Preconception counselling for women with epilepsy

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The objectives of this systematic review are three-fold:

  • first, to assess the effects of preconception counselling interventions for women with epilepsy, measured by pregnancy outcomes for both mother and child;

  • second, to assess the effects of preconception counselling on knowledge of preconception issues, measured by female and partner knowledge of key issues (e.g. use of folic acid, risk estimates), intentions to plan a pregnancy, and adherence to preconception interventions and antiepileptic drugs;

  • third, to explore experiential aspects of receiving preconception interventions as experienced by women with epilepsy and their partners, using qualitative methods, to increase understanding of factors influencing the experience of pregnancy planning (e.g. risk perceptions and reproductive decision-making).

Background

Description of the condition

Epilepsy is a common neurological disorder affecting up to 1% of the population (Hauser 1990). It affects individuals who show a tendency to experience recurrent unprovoked seizures as a result of abnormal and excessive neuronal discharge (Sanders 1996). Antiepileptic drugs are the mainstay of treatment for the majority of individuals. Approximately one third of people receiving antiepileptic drugs (AEDs) are women of reproductive age (Yerby 1994). It is estimated that 0.3% to 0.7% of all births are to women with epilepsy (WWE), most of whom require continuation of AEDs during pregnancy, because uncontrolled seizures might harm the mother and fetus (Joint Epilepsy Council 2011; Lunardi 2011; Tomson 2011). This represents an estimated 22,800 children born each year following in utero AED exposure in the US (Meador 2004). In the UK, 2400 children born to WWE are exposed to AEDs in utero per annum (Kinney 2011). Whilst the outcome of pregnancy for the majority of WWE is normal, there is a two- to threefold increased risk of adverse pregnancy outcomes; these include risks of maternal mortality and morbidity, together with fetal risks of death, major congenital malformations (MCMs), dysmorphism (anatomical malformation) and long-term cognitive delay (Barrett 2003; Yerby 1997). The magnitude of fetal risk is influenced not only by the type of AED, but also by dosage and other variables (e.g. maternal age and parental history of major congenital malformation), all of which need to be taken into account in the management of epilepsy in women of childbearing potential (Tomson 2011). The challenges facing preconceptual WWE and their supporters highlight the importance of adequate risk information prior to conception to inform reproductive decision-making and reduce risks including maternal mortality (CMACE 2011).

Description of the intervention

Preconception refers to the period of time from the decision to have a baby up to becoming pregnant, and includes the stages of preparation for pregnancy. The effectiveness of preconception interventions relies on the identification of and reduction in (modifiable) risk factors before conception in order to improve obstetric outcome (Steegers 2005). The principle components of preconception counselling interventions include: i) risk assessment, ii) health education and promotion, and iii) targeted advice concerning specific medical problems that might concern women and their partners before embarking on pregnancy (Chamberlain 1986).

Risk assessment

Risk assessment involves identification and quantification of modifiable health risks prior to pregnancy, and is associated with improved pregnancy outcomes. Identification of potential exposure to teratogenic agents is an important goal of preconception interventions, where a teratogen is defined as an "agent or factor that can cause abnormalities of form, function (physically resulting in birth defect and altered central nervous system performance resulting in neurological dysfunction, behavioural and cognitive abnormalities) or both in an exposed fetus" (Hanson 1997). For WWE, the teratogenic risks of all AEDs are established; all older generation AEDs (e.g. valproate) are classed as harmful to fetal health, and most of the newer AEDs (e.g. levetiracetam) are classed as potentially harmful (Holmes 2011). Assuming the effect of AEDs is important to pregnancy outcomes, then changing to newer AEDs may lead to changes in the risks of adverse pregnancy outcomes (Borthen 2011). However, whatever reduction in specific MCMs changes to AEDs may afford, any reduction in the rate of MCMs relies on comprehensive changes in the medical care of preconceptual and pregnant WWE (Bánhidy 2011). The value of research to clarify the MCM risks of AEDs is to assist clinicians and the individual women they treat to plan pregnancy, where "the goal for all concerned is a healthy, seizure-free mother and an undamaged child" (Lander 2008). The MCM risk information serves to support epilepsy management decision-making, where the issues of maternal and fetal need require concurrent consideration, and a balance is likely required between acceptable MCM risk for a specific treatment regimen and the dosage required to establish effective seizure control (Lander 2008). Data from the European Epilepsy and Pregnancy Register and UK Register have identified dose-dependent risks, supporting the recommendation to aim for the lowest dose of an AED associated with optimum seizure control (Hauser 2011; Morrow 2006; Tomson 2011).

Health education and promotion

Preconception interventions target improvements in parental health behaviours including smoking cessation, reduction of alcohol consumption, and weight management (Whitworth 2009). The health promotion activities for WWE target improving health knowledge and awareness in advance of sexual activity. The teratogenic risk of AED therapy is present from the first weeks of pregnancy, often before the woman is aware of being pregnant (Rapcencu 2012). This underscores the importance of proactive information provision to all WWE of childbearing potential who use AEDs, in order to accomplish treatment adjustments prior to conception (Betts 1999). Clinical guidelines published by the National Institute for Health and Care Excellence (NICE) recommend the provision of information and counselling to women and girls in advance of sexual activity and pregnancy, requiring information to be tailored to the person's individual needs on topics including: contraception, conception, pregnancy, caring for children and breastfeeding (NICE 2012). The information should also be given, as needed, to people who are closely involved with women and girls with epilepsy, including family, spouse and/or carers.

