studies on the perinatal and neonatal risk factors for ASD showed little evidence to support the dominant influence of any single factor on its development (Gardener et al., 2011).

For observational studies, it is unavoidable that methodological limitations (e.g. selection bias) and uncontrolled confounders may contribute to an overestimation of the association (A. J. Butwick et al., 2022; A. J. Butwick & Wall-Wieler, 2021 ; McKeen & Zaphiratos, 2021; Saito et al., 2021). Regarding selection bias, LEA is often used in parturients with a complicated peripartum course. For instance, an abnormal fetal presentation is more likely to be associated with severe pain that predisposes to the choice of LEA (Alexander et al., 2001). In addition, LEA remains the preferred analgesic approach for women with preeclampsia (Russell, 2020). Therefore, the invisible links between such unfavorable peripartal conditions and LEA exposure render it impossible to attribute an increased risk of ASD exclusively to the latter, provided that the former has been reported to be potential contributors to ASD development (Agrawal et al., 2018; Dachew et al., 2018). Following this argument, although the included studies in the current meta-analysis had adjusted some conceivable covariates (Supplemental Table 3) to minimize potential bias, the multiple etiologies of ASD (Agrawal et al., 2018; Dachew et al., 2018; Gardener et al., 2009; Hyman et al., 2020; Muhle et al., 2018) make it impossible to control all confounders.

On the other hand, the possible risk of underestimating the true effect of LEA based on the adjusted effect size remains an important concern as some of the control variables may be mediators (or correlate with a mediator) of the association between LEA and ASD. For instance, in a population-based cohort of pregnant women (n = 210,708) without major obstetrical complications, LEA was associated with an increased risk of CS (Bannister-Tyrrell et al., 2014). As elective CS and emergency CS have been reported to be associated with an increased risk of ASD when compared with unassisted vaginal delivery (Curran, Dalman, et al., 2015), this control variable (i.e. CS) may be a mediator in this association. Accordingly, the adjustment of the potential mediator (i.e. elective CS) in one of the included studies (Mikkelsen et al., 2021) may underestimate the potential impact of LEA on the risk of ASD.

Observational studies adopting a sibling-matched design have the merit of controlling for some genetics-related confounding effects on study outcomes (Sudan et al., 2014). The finding of a non-significant association between LEA exposure and the risk of ASD on sibling-matched analyses in previous studies (Hanley et al., 2021; Mikkelsen et al., 2021; Wall-Wieler et al., 2021) may implicate bias arising from unmeasured confounding effects in the report that demonstrated a possible correlation (Qiu et al., 2020). Nevertheless, our pooled results based on sibling-matched analysis, which revealed a slightly elevated risk of ASD, were also inconsistent with those from other studies using the same approach (Hanley et al., 2021; Mikkelsen et al., 2021; Wall-Wieler et al., 2021). However, the demonstration of a weakness of our pooled evidence on sensitivity analysis warrants further studies for clarification of this issue through controlling for within-family factors to enhance the statistical power.

Previous epidemiological investigations have highlighted the potential contributions of peripartum maternal conditions to the development of some mental disorders in the offspring (e.g. schizophrenia) (Cannon et al., 2002; Milberger et al., 1997). Although a previous meta-analysis (Curran, O’Neill, et al., 2015) has reported an increased odds of ASD in children delivered by CS, such an association may be attributed to the common need for CS during complicated deliveries in an emergency setting (e.g. fetal distress) and in women with pre-existing medical morbidities (Kolås et al., 2003). Therefore, to minimize potential bias, we performed subgroup analysis on children who were delivered vaginally and consistently demonstrated a weak association between LEA exposure and the risk of ASD. Nevertheless, the inability to completely exclude the possibility of selection bias on subgroup analysis weakened the pooled evidence that requires further studies to support.

