A systematic review protocol was developed and submitted for registration in the PROSPERO database (https://www.crd.york.ac.uk/prospero/) on 19/08/2020. Preparation of our systematic review protocol was done following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols (PRISMA-P) checklist.(20,21)
This systematic review will include articles regarding pregnant women exposed to AEDs. No restrictions will be applied in terms of the comparison group, as we will include studies on women with epilepsy (WWE) on AED (active comparison), WWE not on AED, women without epilepsy (WWOE) on AED, and WWOE not on AED. Study designs that will be included in the review include experimental studies (RCTs and quasi-RCTs), observational studies (e.g. cohort and case-control), and grey literature (thesis and dissertations). Only studies published in English and French will be considered.
Studies that include intrauterine growth restriction (IUGR) as an outcome but do not include any of the birth weight outcomes detailed below will be excluded. Studies with AEDs given exclusively to infants and not mothers during pregnancy will be excluded. Animal studies, studies containing no original research or data (e.g., reviews), conference abstracts, case reports, case series, and editorial letters will not be included. Studies that fulfill our eligibility criteria (Additional file 1) will be included in the review.
Primary outcomes for this systematic review include:
- Small for gestational age (SGA): A birth weight classified as small for gestational age within the study or when SGA is not named explicitly but defined as Infants ≤10th percentile in birth weight, based on birth weight, gestational age.
- Low birth weight (LBW): A birth weight classified as low birth weight as defined within the study or birth weight less than 2500 grams (g).
- Birth weight (BW): weight at birth in grams (g).
Secondary outcomes include head circumference, cephalization index, and birth length (height) defined as:
- Head circumference: Head circumference at birth in centimeters (cm).
- Length: Height of the infant in centimeters (cm),
- Cephalization index: Ratio of the head circumference (HC) to body weight.
Studies that report any of the outcomes above with different terminology (e.g.,, neonatal growth restriction or intrauterine growth restriction to substitute for SGA) will be reclassified according to the definitions specified above.
Information sources and literature search
A systematic search strategy was developed with the assistance of a librarian (MLL). We will search MEDLINE, EMBASE, Cochrane Library, Scopus, CINAHL, IPA, and Global Health. See Additional file 2 for the search strategy that will be used in MEDLINE. The references from eligible publications will be reviewed for additional studies. Open grey, Theses Canada, EBSCO Open Dissertations, and ProQuest Dissertations will be searched using relevant keywords to locate additional studies and reports not published in the seven electronic databases previously stated.
The following key terms and subject headings (MeSH) will be used in various combinations and adapted according to each included database: anticonvulsants, convulsion, epilepsy, body weight, infant, low birth weight, small for gestational age, fetal growth retardation, body height, body size, cephalometry, fetal development, pregnancy outcome, pregnant woman, prenatal exposure.
Study selection process
Two authors (AL and CV) will independently screen titles and abstracts for studies that meet our inclusion criteria using Rayyan (22), as determined by our eligibility criteria. Selected studies will be eligible for full-text review. Any disagreements will be resolved by consensus with a third reviewer. Two authors (SE and WS) will independently screen relevant studies in French.
Data collection process
Two team members (AL and CV) will independently extract information from eligible studies using a data extraction tool. A third member will revise the chart and help resolve any disagreements. Data will include study design, country, data source, drug exposure, sample sizes in exposure and control groups, control groups definitions, birth weight outcomes, and effect estimates including crude and adjusted odds ratios, prevalence ratios, relative risks and mean differences, as well as their confidence intervals and p-values.
Methodological quality/risk of bias appraisal
We will use the Newcastle-Ottawa Scale to assess the methodological quality of observational studies. Funnel plots will be used to assess publication bias and kappa value will be calculated to assess the agreement between the reviewers’ screening and methodological quality scores. The risk of bias of experimental and quasi-experimental studies will be appraised using the Cochrane risk-of-bias tool for randomized trials (RoB 2).(23) The risk of bias analysis will be conducted individually, by two reviewers, and any disagreement will be resolved by consensus.
Synthesis of included studies
Characteristics of the included studies for primary and secondary birth weight outcomes will be presented both descriptively and in tables. Pooled estimates of SGA, LBW, BW, head circumference, height, and cephalization index will be presented. Statistical, clinical, and methodological heterogeneity will be examined before conducting the meta-analysis. We will also assess the strength of the evidence and combine the results quantitatively. Whenever methodological homogeneity is considered sufficient for an outcome, a meta-analysis will be conducted. We will conduct a random-effects meta-analysis to calculate pooled odds ratios for dichotomous data and pooled mean differences for continuous data.(24),(25) The study weights, size of the effect, effect consistency, and direction of effect will be represented in each forest plot. (24)
Funnel plots will be depicted for primary and secondary outcomes, including at least ten studies to explore asymmetry that might be explained by clinical, statistical, and methodological heterogeneity.(26) When the individual peculiarities of the studies under investigation are identified, sensitivity analysis will be done accordingly and reported in a summary table.(24) Projected sensitivity analyses include subgroup analysis by dose, AED exposure period during pregnancy (first trimester, second trimester, and third trimester) and therapy type (monotherapy and polytherapy).