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Global variation in pregnancy complications in women with epilepsy: A meta-analysis
Accepted Manuscript Title: Global variation in pregnancy complications in women with epilepsy: A meta-analysis Authors: John Allotey, David Aroyo-Manzano, Patricia Lopez, Luz Viale, Javier Zamora, Shakila Thangaratinam PII: DOI: Reference:
S0301-2115(17)30251-8 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.05.016 EURO 9908
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EURO
Received date: Accepted date:
25-3-2017 19-5-2017
Please cite this article as: Allotey John, Aroyo-Manzano David, Lopez Patricia, Viale Luz, Zamora Javier, Thangaratinam Shakila.Global variation in pregnancy complications in women with epilepsy: A metaanalysis.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.05.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Global variation in pregnancy complications in women with epilepsy: A meta-analysis
John Allotey, MSc1,2, David Aroyo-Manzano, MSc3,4, Patricia Lopez, MD3,4, Luz Viale, MD5, Prof Javier Zamora, PhD1,3,4, Prof Shakila Thangaratinam, PhD1,2
Affiliation: Women’s Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 1
2
Multidisciplinary Evidence Synthesis Hub (MESH), Queen Mary University of London London, UK 3
Hospital Ramón y Cajal (IRYCIS), Madrid, Spain
4
CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
5
Centro Rosarino de Estudios Perinatales, Rosario, Argentina
Corresponding author John Allotey Women’s Health Research Unit, Multidisciplinary Evidence Synthesis Hub (MESH) Barts and the London School of Medicine and Dentistry Queen Mary University of London, London Tel: +44 2078826048, E-mail: [email protected]
Structured abstract Objective: Women with epilepsy are at risk of pregnancy complications. Whether these vary globally is unknown. We undertook a systematic review to assess the overall rates of obstetric outcomes in
1
women with epilepsy, and variations in estimates across geographical region, economic status of country, and over time. Study design: We searched Medline, Embase, Cochrane, AMED and CINAHL, (January 1, 1990 and November 29, 2016), without any language restrictions for studies reporting core maternal and fetal outcomes in women with epilepsy. We pooled the results using Freeman-Tukey Transformation random effects meta-analysis, and reported our findings as rates of complications per 100 pregnancies with 95% confidence intervals (CI). We assessed for differences in risk across World Health Organisation (WHO) regions, income status, and year of publication. Results: From the 7,420 articles screened, we included 60 studies (62 articles). In women with epilepsy (116,105 pregnancies), the commonest complications were caesarean section (29.2 per 100 pregnancies; 95% CI 25.4 – 33.1, I2=98.44%), and admission to the neonatal intensive care unit (12.5 per 100 pregnancies; 95% CI 9.6 – 15.8, I2=60.63%). There were significant differences across the WHO regions, with the highest rates of caesarean section (37%, 95% CI 32% 42%); spontaneous miscarriage (39%, 95% CI 35% - 44%) and preterm birth (10%, 95% CI 8% - 12%) in the Americas; postpartum haemorrhage (9%, 95% CI 7% - 12%), hypertensive disorders (14%, 95% CI 8% - 21%) and perinatal death (2%, 95% CI 1% - 7%) in the Western Pacific; induction of labour (30%, 95% CI 19% - 41%) in South East Asia and antepartum haemorrhage (10%,95% CI 5% - 17%) in the Eastern Mediterranean . The reported rates of antepartum haemorrhage, caesarean section, gestational diabetes and spontaneous miscarriage 2
were highest in high income and high-middle income countries. Over time, there was a significant increase in caesarean section, and reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care unit in women with epilepsy.
Conclusion: There is significant variation in reported maternal and offspring outcomes in pregnant women with epilepsy across geographical regions, economic status of country and over time, which needs to be considered in setting priorities for clinical management and research.
Keywords: Epilepsy, pregnancy; maternal, fetal, core outcomes
Word Count: 359
Introduction Epilepsy is one of the commonest neurological conditions affecting women of reproductive age.1-3 Risk of maternal death is ten-fold higher in women with epilepsy than those without the condition,3 with increase in rates of obstetric complications. 4 In UK, successive confidential enquires have highlighted the need to manage mothers with epilepsy as a high-risk condition, and for provision of information on risk status.5 However, in the absence of robust information on the rates of various maternal and fetal complications in women with epilepsy, counselling during pre-conception and in pregnancy is limited.
