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. 2023 Oct 5;18(10):e0292226. doi: 10.1371/journal.pone.0292226

The association between maternal infection and intellectual disability in children: A systematic review and meta-analysis

Mahroo Rezaeinejad 1, Seyed Mohammad Riahi 2, Kimia Behzad Moghadam 3, Mehrdad Jafari Tadi 4, Zahra Geraili 5, Hamid Parsa 6, Elika Marhoommirzabak 6, Malihe Nourollahpour Shiadeh 7,*, Ali Alizadeh Khatir 8,*
Editor: Zemenu Yohannes Kassa9
PMCID: PMC10553326  PMID: 37796792

Abstract

Background

There is arguing evidence regarding the association between maternal infections during pregnancy and the risk of intellectual disability (ID) in children. This systematic review and meta-analysis are essential to determine and address inconsistent findings between maternal infections during pregnancy and the risk of ID in children.

Methods

The MOOSE and PRISMA guidelines were followed to perform and report on this study. The Medline/PubMed, Web of Science, Embase, and Scopus databases were searched from inception up to March 15, 2023, to identify potentially eligible studies. Inclusion and exclusion criteria were applied, as well as the Newcastle-Ottawa Scale was used to assess the methodological quality of studies included. The included studies were divided into two types based on the participants: (1) ID-based studies, which involved children with ID as cases and healthy children as controls and evaluated maternal infection in these participants; (2) infection-based studies, which assessed the prevalence or incidence of ID in the follow-up of children with or without exposure to maternal infection. We used Random-effects models (REM) to estimate the overall pooled odds ratio (OR) and 95% confidence intervals (CIs). The between-studies heterogeneity was assessed with the χ2-based Q-test and I2 statistic. Subgroup and sensitivity analyses were applied to explore the source of heterogeneity and results consistency.

Results

A total of eight studies including 1,375,662 participants (60,479 cases and 1,315,183 controls) met the eligibility criteria. The REM found that maternal infection significantly increased the risk of ID in children (OR, 1.33; 95% CI, 1.21–1.46; I2 = 64.6). Subgroup analysis showed a significant association for both infection-based (OR, 1.27; 95%CI, 1.15–1.40; I2 = 51.2) and ID-based (OR, 1.44; 95%CI, 1.19–1.74; I2 = 77.1) studies. Furthermore, subgroup analysis based on diagnostic criteria revealed a significant association when maternal infection or ID were diagnosed using ICD codes (OR, 1.33; 95% CI, 1.20–1.48; I2 = 75.8).

Conclusion

Our study suggests that maternal infection during pregnancy could be associated with an increased risk of ID in children. This finding is consistent across different types of studies and diagnostic criteria. However, due to the heterogeneity and limitations of the included studies, we recommend further longitudinal studies to confirm the causal relationship and the underlying mechanisms.

Introduction

Intellectual disability (ID) is a lifelong abnormality characterized by an IQ below 70 and deficits in both intellectual functioning and adaptive abilities, mostly identified in childhood or adolescence [1]. ID not only affects the people who suffer from it, but also considered as a family and social health problem [2]. The global prevalence of ID is between 1% and 3% in the general population with some regional variations [1]. According to the Global Burden of Disease Study, out of the 2.6 billion children and adolescents in 2017, ~83.2 million were affected by ID, representing a global prevalence of 3.2% (95% UI: 2.5%–3.9%) [3]. According to global estimates, ID accounted for approximately 10.7 million years of living with disability (YLD) in people aged below 20 years [3].

The main etiology of ID is still not well understood. While genetics or chromosomal factors are established to be the cause of ID in approximately half of cases, there is also some strong evidence for the role of environmental factors during pregnancy and embryonic neurodevelopment as causes of ID, including maternal infections [4,5]. Maternal infections are well-established risk factors for the neurological and behavioral abnormalities in children, mainly due to the teratogenic effect of neurotropic infectious agents such as rubella, cytomegalovirus or Toxoplasma gondii on the fetal brain [6,7]. The neurodevelopmental abnormalities associated with maternal infections could be due to brain damage directly induced by the infectious agents, or host immune responses to infection and subsequent inflammation, or indirectly by adverse birth outcomes induced by infections such as preterm birth, low birthweight, or neonatal brain injury [8–11].

There have been substantial epidemiological studies of the associations between maternal infection and neurodevelopmental abnormalities (e.g., autism, schizophrenia and cerebral palsy) [12–14], but very few studies have been done on the causal relationship between maternal infection and ID, with a degree of controversy in the results [15–17]. Moreover, no study has yet been carried out to systematically review existing data on this topic. A better knowledge of this issue may have important public health and clinical implications. Therefore, we designed and performed the present systematic review and meta-analysis and scrutinized all publicly available observational studies to calculate the risk of ID in children who are born after being exposed to maternal infection.

Methods

We used the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) guidelines to perform and report of this study, respectively [18,19].