Labor pain, which is very severe and intolerable (Ranta et al., 1995), not only may predispose to emotional distress and even postpartum depression (Hiltunen et al., 2004; Suhitharan et al., 2016) among parturients but can also trigger a cascade of physiologic changes such as neuroendocrine stress response as well as contribute to unfavorable maternal and fetal outcomes (Brownridge, 1995; Shnider et al., 1979; Vogl et al., 2006). Therefore, pain relief is crucial to the improvement of labor course through alleviating the adverse effects of catecholamines on maternal respiration and circulation (e.g. reduced uteroplacental perfusion) (Minnich et al., 1990; Rooth, 1982; Shnider et al., 1979). Neuraxial analgesia, which is technically simple with the requirement of only an indwelling epidural catheter, is the most common and effective means of peripartum pain relief because of its association with only transient side effects such as pruritus and hypotension and rare life-threatening complications (Halliday et al., 2022) as well as its ability to allow unplanned intrapartum CS when necessary (A. J. Butwick & Wall-Wieler, 2021). Its popularity is also boosted by the possibility of avoiding general anesthesia, which is known to be related to an increased risk of maternal and perinatal morbidities, including failed intubation, intraoperative hemorrhage, postoperative pain, nausea, and vomiting as well as fetal exposure to general anesthesia (A. J. Butwick & Wall-Wieler, 2021). Therefore, the known benefits of LEA from previous pooled evidence appear to outweigh our finding of a weak association between LEA exposure and the risk of ASD in offspring.

There are several limitations in the current meta-analytic study. First, identification of ASD cases in our included studies was based on specific procedure and diagnostic codes described in each study that may underestimate the true number of children with ASD (Straub et al., 2021). Second, despite our performance of subgroup analyses to minimize potential bias, residual confounding remains a possibility (Straub et al., 2021). Third, our results, which were derived from data of only three countries, may not be extrapolated to populations of different ethnic and geographic backgrounds. Fourth, the non-significant results of our funnel plot and Egger’s test could not rule out publication bias due to the limited number of included studies that underpowered the analyses (Peters et al., 2006). Therefore, whether publication bias contributed to an inflation of the pooled effect sizes in the present study remains unclear. Fifth, because our seven included studies were from three countries, there could be a substantial overlap of participants in some of the databases that would double the weight for analysis. Nevertheless, our subgroup analysis focusing on the countries of origin by selecting only one database from each country (i.e. Denmark, the United States, and Canada) based on a larger sample size demonstrated findings comparable to those of the original design. Sixth, because the diagnosis of ASD is made only during adolescence and adulthood in a significant number of patients (Chiarotti & Venerosi, 2020), the inclusion of studies that followed children up to only 7–10 years may bias our findings. Finally, our meta-analysis did not analyze the impact of LEA on other neonatal outcomes (e.g. Apgar score or intensive care admission) due to lack of relevant information.

Conclusion

Despite the demonstration of a slight association between labor epidural analgesia exposure and an increased risk of ASDs in the current study on over 4 million children, the small effect size and the very low quality of evidence could not exclude the effects of residual confounding. Healthcare providers should balance between the benefits of labor epidural analgesia and the potential risks based on the best evidence when providing counseling for parturients.

Supplemental Material

sj-docx-1-aut-10.1177_13623613221138690 – Supplemental material for Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies

Supplemental material, sj-docx-1-aut-10.1177_13623613221138690 for Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies by Kuo-Chuan Hung, Jen-Yin Chen, Chung-Hsi Hsing, Chih-Wei Hsu, Ping-Hsin Liu, Ying-Jen Chang, Jui-Yi Chen, Sheng-Fu Chiu and Cheuk-Kwan Sun in Autism

Footnotes

Author contributions

Conceptualization and literature search: K.-C.H. and J.-Y.C.; Methodology: C.-H.H.; Trial selection: C.-W.H. and P.-H.L.; Data analysis: K.-C.H.; Data extraction: Y.-J.C. and J.-Y.C.; Writing—original draft preparation: K.-C.H., S.-F.C. and C.-K.S.; Writing—review and editing: K.-C.H. and C.-K.S. All authors have read and agreed to the published version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Cheuk-Kwan Sun

Supplemental material

Supplemental material for this article is available online.

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