Targeted advice concerning epilepsy

Preconception interventions for WWE target the review of diagnosis and AED regimen to ensure appropriate treatment prior to conception to improve seizure control through rationale AED selection, seeking where possible the reduction or withdrawal of AEDs prior to conception. For women experiencing frequent seizures, interventions may focus on reducing the number and dose of AEDs, moving from polytherapy to monotherapy where possible (Bánhidy 2011; Morrow 2006).

Epilepsy-specific advice includes the appropriate use of contraception to delay pregnancy until optimal epilepsy management is achieved and includes improved adherence to preconception supplementation with folic acid (De Weerd 2002; Pack 2009). Evidence of the effectiveness of folic acid in reducing the rate of AED-related MCMs, and specifically spina bifida, remains limited and is confounded by the variable uptake of folic acid either at the recommended doses or timings (Czeizel 2011; Fairgrieve 2000). Further, the ability to extrapolate population-based research to treated WWE is unclear, with only limited evidence of its influence on reducing risks of spina bifida amongst sodium valproate-exposed pregnancies (Craig 1999; Morrow 2009). However, WWE continue to be recommended folic acid supplementation, with benefit reported for reduction of congenital malformations in children unexposed to AEDs and those exposed in utero to carbamazepine, primidone, phenobarbital and phenytoin (Jentink 2010; Kjær 2008; Morrow 2009; National Clinical Guideline Centre 2012). Further, the opportunity to influence neurodevelopmental outcomes has been proposed by Meador and colleagues (Meador 2011) who also report preconception folate as positively associated with higher verbal outcomes in AED-exposed children. Preconception counselling is an ideal time-window to provide targeted health information regarding the management of epilepsy during pregnancy, and the potential need for adjustment of AEDs to maintain seizure control during pregnancy.

Cost effectiveness

Improvements in preconception health to increase awareness of modifiable risk factors has been identified by the Center for Disease Control & Prevention 2006 as a primary means of preventing MCMs, thereby reducing societal costs. The Centre for Maternal and Child Enquiries (CMACE 2011) has extended this to include reduction in preventable indirect maternal deaths. The impact of substandard care received by WWE in the UK was highlighted as being instrumental in the epilepsy-related deaths reported (de Swiet 2011). Deaths of WWE during 2006 to 2008 represented a rate of 0.61 per 100,000 mothers, many of whom did not receive preconception counselling. As a result, these women and their carers were unaware that closer surveillance or changes to medication during pregnancy were appropriate (de Swiet 2011; Lewis 2011).

In promoting the benefits of preconception care of WWE, Kinney (Kinney 2011) reports the potential cost reduction of preventing 31 children each year born to mothers with epilepsy being affected by MCMs, from changes in prescribing practices. He identifies that avoidance of sodium valproate alone would reduce the economic burden by preventing 5 cases of spina bifida per year at an estimated cost saving of £1,746,000 (Kinney 2011). Improvements in pregnancy planning have been estimated to represent an unadjusted relative risk reduction of 3.0 (95% CI 2.0 to 4.5) for first trimester exposure to potential teratogenic medications (Han 2005) when compared to medication exposure in women experiencing unintended pregnancy (total number of women surveyed 1354; medication exposure reported 82/657 12.5% unintended pregnancies versus 29/697 4.2% planned pregnancies).

How the intervention might work

Preconception counselling interventions bring together an interventional process involving assessment, planning, treatment, education, decision support and counselling, resulting in a wide range of potential health outcomes before, during and after pregnancy for both the woman and her future offspring (see Figure 1 for driver diagram of preconception counselling interventions).

Figure 1.

The benefits of preconception counselling are achieved by timely identification of risk, lifestyle modifications, informed decisions about pregnancy and the opportunity to plan pregnancy (Cefalo 1995). The context of preconception counselling for WWE emphasises the chronic nature of epilepsy, in which women require an ongoing process of preparation and review of epilepsy management, to ensure they conceive with a minimum of risk factors, are fully aware of any risks and benefits of treatment, and are able to make informed decisions about future pregnancies (Crawford 2005).

Why it is important to do this review

Women with epilepsy are frequently presented with information when preparing for pregnancy, much of which includes statements of risk either concerning the health of the woman or her future child. Little is known about how women consider, use, are influenced by, trust and either act on or disregard information provided prior to conception, how they make decisions about conception, and what might influence their pregnancy planning. Several studies report the numbers of women not receiving advice prior to getting pregnant, but these studies do not help in understanding why this occurs, and little is known about the potential to influence the involvement of women in preconception counselling. A number of questions have been raised, including the continued struggle faced by WWE to adequately prepare for pregnancy and the potential influence of partners and significant others upon decision-making and risk perception (Winterbottom 2012). The interventional components influencing preconception decision-making remain unclear,including the influence of health education upon service utilisation, both of which may result in women experiencing pregnancy unaware of potential risks and resorting to stopping AEDs without discussion with their clinician. Evidence from this review will develop understanding of the views of WWE, their beliefs, attitudes and perceptions of future pregnancy, and the effectiveness of preconception interventions to improve the health of mothers with epilepsy and their offspring.