Search strategy and study selection

To identify the relevant studies, two independent investigators (M.R. and H.P.) systematically explored published literature in the online scientific databases including, Medline through PubMed, Web of science collection, Embase, and SCOPUS from the date of inception until 15 March 2023 (S1 Fig). The search strategy was designed and we adapted it to each database by a medical library expert (Z.G). The following keywords were used in the databases search: “maternal infection” OR “gestational infection” OR “infection” OR “infectious” AND “mental retardation” OR “intellectual disability” OR “intellectual development” OR “development disorders” OR “mental deficiency”. Furthermore, two investigators (M.J. and M.J.) searched the first 20 pages of the Google Scholar engine using the above keywords and the bibliographies of retrieved articles to find additional relevant studies and gray literature. There was no time, geographical or language limitation, although we limited literature search to “human-subjects” studies. Retrieved studies from different sources were imported into the EndNote X9.0 reference manager software (Thompson and Reuters, Philadelphia, PA), and duplicates were removed. Subsequently, two investigators independently (M.R. and H.P.) scrutinized titles, abstracts, and then full-text articles to identify potentially relevant studies for inclusion in the meta-analysis. The following inclusion criteria were applied: (1) observational (cross-sectional, case-control, and cohort) studies that evaluated the association between maternal infection (interested exposure) and development of ID (interested outcome) in children (interested population), (2) studies that utilized universally recognized diagnostic criteria or tests to detect maternal infection or ID in children, involving International Classification of Diseases (ICD) codes or laboratory techniques (serology, molecular or culture methods); (3) studies that provided the odds ratios (ORs), hazard ratios (HRs) or relative risks (RRs) of interested outcomes, or the information was presented to calculate of these risk estimates. Studies were excluded if they failed to quantitatively evaluate of the association between the maternal infection and ID; had not enough data to calculate of an OR and 95% CI; were case reports, case-series, conference papers, systematic reviews, and letters without original data.

Data extraction and study quality assessment

Two investigators (M.R. and H.P.) independently scrutinized all eligible studies and extracted the following information: first author, publication year, study implementation period, country, diagnostic methodology, type of participants (infection-based or ID-based), study design, the numbers of cases and control subjects, and the prevalence of ID or maternal infection in each of the subject groups. All extracted data were transferred into a standardized Microsoft Excel 2016 spreadsheet (Microsoft Corporation, Redmond, WA). To assess the methodological quality of studies included, we used the Newcastle-Ottawa Scale, which has been recommended by the Cochrane collaboration network [20,21]. This scoring system measures the risk of bias of observational studies based on three dimensions: subject selection criteria (0–4 points), comparability of subjects (0–2 points), and ascertainment of the outcome of interest (0–3 points)—with scores ranging from 0 (low quality) to 9 (high quality). Studies with scores ≥7, 4–6, and ≤3 were considered to be of high, moderate and low quality. All disagreements in study search, study selection and data extraction were resolved in consultation with the lead investigators (M.N.S and A.A.K.).

Data synthesis and statistical analysis

All statistical analyses were conducted using Stata software (version 17; Stata Corporation, College Station, Texas). The pooled prevalence of the outcome of interest with a 95% confidence interval (95% CI) in each case and control group was estimated using the DerSimonian-Laird random-effects model (REM) [22,23]. Then, the OR and 95% CI were calculated for each individual study with dichotomous data. To assess the association between maternal infection and ID in children, ORs from individual studies were combined to produce a pooled OR and 95% CI, employing the REM with a restricted maximum-likelihood estimator. Between-studies heterogeneity was examined using the Q-test with a p-value < 0.05 and I2 statistics with a cutoff of ≥ 50% as a significant heterogeneity [24]. In addition, we performed sub-group analyses on type of participants, publication years and diagnostic criteria to identify the sources of heterogeneity and effects of these study characteristics on the outcome of interest. We also performed sensitivity analysis, by iteratively removing each study, to examine the robustness of our pooled estimation for the outcome of interest. Publication bias was evaluated by applying the Begg’s and Egger’s publication bias methods [25]. A p-value of less than 0.05 was considered to be statistically significant.

Results

Study characteristics

The PRISMA flow diagram is depicted in Fig 1. Our systematic search yielded 9583 potentially relevant studies. Of those, 2365 articles were excluded following duplicate-removal and 7445 articles were excluded as irrelevant following screening of the title and/or abstract, leaving 43 articles that underwent detailed full-text evaluation according to the inclusion and exclusion criteria. Finally, eight studies examining 60,479 cases and 1,315,183 healthy controls met the criteria for the meta-analysis [15–17,26–30].

Fig 1. PRISMA flow chart showing study selection process.

Fig 1

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The main characteristics of the included studies are summarized in Table 1. All studies had a cohort design, were published between 1998 and 2020, and were performed in three countries: United States (five studies), Sweden (two studies) and China (one study). Four studies were defined as ID-based studies; these studies recruited children affected by ID (12,595 children) as cases and healthy children (736,466 children) as controls and assessed maternal infection in these subjects. On the other hand, four studies were defined as infection-based studies; these studies evaluated the prevalence or incidence of ID in the follow-up of children with- (47,884 children) and without- (578,717 children) exposure to maternal infection. Six studies used International Classification of Diseases (ICD) codes (ICD 8–10) to determine ID and maternal infection, while two other studies used laboratory methods (ELISA and microbial culture) to determine the maternal infection and Wechsler Intelligence Scale for Children (WISC) to identify the children with ID. Based on the methodological quality assessment scores, all studies were deemed to be of high quality.

Table 1. Main characteristics of included studies.