3
Numerous studies have reported on risks of seizure deterioration in pregnancy. Our systematic review on association of epilepsy with obstetric complications was limited to data from comparative cohorts.4 Studies have not assessed if there are any variations in risks of core obstetric outcomes required for reporting in clinical studies 6 on women with epilepsy across geographical regions, countries grouped by income status, and variation in risk over time are not known. Disparities in geographical distribution of health care resources and clinical practice, as well as advances in medical care, are factors expected to contribute to variations in the reported obstetric outcomes in women with epilepsy.
We undertook a systematic review of the literature to obtain precise estimates of the rates of obstetric outcomes in women with epilepsy, and assessing global variation in core pregnancy outcome rates in women with epilepsy.
Methods We undertook our systematic review using a prospective protocol in line with current recommendations, and reported using PRISMA guidelines (Appendix 1).7,8
Search strategy and study selection We searched the electronic databases Medline, Embase, Cochrane, AMED and CINAHL from January 1, 1990 without language restrictions for comparative studies on pregnant women with epilepsy and complications, as part of our previous meta-analysis.4 We updated this search to November 29, 2016, and additionally included studies that provided risk estimates of various complications. We only included studies that provided data on reproductive outcomes in women and excluded abstracts, case reports, case series, in vitro and animal studies. We 4
included outcomes that are considered relevant to clinical practice such as spontaneous miscarriage, induction of labour (IOL), caesarean section, antepartum haemorrhage (APH), postpartum haemorrhage (PPH), any preterm birth (<37 weeks), hypertensive disorders and gestational diabetes. The fetal and neonatal outcomes assessed were fetal death, fetal growth restriction that included both low birth weight and small for gestational age babies, admission to the neonatal intensive care unit (NICU) and perinatal death.
Quality assessment and data extraction Two independent reviewers (JA and LV/PL) undertook quality assessment, with any disagreements resolved after discussion with a different reviewer (JZ). We assessed the methodological quality of included studies for internal validity.9 Characteristics of study design, adequacy of sampling, sufficiently high response rate, assessment of outcome, and sample size calculation were evaluated to determine the quality of studies. Prospective studies were given one point for study design, while random or consecutive sampling methods received a point as an adequate method of participant sampling. 9 Studies with a response rate of at least 80% were given a point and the use of a validated tool for assessing the outcome during the study also received a point. Appropriate sample size calculation had to be undertaken before the start of the study for a point to be scored on this criterion. Studies were ranked as high or low quality, with high quality studies scoring at least 3 of the 5 possible points.9
Data were extracted in duplicates (JA and LV/PL) with pre-designed data extraction forms. The estimates of overall rates of adverse maternal and fetal outcomes in pregnant women with epilepsy were reported with 95% CI. When the same cohort was reported twice, we extracted data from the most recent study with the largest sample size for relevant outcomes. For regional 5
prevalence estimates, countries were grouped into six WHO world regions of African, Americas, South East Asia, European, Eastern Mediterranean and Western Pacific. Countries were also separated based on their WHO income levels of Low, Lower-middle, Upper-middle and High-income economies. We reported on the core obstetric outcomes determined by Delphi consensus. 10
Statistical analysis We computed rates of complications with pregnancy as the unit of analysis. We reported the results obtained after pooling individual study estimates using Freeman-Tukey Transformation random effects meta-analysis as outcomes per 100 pregnancies with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic. Rates were calculated for three time periods: 1990s, 2000s and 2010s and further a priori planned subgroup analysis was done based on quality of the study (low or high). We assessed publication bias and the effect of small studies using funnel plots and Begg’s11 and Egger’s tests.12 All analysis were done with Stata (version 14).13
Results From the 7,420 citations identified, we selected 113 articles for detailed assessment (Figure 1). Sixty studies published in 62 articles, including 116,105 pregnancies met our inclusion criteria. Of the 51 excluded articles, nine were reviews, 20 did not have extractable data and 22 had inappropriate populations or outcomes.