Objectives

The objectives of this systematic review are three-fold:

  • first, to assess the effects of preconception counselling interventions for women with epilepsy, measured by pregnancy outcomes for both mother and child;

  • second, to assess the effects of preconception counselling on knowledge of preconception issues, measured by female and partner knowledge of key issues (e.g. use of folic acid, risk estimates), intentions to plan a pregnancy, and adherence to preconception interventions and antiepileptic drugs;

  • third, to explore experiential aspects of receiving preconception interventions as experienced by women with epilepsy and their partners, using qualitative methods, to increase understanding of factors influencing the experience of pregnancy planning (e.g. risk perceptions and reproductive decision-making).

Methods

Criteria for considering studies for this review

Types of studies

Quantitative studies including:

  • randomised control trials;

  • quasi-randomised and cluster randomised trials;

  • prospective cohort studies;

  • controlled before and after studies; and

  • interrupted time series studies.

Qualitative studies including:

  • focus group studies;

  • interviews;

  • observational studies; and

  • studies meeting quality criteria.

Types of participants

Quantitative studies

Participants of interest are women of childbearing potential aged 12- to 0 years with a confirmed diagnosis of epilepsy, on or off treatment who are not already pregnant. Potential control groups might include women who have not experienced preconception interventions, as well as those who have experienced differing interventional components or healthcare settings.

Qualitative studies

Women of childbearing potential aged 12 to 50 years with a diagnosis of epilepsy who have attended preconception counselling care or who have expressed an interest in preparing for pregnancy. Women with epilepsy (WWE) who have failed to attend preconception counselling might also be included. Participants may also extend to include partners, carers or other family members, members of the healthcare team, and the wider health economy.

Types of interventions

Preconception counselling interventions include any educational and/or counselling interventions targeting WWE before the decision to have a baby, up until pregnancy, with interventions involving assessment of lifestyle, health and fitness by a healthcare professional (CSK 2012). Preconception counselling interventions include epilepsy review with the intention of reducing antiepileptic drug (AED) or seizure-related risk and improving the chances of healthy pregnancy outcome. Preconception defines the time leading up to a pregnancy, or the interval between subsequent pregnancy; starting at commencement of menstrual period up until a women has made permanent measures to prevent conception, or has entered the menopause.

Quantitative studies

(1) Intervention group

Women with epilepsy receiving preconception counselling.

(2) Control groups

Women with epilepsy receiving standard care (no intervention).

Women with epilepsy receiving a comparison intervention or comparison version of preconception counselling.

Qualitative studies

Studies using qualitative methods will not be delivering an intervention but will explore preconception counselling from the perspective of the women with epilepsy, their partners and family. Studies may focus on care pathways from the patient and health professional perspective (see Types of participants; Types of outcome measures).

Types of outcome measures

Primary outcomes

Quantitative outcomes

Pregnancy outcomes including:

  1. Obstetric outcomes;

  2. Congenital malformations;

  3. Neurodevelopmental outcomes;

  4. Infant mortality and morbidity.

Qualitative outcomes

Experiences of women with epilepsy and their partners receiving preconception counselling including:

  1. Pregnancy planning;

  2. Use of folic acid;

  3. Satisfaction with care;

  4. Relationships with healthcare professionals;

  5. Shared decision-making; and

  6. AED treatment.

Secondary outcomes

Quantitiative outcomes

  • Intention to plan pregnancy, including attendance at preconception review, and commencement of folic acid;

  • Knowledge of AED-related contraceptive interactions, and alternative effective contraceptive methods;

  • Knowledge of the role and dose of folic acid, including knowledge of the appropriate time to commence folic acid;

  • Health improvement including smoking/alcohol cessation, weight management;

  • Satisfaction with care, including involvement in shared decision-making;

  • Health-related quality of life;

  • Concordance with treatment/intervention regime;

  • Breastfeeding; and

  • Infant and child injuries secondary to maternal seizures.

Qualitative outcomes

The list of potential qualitative outcomes is broad and may include:

  • Perspectives;

  • Awareness of risk;

  • Improvements in health (smoking cessation/weight management);

  • Quality of life changes.

This list is not exhaustive and we aim to explore other issues reported within the qualitative reports.

Search methods for identification of studies

Electronic searches

We intend to search the following databases:

  1. The Cochrane Epilepsy Group’s Specialized Register;

  2. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) using the search strategy set out in Appendix 1;

  3. MEDLINE (Ovid) using the search strategy set out in Appendix 2;

  4. SCOPUS, see Appendix 3;

  5. CINAHL, see Appendix 4; and

  6. PsycINFO, see Appendix 4.

The MEDLINE search strategy will be adapted to meet the requirements of the SCOPUS, CINAHL and PsycINFO databases and no restrictions will be placed on date of publication or language.