Studies* Implementation year Country Case Outcome Control Outcome Method to confirm infection ID diagnostic criterion
Camp et al. (1998) [27]# 1959–1965 USA 5244 244 30476 1068 Microbial culture WISC
Mcdermoot et al. (2000) [28]# 1995–1998 USA 8578 673 32237 2205 ICD-9 codes ICD-9 codes
Zhang et al. (2007) [29] # 1997–2000 China 49 4 50 1 ELISA WISC
Mann et al. (2009) [17]֍ 1996–2002 USA 5388 1366 129208 27961 ICD-9 codes ICD-9 codes
Bilder et al. (2013) [16] ֍ 1994–2001 USA 146 3 16936 47 ICD-9 codes ICD-9 codes
Lee et al. (2015) [26] ֍ 1984–2011 Sweden 2280 124 471056 16352 ICD-9, and ICD-10 codes ICD-9, and ICD-10 codes
McCarter et al. (2020) [30]֍ 2004–2013 USA 4781 154 119266 2774 ICD-9 codes ICD-9 codes
Brynge et al. (2022) [15]# 1987–2016 Sweden 34013 445 515954 5087 ICD-8, ICD-9, and ICD-10 codes ICD-9 codes
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* All studies had retrospective cohort design and were classified as high-quality studies based on Newcastle-Ottawa Scale.

#Infection-based studies; these studies evaluated prevalence or incidence of ID in follow-up of children with- and without- exposure to maternal infection.

֍Intellectual disability-based studies; these studies recruited children affected by ID as cases and healthy children as controls and assessed maternal infection in these subjects retrospectively.

Abbreviation; WISC, Wechsler Intelligence Scale for Children; ICD, International Classification of Diseases.

Results of meta-analysis

The results of the overall meta-analysis demonstrated that maternal infection significantly increased the risk of ID in children (OR, 1.33; 95%CI, 1.22–1.44) (Table 2 and Fig 2). The between-study heterogeneity was substantial (χ2 = 23.88; I2 = 64.6). Sensitivity analysis indicated that exclusion of any individual study did not have a significant influence in pooled OR overall (S2 Fig), revealing high stability of our results. Moreover, a significant association was found in both infection-based- (OR, 1.27; 95%CI, 1.15–1.40) and ID-based-(OR, 1.44; 95%CI, 1.19–1.74) studies (Table 2, Fig 2). A meta-analysis on four studies that had adjusted OR also indicated a significant association (OR, 1.39; 95%CI, 1.28–1.50; I2 = 0.0) (Fig 3).

Table 2. Sub-group analysis of the pooled prevalence and odds ratios for the association between maternal infection and intellectual disability.

Variables (number of datasets) Pooled prevalence of outcome in cases
% (95% CI)		 Pooled prevalence of outcome in controls
% (95% CI)		 Odds ratios
(95% CI)		 Heterogeneity (I2%)
Study design
Infection-based 4.68 (1.20–10.08) 3.03 (0.50–7.31) 1.27 (1.15–1.40) 53.6
ID-based 7.34 (0.45–21.13) 4.73 (0.36–13.69) 1.44 (1.19–1.74) 82.5
Diagnostic criteria for maternal infection and ID
ICD-codes 6.09 (1.28–14.04) 4.22 (0.98–9.57) 1.33 (1.19–1.48) 0.0
Laboratory methods 4.24 (3.69–4.83) 3.06 (2.85–3.27) 1.40 (0.92–1.13) 99.8
Publication year
Before 2010 10.59 (3.00–21.88) 7.46 (0.91–19.09) 1.23 (1.15–1.31) 30.4
2010–2022 2.86 (1.13–5.30) 1.51 (0.48–3.11) 1.49 (1.23–1.79) 72.5
Overall 6.07 (1.93–12.20) 3.86 (1.05–8.25) 1.33 (1.22–1.44) 70.7
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Abbreviation; WISC, Wechsler Intelligence Scale for Children; ICD, International Classification of Diseases.

Fig 2. Forest plot for the association between maternal infection and ID.

Fig 2

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Subgroups are based on different type of studies (infection-based- and ID-based- studies). The center of each square represents the OR, the area of the square is the weighted percentage in the meta-analysis and the horizontal line indicates the 95% CI. % weight: weight of each study compared with all the studies.

Fig 3. Forest plot for the association between maternal infection and ID in four studies having adjusted OR.

Fig 3

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Five studies were performed in the United States, and a REM on these studies indicated a significant positive association (OR, 1.34; 95%CI, 1.19–1.50) (S3 Fig). A subgroup analysis of the results according to diagnostic criteria for both ID and maternal infection revealed a significant association when ICD codes (OR, 1.33; 95% CI, 1.19–1.48) were used, while a non-significant association was observed when WISC or laboratory methods (OR, 1.40; 95% CI, 0.92–1.13) were used (S4 and S5 Figs). When the sub-groups were analyzed according to the year of publication, both groups of studies that were published before (OR, 1.23; 95% CI, 1.15–1.31) and after (OR, 1.49; 95% CI, 1.23–1.79) 2010 showed significant positive association (S6 Fig).

We assessed the possibility of publication bias using Egger’s test and Funnel plot for crude and adjusted ORs. S7 Fig shows a significant publication bias (Egger’s test p-value = 0.01 and asymmetrical Funnel plot) for the bivariable association between maternal infection and ID in children (crude OR). However, we did not find any evidence of publication bias in studies that examined the multivariable association (adjusted OR) between maternal infection and ID in children (Egger’s test p-value = 0.11 and symmetrical Funnel plot; S8 Fig). We also performed a Fill and Trim sensitivity analysis to investigate the effect of publication bias, and found no significant change in the result (pooled OR crude, 1.34; 95% CI, 1.05–1.63) (Fig 4).

Fig 4. Fill and Trim sensitivity analysis for publication bias in crude OR.

Fig 4

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Discussion

ID is a very significant health problem with varied etiology that first develops during pregnancy and is mostly diagnosed in childhood. An improved understanding of the potential risk factors for development of ID may have important public health and clinical implications. The main aim of the present study was to assess whether maternal infection increases the risk of ID in the children. Our meta-analysis findings of eight observational studies concluded that maternal infection during pregnancy could be associated with a significantly increased risk of ID (OR, 1.3; 95% CI, 1.21–1.46) in children. Moreover, almost all subgroup analyses according to type of studies, publication year, and diagnostic criteria also indicated a positive association. These findings are in line with previous meta-analyses indicating that maternal infection is associated with increased risk of psychosis, cerebral palsy, and autism spectrum disorders [12–14].

Although precise biological mechanisms have not been clearly elucidated, maternal infection could play an important role in the cause of ID through multiple mechanisms [31]. Experimental/mechanistic studies on the role of maternal infections in development of ID are very rare [15]. But because ID and autism spectrum disorders (ASD) have some common phenotypic and genotypic features [32], and 25–30% of people with ASD are also diagnosed with ID [33], therefore, it has been suggested that infectious organisms can cause ID in the same pathways that they induce ASD [15]. First, it is well-known that some infectious organisms (e.g. Toxoplasma gondii, rubella, and cytomegalovirus) can cross the placenta, entering the fetal environment and induce adverse fetal neurodevelopmental outcomes and brain damage [34–37]. Furthermore, proinflammatory mediators/cytokines (TNF, IL-17, IL6, IL-2, and IL-1β) and maternal antibodies induced by host immune system in response to infections, are release into maternal serum and amniotic fluid, could cross the placenta and disrupt fetal neurodevelopment [38–40]. Second, infections during pregnancy, either neurotropic or sexually transmitted infections, are associated with adverse pregnancy outcomes (e.g., low birth weight and preterm delivery), which increase the risk of ID.

The strength of this meta-analysis lies in its rigorous statistical methodology based on cohort studies, large sample size and stratified analyses according to study design, publication year and diagnostic criteria. However, several limitations should be considered regarding this study. Firstly, there was a low number of eligible studies in a few countries (USA, Denmark and China), and there was no study from less developed countries (South America, Africa, South Asia and Middle-East), where the rate of both maternal infection and childhood ID is higher than in developed countries. Second, due to lack of stratified data in original studies, we were unable to perform the subgroup analyses based on specific infections, therefore we were unable to interpret which infection organism had more impact on inducing of ID. Third, there was substantial heterogeneity between studies and a significant publication bias was found by Egger test. According to our analyses publication year and diagnostic criteria might be the source of heterogeneity, although it should be addressed in more well-controlled studies in future.

In conclusion, this meta-analysis study indicated that children exposed to maternal infection during pregnancy are at a greater risk of developing ID. Further multicenter longitudinal studies, especially in less developed countries, that consider the type of infectious agent and more confounding factors are needed to confirm our findings.

Supporting information

S1 Checklist. PRISMA 2020 checklist.

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Click here for additional data file. (31KB, docx)
S1 Fig. Search strategy.

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S2 Fig. Sensitivity analysis after each study was excluded.

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S3 Fig. Pooled OR estimates in subgroups according to the countries for studies assessing the association between maternal infection and intellectual disability (ID) in children.

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S4 Fig. Pooled OR estimates in subgroups according to the diagnostic criteria for ID in studies assessing the association between maternal infection and ID in children.

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S5 Fig. Pooled OR estimates in subgroups according to the diagnostic criteria for maternal infection in studies assessing the association between maternal infection and ID in children.

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S6 Fig. Pooled OR estimates in subgroups according to the publication year for studies assessing the association between maternal infection and ID in children.

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S7 Fig. Publication bias for studies assessing the association between maternal infection and ID in children, indication a significant publication bias.

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S8 Fig. Publication bias for four studies having adjusted odds ratio, indication that there is no publication bias in these studies.

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Acknowledgments

The authors would like to thank Dr. Vahid Fallah Omrani (Calgary University, Canada), for his assistance during the preparation of this manuscript.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Zemenu Yohannes Kassa

19 Jun 2023

PONE-D-23-15712Maternal infection and risk of intellectual disability in children: a systematic review and meta-analysisPLOS ONE

Dear Dr. Nourollahpour Shiadeh,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 03 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Zemenu Yohannes Kassa, Msc

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

Additional Editor Comments :

General comments

Your methods and results sections lack clarity and need attention and revision should bed needed.

# Abstract

In lines 30 and 31, the sentence has grammar errors and is rewritten again in an understandable way.

Line 32 and 33 also lack clarity, and it needs revision to make them clear for the reader.

How to assess publications in this meta-analysis, and you should indicate it for a reader in the abstract.

You should clearly show and convey to the readers in the methods part. It lacks clarity and is not written scientifically.

The result part also is not well written. for example, lines 38 and 39.