Searching other resources

We will search conference abstracts for the last 5 years (2009 to 2014) from conferences including:- International Epilepsy Congress, European Congress on Epileptology and American Epilepsy Society Meeting.

The Epilepsia Journal supplements from the past 5 years (2009 to 2014) will be searched for conference proceedings.

Reference lists of original research and review articles will be cross matched to the studies generated from the electronic searches. Reference lists of recent review articles will be searched and lead corresponding authors in the area will be contacted for any relevant unpublished material.

Data collection and analysis

Selection of studies

Three review authors (JW, JP, JG) will independently take part in all stages of study selection. Firstly, review authors will independently scan the titles and abstracts of references identified by searching. Full details of possibly relevant studies will be obtained and assessed independently for inclusion in the review. Multiple reports of the same study will be linked together. If necessary, authors will be contacted to clarify study eligibility. If a disagreement occurs, the review authors will attempt to reach a consensus by discussion or involve a fourth opinion (AGM). Studies that do not meet all of the inclusion criteria will be excluded and their bibliographic details listed with reasons for exclusion. Ongoing studies that do not report relevant outcomes but meet the inclusion criteria will be listed for future review. For studies published in abstract form only, if it is clear that a study is eligible then it will be included. If it is not clear, authors will be contacted for further information and will be placed in ‘awaiting assessment’ until a reply is received (in an appropriate timeframe).

Data extraction and management

Quantitative studies

The following information will be extracted for each study independently by three authors (JW, JP, JG) using a data extraction form:

Methodology/study design
  1. Study type/design;

  2. Method of recruitment;

  3. Information regarding all aspects of risk of bias (see below);

  4. Source of funding.

Participants/demographics
  1. Total number of participants;

  2. Age and gender of participants;

  3. Seizure type/classification;

  4. Seizure frequency; and

  5. Treatment status.

Results
  1. Number of participants allocated to each group;

  2. Sample size for each outcome;

  3. Summary data for each outcome including means and standard deviations;

  4. Estimate of effect for each outcome.

See list of outcomes (Types of outcome measures) for details for extraction.

Qualitative studies

The following information will be extracted for each study independently by three authors (JW, JP, JG) using a data extraction form:

Methodology/study design
  1. Method of collecting data (e.g. focus groups/interviews etc.);

  2. Method of analysis (e.g. thematic/discourse analysis etc.);

  3. Method of sampling (e.g. stratified, purposeful etc.);

  4. Location;

  5. Settings; and

  6. Study aims.

Participants/demographics
  1. Number of participants;

  2. Age and gender of participants;

  3. Seizure type/classification;

  4. Seizure frequency; and

  5. Treatment status.

Results
  1. Quotes reported; and

  2. Themes identified.

Assessment of risk of bias in included studies

Quantitative studies

Three authors (JW, JP and JG) will independently assess the risk of bias in all included studies and judgements will be cross-checked. Due to the observational design of some of the studies, we will utilise a version of the extended Cochrane Collaboration tool for assessing risk of bias, currently being developed by the Cochrane Non-Randomised Studies Methods Group. The tool examines selection bias (sequence generation, allocation concealment), performance bias (blinding), attrition bias (incomplete outcome data), detection bias (blinding, other potential threats to validity), reporting bias (selective outcome reporting), and the influence of confounding variables. The domains of blinding, incomplete outcome data, selective outcome reporting, confounding variables and other bias will be rated on a five-point scale ranging from low risk of bias to high risk of bias according to the risk on the outcome. See Appendix 5 for the extended 'Risk of bias' tools. The parameters of this scale were determined by the review authors (see Table 1). For RCTs, all domains of the Cochrane Collaboration's current tool for assessing risk of bias will be applied (Higgins 2011). We will make an overall summary judgement of risk of bias for each study per outcome, followed by an overall judgement per outcome across studies.

Table 1. Risk of bias scale parameters
  1. 1 Important confounders include patient specific factors (maternal age, parity, previous affected child, maternal IQ, socio-economic status, epilepsy type, seizure exposure, AED use and pre-intervention knowledge of AED and seizure-related pregnancy risks); resources/service specific factors (attendance rate of preconception counselling sessions).

    2 Reported demographic information and other confounders.

    3 Matching scores, multiple regression, analysis of co-variance, stratification.

    4 At least five out of ten of important confounders including maternal educational level or IQ, pre-intervention knowledge of AED and seizure related pregnancy risks and attendance of preconception counselling sessions.

    5 At least two out of ten of important confounders.

    6 Full adjustment of confounding variables e.g. see footnote 2, or partial adjustment e.g. researchers select limited number of variables to adjust for.

    7 Assessors of outcome are only blinded to certain groups e.g. blinded to intervention group but not controls.

    8 Intention-to-treat analysis.

    9 An a priori statement is made in methods section of main report regarding measurement and analysis of outcome.

    10 For example, failure to report full scale IQ when all other indices are reported.

 1 Low risk2345 High risk
ConfoundingAll important1 confounders considered2 and suitable method of adjustment3 employed. Outcome unlikely to be affected.Most important4 confounders considered and suitable method of adjustment employed. Outcome unlikely to be affected.Some confounders5 considered and full or partial adjustment employed.6 Possible implication on outcome.Some confounders considered and no adjustment employed. Likely to affect outcome.No important confounders considered and no adjustment employed. Likely to affect outcome.
BlindingAssessors blinded to participant’s drug regime and/or intervention and participants blinded to drug regime and/or intervention. Outcome unlikely to be affected.Assessors blinded to participants drug regime and/or intervention. Outcome unlikely to be affected.Partial blinding7 involved in study. Possible implication on outcome.Partial or no blinding involved in study. Outcome likely to be affected.No blinding involved in study.  Outcome likely to be affected.
Incomplete outcome data

No missing data and/or

appropriate analysis8 used to deal with missing data. Unlikely to affect outcome.

Smaller amount (< 25%) of missing data with reasons given, balanced across groups. Unlikely to affect outcome.Larger amount of missing data (> 25%) with or without reasons given, balanced across groups. Possible implication on outcome. 

Larger amount (> 25%) of missing data, imbalance across groups. Outcome likely to be affected.

 

No information provided regarding missing data. Likely to affect outcome. 
Selective outcome reporting A priori outcomes measured, analysed and reported in main report. Protocol available. Unlikely to affect outcome. A priori outcomes measured, analysed and reported in main report9. Protocol not available. Unlikely to affect outcome.Limited information regardinga priori outcomes and measures. Possible implication on outcome.Outcomes measured but not analysed or reported.Outcomes measured  but not analysed or reported and clinical judgement infers the presence of an unreported measured outcome.10
Other biasNo bias identified.  Bias identified. Unlikely to affect outcome.Bias identified. Possible implication on outcome.Bias identified. Likely to affect outcome.Bias identified. Extremely likely to affect outcome.

The 'Risk of bias' judgements will be incorporated into the analysis using sensitivity analysis, in that a secondary analysis of the data will include only studies rated as low in overall risk of bias. Both results will be presented in the Results section of the review. Where applicable, we will create 'Summary of findings' tables for outcomes, and each outcome will be graded accordingly using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach (Guyatt 2008).

Qualitative studies

Quality assessments will be carried out by three review authors independently using the Critical Appraisal Skills Programme (CASP 2010) tool for qualitative studies (see Appendix 6). This tool examines the quality of a study over 10 questions relating to research aims, appropriateness of methodology and design, recruitment strategy, data collection, relationship of researcher, consideration of ethical issues, data analysis, statement of finding and the value of the research.

We plan to use the results of the quality assessments to categorise each paper as either a key paper (KP – to be included in review), satisfactory paper (SAT – to be included in review), unsure (? – unsure whether paper should be included), fatally flawed (FF – paper to be excluded on grounds of being fatally flawed) (Dixon-Woods 2007).

Measures of treatment effect

Quantitative studies

We will present dichotomous data as a relative risk with 95% confidence intervals. For continuous data, we will present the overall effect estimates as mean differences or standardised mean differences (SMDs) depending on the nature of the measures being used. For example, we will calculate SMDs if measures used are different, but measure the same outcome.

Qualitative studies

For qualitative studies, data will be presented as themes in the format of a flow diagram.

Unit of analysis issues

Quantitative studies

We anticipate that studies will allocate individuals to one of two intervention groups and a single measurement will be made for each participant for each outcome. We do not expect to find cluster randomised trials, cross over trials or studies that use repeated measures.

Qualitative studies

For qualitative studies, a variety of methods of analysis such as Grounded Theory, Interpretive Phenomenological Analysis, Thematic Analysis and Discourse Analysis may have been employed. This will be investigated and an appropriate method of synthesis employed. These may not be amenable to meta-synthesis.

Dealing with missing data

Quantitative studies

Missing data from studies will be sought through contact with study authors. We will assess the reasons for missing data to determine if data are missing at random or not. For RCT evidence we intend to carry out Intention-to-treat analyses.

Assessment of heterogeneity

Quantitative studies

For quantitative data, we will assess clinical heterogeneity by examining the difference in study characteristics in order to inform decisions regarding the combination of study data. We will also assess statistical heterogeneity by examining the I2 statistic and using a Chi2 test (Higgins 2011).

Qualitative studies

For qualitative data, we will assess heterogeneity by examining study differences including methods of analysis and types of participants to allow appropriate synthesis of data.

Assessment of reporting biases

Quantitative studies

We will investigate outcome reporting bias using the ORBIT matrix system (Kirkham 2010).

We will examine publication bias by identifying unpublished data, by carrying out a comprehensive search of multiple sources and requesting any unpublished data from authors. We will look for small-study effects and funnel plots to establish the likelihood of publication bias in the event an appropriate number of studies are able to be combined (Higgins 2011).

Data synthesis

Quantitative studies

For quantitative data, we will employ a fixed-effect meta-analysis.The comparisons we expect to carry out include:

  1. intervention group versus standard care on all outcomes; or

  2. intervention group versus comparison intervention on all outcomes.