You can write like …… maternal infection significantly increased ID………

Lines 41 -43 also are not written clearly and need modifications.

# Results

Line 67, please state the laboratory methods they used to identify maternal infections.

In the methods section, you did not explain your outcome variable using PICO or others, which is challenging to catch infection-based and ID findings.

Lines 198 -202, It is confusing the reader, and it needs to rewrite again.

Please revise PRIMA, Figure 1,

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Rezaeinejad et al., has performed a meta-analysis study on a very interesting topic about Maternal infection and risk of intellectual disability in children. There are some technical and grammatical errors requiring revision from the authors. Please see my comments in details.

1- Please note that Lee et al. (2015) is not an American study, but it is performed on a Swedish population-based register study. Please correct tables and text.

2- The values in the following sentence “Moreover, a significant relationship was found in both infection-based- (OR, 7.10;180 95%CI, 3.50–14.38) and ID-based-(OR, 1.70; 95%CI, 0.99–2.91) studies (Table 2, Figure 2).” are different from those reported in Table 2. Please modify them.

3. Lines 87, 88 “The search strategy was designed and adapted it to each database by a medical library expert (Z.R).” although there is no author with these initials in the authors list.

4. Please use same format to write p value throughout the manuscript.

5. Throughout the manuscript needs to be edited for English language to modify some minor grammatical errors.

Reviewer #2: I read with interest this systematic review and meta-analysis about the maternal infection and risk of intellectual disability in children. The topic is interesting and the paper well written and the methodology correct.

I have some concerns:

1) The term relationship should be replaced by association, as this term is inappropriate for scientific material.

2) The Higgins index (I2), should be added to effect sizes in abstract.

3) There is controversy (typographical error) between Table 2 and results in main text and abstract especially sub-group analysis.

4) It is better to separate the introduction in several paragraphs not two long paragraphs. A paragraph is a group of sentences that convey an idea. Each sentence works together as part of a unit to create an overall thought or impression. A paragraph is the smallest unit or cluster of sentences in which one idea can be developed adequately. Paragraphs can stand alone or function as part of an essay, but each paragraph covers only one main idea. The most important sentence in your paragraph is the topic sentence, which clearly states the subject of the whole paragraph. The topic sentence is usually the first sentence of the paragraph because it gives an overview of the sentences to follow. The supporting sentences after the topic sentence help to develop the main idea. These sentences give specific details related to the topic sentence. A final or concluding sentence often restates or summarizes the main idea of the topic sentence.

5) It is better to write: Medline through PubMed not only PubMed.

6) As, the authors conducted a perfect sub-group analysis, it is better to omit meta-regression.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Mahdi Sepidarkish

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Oct 5;18(10):e0292226. doi: 10.1371/journal.pone.0292226.r002

Author response to Decision Letter 0

23 Jul 2023

Dear Dr Yohannes Kassa

Academic Editor

Plos One

Thank you very much for reviewing our manuscript. Comments by you and reviewers were very helpful. We revised the manuscript according to the comments raised by the you and reviewers. All the changes based on the reviewer’s comments are highlighted yellow in the revised manuscript as I explained in follow.

Sincerely yours

Additional Editor Comments :

General comments

Your methods and results sections lack clarity and need attention and revision should bed needed.

# Abstract

In lines 30 and 31, the sentence has grammar errors and is rewritten again in an understandable way.

Line 32 and 33 also lack clarity, and it needs revision to make them clear for the reader.

How to assess publications in this meta-analysis, and you should indicate it for a reader in the abstract.

You should clearly show and convey to the readers in the methods part. It lacks clarity and is not written scientifically.

The result part also is not well written. for example, lines 38 and 39.

You can write like …… maternal infection significantly increased ID………

Lines 41 -43 also are not written clearly and need modifications.

Response: Many thanks for your valuable suggestions. we re-written the abstract section to resolve your concerns.

# Results

Line 67, please state the laboratory methods they used to identify maternal infections.

Response: Many thanks for your valuable suggestions. we added related diagnostic methods.

In the methods section, you did not explain your outcome variable using PICO or others, which is challenging to catch infection-based and ID findings.

Response: Many thanks for your valuable comment. We included those studies that evaluated the association between maternal infection and development of ID in children. So, we expressed the PICO specifically. The interested exposure and outcome are maternal infection and intellectual disorders, respectively. We revised the eligibility criteria as follow: “The following inclusion criteria were applied: (1) observational (cross-sectional, case-control, and cohort) studies that evaluated the association between maternal infection (interested exposure) and development of ID (interested outcome) in children (interested population)…”.

Lines 198 -202, It is confusing the reader, and it needs to rewrite again.

Response: Many thanks for your valuable suggestions. We re-written the paragraph to resolve your concerns.

Please revise PRIMA, Figure 1.

Response: Many thanks for your valuable suggestions. we edited throughout the manuscript to resolve your concerns.

Reviewer #1: Rezaeinejad et al., has performed a meta-analysis study on a very interesting topic about Maternal infection and risk of intellectual disability in children. There are some technical and grammatical errors requiring revision from the authors. Please see my comments in details.

Response: thanks for your valuable comments. We modified all of them.

1- Please note that Lee et al. (2015) is not an American study, but it is performed on a Swedish population-based register study. Please correct tables and text.

Response: thanks, addressed.