Qualitative studies

For qualitative studies, all data will be entered into a data extraction form consisting of a table of all published data extracts (first-order constructs), analytic commentary (second-order constructs), conclusions and implications and themes/categories. We plan to compile a matrix of first- and second-order constructs and develop conceptual maps in the form of flow diagrams in order to show the relation between second-order constructs. We then aim to compare the study constructs and create a list of conceptual terms and definitions,and code the data according to the concepts (Dixon-Woods 2005).

Subgroup analysis and investigation of heterogeneity

Two separate analyses will be conducted for each type of data (i.e. quantitative/qualitative). Subgroup analysis will be stratified by study design (i.e. RCT/non-randomised evidence) and type of control group/comparison (i.e. standard care/alternative intervention).

If unexplained heterogeneity is present, we will conduct a random-effects analysis. Differences between analyses will be examined and the appropriate analysis will be reported.

Sensitivity analysis

We intend to carry out sensitivity analysis if discrepancies between studies are found with regards to quality. Data will be presented with and without low quality studies to enable differences in findings to be examined.

Acknowledgements

We thank Bridget Young for providing comments on the draft protocol.

Appendices

Appendix 1. CENTRAL search strategy

#1         (epilep*)

#2         MeSH descriptor Epilepsy explode all trees

#3         (seizure*)

#4         MeSH descriptor Seizures explode all trees

#5         (#1 OR #2 OR #3 OR #4)

#6         MeSH descriptor Preconception Care explode all trees

#7         (prepregnancy) or (pre-pregnancy) or "pre pregnancy"

#8         (plan* NEAR/3 pregnan*)

#9         plan* NEAR/3 conceive

#10       plan* NEAR/3 conception

#11       (preconception*) or (pre-conception*) or "pre conception"

#12       (reproductive health)

#13       MeSH descriptor Family Planning Services explode all trees

#14       (family planning) or (planned parenthood)

#15       MeSH descriptor Folic Acid explode all trees

#16       MeSH descriptor Counseling explode all trees

#17       (counsel*) or (educat*) or (inform*) or (advice) or (advise)

#18       (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)

#19       (#16 OR #17)

#20       (#18 AND #19)

#21       (#20 OR #6)

#22       (#5 AND #21)

Appendix 2. MEDLINE search strategy

1. epilep$.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
2. exp EPILEPSY/
3. seizure$.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
4. exp SEIZURES/
5. 1 or 2 or 3 or 4
6. exp Preconception Care/
7. (prepregnancy or pre-pregnancy or "pre pregnancy").mp. [mp=title, original title, abstract, name of substance word, subject heading word]
8. (plan$ adj3 pregnan$).ti,ab.
9. (plan$ adj3 conceive).ti,ab.
10. (plan$ adj3 conception).ti,ab.
11. (preconception$ or pre-conception$ or "pre conception").mp. [mp=title, original title, abstract, name of substance word, subject heading word]
12. reproductive health.mp.
13. exp Family Planning Services/
14. (family planning or planned parenthood).ti,ab.
15. exp FOLIC ACID/
16. exp Counseling/
17. (counsel$ or educat$ or inform$ or advice or advise).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
18. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15
19. 16 or 17
20. 18 and 19
21. 20 or 6
22. 5 and 21

Appendix 3. SCOPUS search strategy

(TITLE-ABS-KEY(epilep* OR seizure*)) AND ((((TITLE-ABS-KEY(prepregnancy OR pre pregnancy OR pre-pregnancy) OR TITLE-ABS-KEY(preconception* OR pre conception* OR pre-conception*))) OR ((TITLE-ABS-KEY(reproductive health) OR TITLE-ABS-KEY(family planning) OR TITLE-ABS-KEY(planned parenthood) OR TITLE-ABS-KEY(folic acid)))) AND (TITLE-ABS-KEY(counsel* OR advice OR advise OR inform* OR educat*)))

Appendix 4. CINAHL and PsycINFO search strategy

S13S3 and S12
S12S10 or S11
S11(MM "Prepregnancy Care")
S10S8 and S9
S9TI ( Counsel* or educat* or inform* or advise or advice ) or AB ( Counsel* or educat* or inform* or advise or advice )
S8S4 or S5 or S6 or S7
S7AB family planning or AB reproductive health or AB planned parenthood or AB folic acid
S6TI family planning or TI reproductive health or TI planned parenthood or TI folic acid
S5AB ( prepregnancy OR pre-pregnancy OR pre pregnancy ) or AB preconception or AB pre-conception or AB pre conception
S4TI ( prepregnancy OR pre-pregnancy OR pre pregnancy ) or TI preconception or TI pre-conception or TI pre conception
S3S1 or S2
S2MM epilepsy or seizure
S1TI ( epilep* or seizure* ) or AB ( epilep* or seizure* )

Appendix 5. 'Risk of bias' tool for non-randomised studies

ItemJudgement1Description (quote from paper, or describe key information)
1. Sequence generation  
2. Allocation concealment  
3a. Confounding2Outcome 1  
3b. Confounding2Outcome 2  
4a. Blinding?Outcome 1  
4b. Blinding?Outcome 2  
5a. Incomplete outcome data addressed?Outcome 1  
5b. Incomplete outcome data addressed?Outcome 2  
6a. Free of selective reporting?Outcome 1  
6b. Free of selective reporting?Outcome 2  
7. Free of other bias?  
8. A priori protocol?  
9. A priori analysis plan?4   

 Footnotes

1 Some items on low/high risk/unclear scale (double-line border), some on 5 point scale/unclear (single-line border), some on yes/no/unclear scale (dashed border).  For all items, record 'unclear' if inadequate reporting prevents a judgement being made.

2 Based on list of confounders considered important at the outset and defined in the protocol for the review (and assessment against worksheet)

3 Did the researchers write a protocol defining the study population, intervention and comparator, primary and other outcomes, data collection methods, etc. in advance of starting the study?  N.B. May be outcome specific.

4 Did the researchers have an analysis plan defining the primary and other outcomes, statistical methods, subgroup analyses, etc. in advance of starting the study?

Studies for which the 'Risk of bias' tool is intended

Only suitable for ‘cohort-like’ studies, individually or cluster-allocated.  This can include secondary analyses of clinical databases providing the analysis is clearly structured as a comparison of control and intervention participants (XXXXX):

Individually allocated study designs
  • Randomised controlled trial

  • Quasi randomised controlled trial

  • Non-randomised controlled trial

  • Controlled before and after study (not common use of this label, see controlled cohort before and after study below)

  • Prospective cohort study

  • Retrospective cohort study

Cluster allocated study designs
  • Cluster randomised controlled trial

  • Cluster quasi randomised controlled trial

  • Cluster non-randomised controlled trial

  • Controlled interrupted time series

  • Controlled cohort before and after study

Assessment of risk of bias

Issues when using the modified 'Risk of bias' tool to assess cohort-like non-randomised studies:

  • follow principle for existing Cochrane Collaboration's tool for risk of bias: score judgement and provide information (preferably direct quote) to support judgement.

  • modified 'Risk of bias' tool includes an additional item on confounding.

  • five-point scale for some items (distinguish 'unclear' from intermediate risk of bias).

  • keep in mind the general philosophy – assessment is not about whether researchers could have done better but about risk of bias; the assessment tool must be used in a standard way whatever the difficulty/circumstances of investigating the research question of interest and whatever study design features were used.

  • use of a five-point scale is uncharted territory; very interested to know whether this makes things easier or more difficult for review authors.

  • anchors for five-point scale:  '1/No/low risk' of bias should correspond to a high-quality RCT.  '5/high risk' of bias should correspond to a risk of bias that means the findings should not be considered (too risky, too much bias, more likely to mislead than inform).

Sequence generation
  • Low/high/unclear risk of bias item

  • Always high risk of bias (not random) for a non-randomised study

  • Might argue that this item is redundant for non-randomised studies since they are always of high risk of bias – but important to include in 'Risk of bias' table ('level playing field' argument)

Allocation concealment
  • Low/high/unclear risk of bias item

  • Potentially low risk of bias for a non-randomised study, e.g. quasi-randomised (high risk of bias due to sequence generation) but concealed (author judges that the people making decisions about including participants didn’t know how allocation was being done, e.g. odd/even date of birth/hospital number)

Risk of bias from confounding (additional item for non-randomised studies; assess for each outcome)
  • Assumes a prespecified list of potential confounders defined in the protocol for the systematic review

  • Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item

  • Judgement needs to factor in (see 'worksheet'):

    • proportion of confounders (from pre-specified list) that were considered

    • whether most important confounders (from pre-specified list) were considered

    • resolution/precision with which confounders were measured

    • extent of imbalance between groups at baseline

    • care with which adjustment was done (typically a judgement about the statistical modelling carried out by authors)

  • Low risk of bias requires that all important confounders are balanced at baseline, i.e.:

    • not primarily/not only a statistical judgement; or

    • measured 'well' and 'carefully' controlled for in the analysis.

We have provided an optional 'worksheet' to help authors to focus on the task (rows = confounders, and columns = factors to consider). Authors should make a 'Risk of bias' judgement about each factor first and then combine these (by eyeballing rather than quantitatively) to make the judgement in the main 'Risk of bias' table.

Risk of bias from lack of blinding (assess for each outcome, as per the existing 'Risk of bias' tool)
  • Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item

  • Judgement needs to factor in:

    • nature of outcome (subjective/objective; source of information)

    • who was/was not blinded and the risk that those who were not blinded could introduce performance or detection bias

Risk of bias from incomplete outcome data (assess for each outcome, as per the existing 'Risk of bias' tool)
  • Low(1) / 2 / 3 / 4 / high(5) / unclear risk of bias item

  • Judgement needs to factor in:

    • reasons for missing data

    • whether amount of missing data balanced across groups, with similar reasons

    • whether group comparison appropriate (e.g. 'analysed in allocated group' issue)

Risk of bias from selective reporting (assess for each outcome)
  • More wide ranging than existing assessment recommendation. Key issue is whether outcomes were clearly defined, and methods of analysis, were pre-specified and adhered to

  • Low(1) / 2 / 3 / 4 / high(5) /unclear risk of bias item

  • Judgement needs to factor in:

    • existing 'Risk of bias' guidance on selective outcome reporting

    • also, extent to which analyses (and potentially other choices) could have been manipulated to bias the findings reported, e.g. choice of method of model fitting, potential confounders considered/included

    • look for evidence that there was a protocol in advance of doing any analysis/obtaining the data (difficult unless explicitly reported); non-randomised studies are very different from RCTs.  RCTs must have a protocol in advance of starting to recruit (for research ethics committee/institutional review board/other regulatory approval); non-randomised studies need not (especially older studies)

    • Hence, separate yes/no items asking review authors whether they think the researchers had a prespecified protocol and analysis plan.