2- The values in the following sentence “Moreover, a significant relationship was found in both infection-based- (OR, 7.10;180 95%CI, 3.50–14.38) and ID-based-(OR, 1.70; 95%CI, 0.99–2.91) studies (Table 2, Figure 2).” are different from those reported in Table 2. Please modify them.

Response: thanks for your detailed attention, we modified them.

3. Lines 87, 88 “The search strategy was designed and adapted it to each database by a medical library expert (Z.R).” although there is no author with these initials in the authors list.

Response: thanks for your detailed attention, we modified them.

4. Please use same format to write p value throughout the manuscript.

Response: thanks, addressed.

5. Throughout the manuscript needs to be edited for English language to modify some minor grammatical errors.

Response: thanks, we edited throughout the manuscript.

Reviewer #2: I read with interest this systematic review and meta-analysis about the maternal infection and risk of intellectual disability in children. The topic is interesting and the paper well written and the methodology correct.

I have some concerns:

1) The term relationship should be replaced by association, as this term is inappropriate for scientific material.

Response: thanks, we replaced relationship by association throughout the manuscript.

2) The Higgins index (I2), should be added to effect sizes in abstract.

Response: thanks, we added I2 for effect size in abstract.

3) There is controversy (typographical error) between Table 2 and results in main text and abstract especially sub-group analysis.

Response: thanks for your detailed attention, we modified them.

4) It is better to separate the introduction in several paragraphs not two long paragraphs. A paragraph is a group of sentences that convey an idea. Each sentence works together as part of a unit to create an overall thought or impression. A paragraph is the smallest unit or cluster of sentences in which one idea can be developed adequately. Paragraphs can stand alone or function as part of an essay, but each paragraph covers only one main idea. The most important sentence in your paragraph is the topic sentence, which clearly states the subject of the whole paragraph. The topic sentence is usually the first sentence of the paragraph because it gives an overview of the sentences to follow. The supporting sentences after the topic sentence help to develop the main idea. These sentences give specific details related to the topic sentence. A final or concluding sentence often restates or summarizes the main idea of the topic sentence.

Response: thanks, we modified the size of paragraphs in introduction.

5) It is better to write: Medline through PubMed not only PubMed.

Response: thanks, addressed.

6) As, the authors conducted a perfect sub-group analysis, it is better to omit meta-regression.

Response: thanks, addressed.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (21.3KB, docx)

Decision Letter 1

Zemenu Yohannes Kassa

7 Aug 2023

PONE-D-23-15712R1Maternal infection and risk of intellectual disability in children: a systematic review and meta-analysisPLOS ONE

Dear Dr. Nourollahpour Shiadeh,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 15 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Zemenu Yohannes Kassa, Msc

Academic Editor

PLOS ONE

Additional Editor Comments:

#Abstract

Background rewrite like this

There is arguing evidence regarding the association between maternal infections during pregnancy and the risk of intellectual disability (ID) in children. This systematic review and meta-analysis are essential to determine and address inconsistent findings between maternal infections during pregnancy and the risk of intellectual disability (ID) in children.

#Methods

Line 33, from when to when and where?

Lines 35-38 you should rewrite again.

#Result

Line 44, ID-based (OR, 1.70; 95%CI, 0.99–2.91; I 2 44 = 51.2) studies. It did not significantly associate with……… why you reported it here?

Subgroup analysis also, it is not clear to readers. What does mean infection-based and ID-based studies?

#Conclusion, it needs gross modification, please pay attention to this section, you should provide a conclusion and recommendation based on your findings.

Keywords: Please use Mesh terms

#Introduction

Line 62,….. responsible for ~10.7 million years lived with disability……..it needs modifications.

Line 66-68, the sentences are out of your objectives. It focuses on maternal behaviour. but not on maternal infectious and remove it.

#Methods: state the diagnostic criteria that you included in your study?

Why did you not use grey literatures?

Did you research using reference of referencing? if yes state it.

Line 113 odds ratios (ORs), hazard ratios (HRs) or relative risks (RRs) of interested outcomes. How to be pooled it.

Line 131, if the score is how many, you included in your review?

Check your PRISMA.

In the table1, you should write types of laboratory used instead of code, for example, PCR, ELISA …… .

ID diagnostics criteria WISC……but not code

Based on your title, you should on “Infection-based studies; these studies evaluated the prevalence or incidence of ID in the follow-up of children with- and without exposure to maternal infection.” But not Intellectual disability-based studies; these studies recruited children affected by ID. because it might occur other factors like alcohol, cigarette, and others. Or modify your titles.

You expected to show OR and RR of each included study in Table 2.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All my concerns were modified; however, I found a mistake in Figure 1. The number of studies after duplicates removal is 5155, but in next step it is 7488. Please correct.

Reviewer #2: The authors have adequately addressed the comments raised in a previous round of review and the manuscript is now acceptable for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Oct 5;18(10):e0292226. doi: 10.1371/journal.pone.0292226.r004

Author response to Decision Letter 1

23 Aug 2023

Dear Dr Yohannes Kassa

Academic Editor

Plos One

Thank you very much for reviewing our manuscript. Comments by you and reviewers were very helpful. We revised the manuscript according to the comments raised by the you and reviewers. All the changes based on the reviewer’s comments are highlighted yellow in the revised manuscript as I explained in follow.