Assessment of confounding variables  

Assessment of how researchers dealt with confounding

Method for identifying relevant confounders described by researchers:

If yes, describe the method used:

yes/no

Relevant confounders described:

List confounders described below

yes/no

Used for controlling for confounding

  • At design stage: matching by characteristics of subjects (see below for matching by propensity score)

 
    • Variables on which subjects matched:

 
  • At analysis stage:

    • stratification

    • multivariable regression

    • propensity scores (matching)

    • propensity scores (multivariable regression

Describe confounders controlled for below

 

Confounders described by researchers

Enter / preprint prespecified list of confounders (rank order in importance? Important in bold?)
Tick (yes/no judgement) if confounder considered by the researchers [Cons’d?]
Score (1 to 5) precision with which confounder measured
Score (1 to 5) imbalance between groups
Score (1 to 5) care with which adjustment for confounder was carried out

 

 

ConfounderConsideredPrecisionImbalanceAdjustment
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Appendix 6. CASP 2010

CRITICAL APPRAISAL SKILLS PROGRAMME

1. Was there a clear statement of the aims of the research?

Consider:

  • What the goal of the research was

  • Why is it important

  • Its relevance

2. Is a qualitative methodology appropriate?

Consider:

  • If the research seeks to interpret or illuminate the actions and/or subjective experiences of research participants

3. Was the research design appropriate to address the aims of the research?

Consider:

  • If the researcher has justified the research design (e.g. have they discussed how they decided which method to use?)

4. Was the recruitment strategy appropriate to the aims of the research?

Consider:

  • If the researcher has explained how the participants were selected

  • If they explained why the participants they selected were the most appropriate to provide access to the type of knowledge sought by the study

  • If there are any discussions around recruitment (e.g. why some people chose not to take part)

5. Were the data collected in a way that addressed the research issue?

Consider:

  • If the setting for data collection was justified

  • If it is clear how data were collected (e.g. focus group, semi-structured interview etc.)

  • If the researcher has justified the methods chosen

  • If the researcher has made the methods explicit (e.g. for interview method, is there an indication of how interviews were conducted, or did they use a topic guide?)

  • If methods were modified during the study. If so, has the researcher explained how and why?

  • If the form of data is clear (e.g. tape recordings, video material, notes etc.)

  • If the researcher has discussed saturation of data

6. Has the relationship between researcher and participants been adequately considered?

Consider:

  • If the researcher critically examined their own role, potential bias and influence during:

    • Formulation of the research questions

    • Data collection, including sample recruitment and choice of location

  • How the researcher responded to events during the study and whether they considered the implications of any changes in the research design

7. Have ethical issues been taken into consideration?

Consider:

  • If there are sufficient details of how the research was explained to participants for the reader to assess whether ethical standards were maintained

  • If the researcher has discussed issues raised by the study (e.g. issues around informed consent or confidentiality or how they have handled the effects of the study on the participants during and after the study)

  • If approval has been sought from the ethics committee

8. Was the data analysis sufficiently rigorous?

Consider:

  • If there is an in-depth description of the analysis process

  • If thematic analysis is used. If so, is it clear how the categories/themes were derived from the data?

  • Whether the researcher explains how the data presented were selected from the original sample to demonstrate the analysis process

  • If sufficient data are presented to support the findings

  • To what extent contradictory data are taken into account

  • Whether the researcher critically examined their own role, potential bias and influence during analysis and selection of data for presentation

9. Is there a clear statement of findings?

Consider:

  • If the findings are explicit

  • If there is adequate discussion of the evidence both for and against the researcher’s arguments

  • If the researcher has discussed the credibility of their findings (e.g. triangulation, respondent validation, more than one analyst)

  • If the findings are discussed in relation to the original research question

10. How valuable is the research?

Consider:

  • If the researcher discusses the contribution the study makes to existing knowledge or understanding e.g. do they consider the findings in relation to current practice or policy, or relevant research-based literature?

  • If they identify new areas where research is necessary

  • If the researchers have discussed whether or how the findings can be transferred to other populations or considered other ways the research may be used

Contributions of authors

JP, JW and JG developed the protocol and intend to carry out data extraction, quality assessment and data synthesis.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK.

    This review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health.

Notes

Janine Winterbottom is the principal author of a Cochrane review 'Preconception counselling for women with epilepsy to reduce adverse pregnancy outcome' (Winterbottom 2008). This review has now been withdrawn from publication as this protocol supersedes the review.

Ancillary