Sincerely yours

Additional Editor Comments:

#Abstract

Background rewrite like this

There is arguing evidence regarding the association between maternal infections during pregnancy and the risk of intellectual disability (ID) in children. This systematic review and meta-analysis are essential to determine and address inconsistent findings between maternal infections during pregnancy and the risk of intellectual disability (ID) in children.

R: Many thanks for your valuable corrections. We replaced your corrected sentence.

#Methods

Line 33, from when to when and where?

R: Thanks, we searched databases from their inception up to 15 March 2022. We modified this sentence as follow “The Medline/PubMed, Web of Science, Embase, and Scopus databases were searched from inception up to March 15, 2023, to identify potentially eligible studies.”

Lines 35-38 you should rewrite again.

R: We re-write these sentences again.

#Result

Line 44, ID-based (OR, 1.70; 95%CI, 0.99–2.91; I 2 44 = 51.2) studies. It did not significantly associate with……… why you reported it here?

R: Please accept our apologies, in previous revision we forgotten to modify these values. WE corrected them as follow: Subgroup analysis showed a significant association for both infection-based (OR, 1.27; 95%CI, 1.15–1.40; I2 = 51.2) and ID-based (OR, 1.44; 95%CI, 1.19–1.74; I2 = 77.1) studies.

Subgroup analysis also, it is not clear to readers. What does mean infection-based and ID-based studies?

R: we added following sentence in the method section to clarify infection-based and ID-based studies: “The included studies were divided into two types based on the participants: (1) ID-based studies, which involved children with ID as cases and healthy children as controls and evaluated maternal infection in these participants; (2) infection-based studies, which assessed the prevalence or incidence of ID in the follow-up of children with or without exposure to maternal infection.” Moreover, similar explanation is in main text: lines 169-175.

#Conclusion, it needs gross modification, please pay attention to this section, you should provide a conclusion and recommendation based on your findings.

R: we re-write this section as follow: “Our study suggests that maternal infection during pregnancy could be associated with an increased risk of ID in children. This finding is consistent across different types of studies and diagnostic criteria. However, due to the heterogeneity and limitations of the included studies, we recommend further longitudinal studies to confirm the causal relationship and the underlying mechanisms.”

Keywords: Please use Mesh terms

R: thanks, modified.

#Introduction

Line 62,….. responsible for ~10.7 million years lived with disability……..it needs modifications.

R: thanks, paraphrased it.

Line 66-68, the sentences are out of your objectives. It focuses on maternal behaviour. but not on maternal infectious and remove it.

R: thanks, removed.

#Methods: state the diagnostic criteria that you included in your study?

R: thanks, we modified related sentence as follow: “studies that utilized universally recognized diagnostic criteria or tests to detect maternal infection or ID in children, involving International Classification of Diseases (ICD) codes or laboratory techniques (serology, molecular, or culture methods)”.

Why did you not use grey literatures?

Did you research using reference of referencing? if yes state it.

R: we modified following sentence to response your above both questions: “Furthermore, two investigators (M.J. and M.J.) searched the first 20 pages of the Google Scholar engine using the above keywords and the bibliographies of retrieved articles to find additional relevant studies and gray literature.”

Line 113 odds ratios (ORs), hazard ratios (HRs) or relative risks (RRs) of interested outcomes. How to be pooled it.

R: All studies had a cohort design. All studies reported the raw counts with percentage. So, we calculated the odds ratio from the counts in contingency table. The odds ratio (OR), its standard error and 95% confidence interval are calculated according to Altman, 1991.

We used the following formulae to calculate the odds ratio (OR) and its confidence interval (CI).

OR = a*d / b*c, where:

a is the number of times both A and B are present,

b is the number of times A is present, but B is absent,

c is the number of times A is absent, but B is present, and

d is the number of times both A and B are negative.

To calculate the confidence interval, we use the log odds ratio, log(or) = log(a*d/b*c), and calculate its standard error:

se(log(or)) = √1/a + 1/b + 1/c +1/d

The confidence interval, ci, is calculated as:

ci = exp(log(or) ± Zα/2¬*√1/a + 1/b + 1/c + 1/d),

Where Zα/2 is the critical value of the Normal distribution at α/2 (e.g. for a confidence level of 95%, α is 0.05 and the critical value is 1.96).

Additionally, four studies reported adjusted effect size (three studies reported odds ratio and one study reported hazard ratio). As you know there is no precise formula to convert HR to RR or OR. In short, under very specific conditions, the HR and RR will coincide when everyone has complete follow-up (no dropouts or censoring). It may be possible to compute an approximate RR by inspection of the Kaplan-Meier curves by finding the group-specific failure (or event) rates at a fixed time-point, since these are probabilities. In practical meta-analysis the researchers suppose the RR and HR identical. Odds ratios approximate risk ratios when the outcome under consideration is rare but can diverge substantially from risk ratios when the outcome is common. Logistic regression is used frequently in cohort studies and clinical trials. When the incidence of an outcome of interest is common in the study population (>10%), the adjusted odds ratio derived from the logistic regression can no longer approximate the risk ratio. The more frequent the outcome, the more the odds ratio overestimates the risk ratio when it is more than 1 or underestimates it when it is less than 1. In this meta-analysis, we considered the hazard ratio and the odds ratio to be the same.

Line 131, if the score is how many, you included in your review?

R: as mentioned in the result section: “Based on the methodological quality assessment scores, all studies were deemed to be of high quality.”

Check your PRISMA.

R: according to comment by one of the reviewers we modified PRISMA flowchart.

In the table1, you should write types of laboratory used instead of code, for example, PCR, ELISA …… .

ID diagnostics criteria WISC……but not code

Response: Please note that International Classification of Diseases (ICD) are most validated criteria for diagnosis of many diseases. We included related information if there were in the included studies.

Based on your title, you should on “Infection-based studies; these studies evaluated the prevalence or incidence of ID in the follow-up of children with- and without exposure to maternal infection.” But not Intellectual disability-based studies; these studies recruited children affected by ID. because it might occur other factors like alcohol, cigarette, and others. Or modify your titles.

Response: please note that our main was evaluate the association between maternal infection and intellectual disability. According to our consultant with epidemiologists as well as our previous experiences we can include both infection-based and ID-based of studies. However, we are agreeing with you that our title may not be suitable, therefore to resolve your concern we modified the title as follow “The association between maternal infection and intellectual disability in children: a systematic review and meta‐analysis”

You expected to show OR and RR of each included study in Table 2.

Response: Table 2 is related to sub-group analyses. Related OR for each study is presented in Figure 2.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (25.2KB, docx)

Decision Letter 2

Zemenu Yohannes Kassa

11 Sep 2023

PONE-D-23-15712R2The association between maternal infection and intellectual disability in children: a systematic review and meta‐analysisPLOS ONE

Dear Dr. Nourollahpour Shiadeh,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Zemenu Yohannes Kassa, Msc

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

General comments

You should be expected to follow PLOS ONE guidelines.

Abstract

See punctuation.

Lines 27,32, 45, 53

line 46: what is REM?

Discussion

Line 229 -234, see again; this paragraph explains ID related to behaviours.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Oct 5;18(10):e0292226. doi: 10.1371/journal.pone.0292226.r006

Author response to Decision Letter 2

12 Sep 2023

Dear Dr Yohannes Kassa

Academic Editor

PLOS One

Thank you very much for reviewing our manuscript. Comments by you and reviewers were very helpful. We revised the manuscript according to the comments raised by the you and reviewers. All the changes based on the reviewer’s comments are highlighted yellow in the revised manuscript as I explained in follow.

Sincerely yours

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

R: Thank you very much for your inquiry. We have diligently reviewed all the articles referenced in this paper, utilizing both PubMed and the Retraction Watch website (http://retractiondatabase.org/). Regrettably, we did not uncover any retracted papers among the citations. Should you come across any retracted articles, we would greatly appreciate it if you could provide the title of the article so that we can appropriately update our reference list.

Additional Editor Comments:

General comments

You should be expected to follow PLOS ONE guidelines.

Abstract

See punctuation.

Lines 27,32, 45, 53

R: Many thanks for your detailed attention, we followed PLOS ONE guidelines in abstract.

line 46: what is REM?

R: Thanks, REM is an abbreviation for Random-effects models. We added it in Abstract

Discussion

Line 229 -234, see again; this paragraph explains ID related to behaviours.

R: Many thanks for your valuable comments, all your concerns were modified. We deleted this sentence and modified related sentences.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (19.3KB, docx)

Decision Letter 3

Zemenu Yohannes Kassa

18 Sep 2023

The association between maternal infection and intellectual disability in children: a systematic review and meta‐analysis

PONE-D-23-15712R3

Dear Dr. Malihe Nourollahpour Shiadeh,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Zemenu Yohannes Kassa, Msc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Zemenu Yohannes Kassa

25 Sep 2023

PONE-D-23-15712R3

The association between maternal infection and intellectual disability in children: a systematic review and meta‐analysis

Dear Dr. Nourollahpour Shiadeh:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Zemenu Yohannes Kassa

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA 2020 checklist.

    (DOCX)

    Click here for additional data file. (31KB, docx)
    S1 Fig. Search strategy.

    (TIF)

    Click here for additional data file. (285.1KB, tif)
    S2 Fig. Sensitivity analysis after each study was excluded.

    (TIF)

    Click here for additional data file. (137.2KB, tif)
    S3 Fig. Pooled OR estimates in subgroups according to the countries for studies assessing the association between maternal infection and intellectual disability (ID) in children.

    (TIF)

    Click here for additional data file. (279.5KB, tif)
    S4 Fig. Pooled OR estimates in subgroups according to the diagnostic criteria for ID in studies assessing the association between maternal infection and ID in children.

    (TIF)

    Click here for additional data file. (89.2KB, tif)
    S5 Fig. Pooled OR estimates in subgroups according to the diagnostic criteria for maternal infection in studies assessing the association between maternal infection and ID in children.

    (TIF)

    Click here for additional data file. (89KB, tif)
    S6 Fig. Pooled OR estimates in subgroups according to the publication year for studies assessing the association between maternal infection and ID in children.

    (TIF)

    Click here for additional data file. (89.2KB, tif)
    S7 Fig. Publication bias for studies assessing the association between maternal infection and ID in children, indication a significant publication bias.

    (TIF)

    Click here for additional data file. (75.7KB, tif)
    S8 Fig. Publication bias for four studies having adjusted odds ratio, indication that there is no publication bias in these studies.

    (TIF)

    Click here for additional data file. (79KB, tif)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (21.3KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (25.2KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (19.3KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting information files.

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