6
Characteristics and quality of the included studies Sixty studies (116,105pregnancies) provided data on rates of obstetric maternal and fetal core outcomes in pregnant women with epilepsy. Of the 60 primary studies, 28 were prospectively conducted and 32 studies had a retrospective design. According to the WHO regional groupings of Member states,14 half (30/60) of the included studies were conducted in the European region and 11 were conducted in the Americas. Eight studies were carried out in the Western Pacific region, 6 in the Eastern Mediterranean and 5 studies were carried out in the South-East Asian region. There were no studies conducted in the African region and more than three quarters (47/60) of included studies were published after 2000. Based on the income level of their economies, 78.3% (47/60) of studies were conducted in countries classed as high-income, 8 (13.3%) were upper-middle-income and 5 (8.3%) were in lower-middle-income economies. None of the studies were carried out in a low-income country. (Appendix 2)
Most studies (80%, 48/60) included in the review had an overall low risk of bias. Twenty-eight studies (28/60, 47%) had a low risk of bias for study design, while 63% (38/60) had a low risk for method of sampling. For response rate, 93% (56/60) had a low risk of bias; all the studies used a validated method to assess outcomes. None of the studies reported whether a sample size calculation was carried out before the start of the study (Figure 2, Appendix 3).
Maternal and fetal complications in mothers with epilepsy Fifty-seven studies reported maternal core outcomes in women with epilepsy. Overall, the rates of complications were as follows: spontaneous miscarriage 9.1 per 100 pregnancies (95% CI 6.3 – 12.3, I2=96.87%), antepartum haemorrhage 3.8 per 100 pregnancies (95% CI 2.4 – 5.6, I2=91.48%), post-partum haemorrhage 4.6 per 100 pregnancies (95% CI 1.3 – 9.3, I2=99.18%), 7
induction of labour 19.9 per 100 pregnancies (95% CI 16.8 – 23.2, I2=90.19%), caesarean section 29.2 per 100 pregnancies (95% CI 25.4 – 33.1, I2=98.44%), any preterm birth 7.6 per 100 pregnancies (95% CI 6.4 – 8.8, I2=93.73%), hypertensive disorders 6.0 per 100 pregnancies (95% CI 4.5 – 7.5, I2=93.33%) and gestational diabetes 4.1 per 100 pregnancies (95% CI 2.2 – 6.5, I2=91.81%). (Figure 3)
Rates of fetal and neonatal complications were evaluated in 45 studies. The risks included fetal death or stillbirth 0.8 per 100 pregnancies (95% CI 0.5 – 1.1, I2=71.60%), perinatal death 1.3 per 100 pregnancies (95% CI 0.6 – 2.2, I2=69.36%), fetal growth restriction 9.8 per 100 pregnancies (95% CI 7.6 – 12.3, I2=97.86%) and admission to Neonatal Intensive Care Unit (NICU) 12.5 per 100 pregnancies (95% CI 9.6 – 15.8, I2=60.63%). (Figure 3)
Variation in maternal and offspring risks Subgroup analysis based on WHO regions showed significant differences between the groups for spontaneous miscarriage (p<0.001), antepartum haemorrhage (p<0.001), postpartum haemorrhage (p<0.001), induction of labour (p=0.013), caesarean section (p=0.008), any preterm birth <37 weeks (p=0.007), hypertensive disorders (p=0.017) and perinatal death (p=0.013). The highest rates of caesarean section (37%, 95% CI 32% - 42%), spontaneous miscarriage (39%, 95% CI 35% - 44%) and preterm birth (10%, 95% CI 8% - 12%) were in the Americas, postpartum haemorrhage (9%, 95% CI 7% - 12%), hypertensive disorders (14%, 95% CI 8% - 21%) and perinatal death (2%, 95% CI 1% - 7%) in the Western Pacific, induction of labour (30%, 95% CI 19% - 41%) and antepartum haemorrhage (10%, 95% CI 5% - 17%) in South East Asia and Eastern Mediterranean regions respectively. (Table 1a)
8
We observed significant variations in risks when grouped by country economy income for spontaneous miscarriage (p=0.002), antepartum haemorrhage (p=0.000), induction of labour (p=0.003), caesarean section (p=0.02) and gestational diabetes (p=0.009), with the highest rates of antepartum haemorrhage (9%, 95% CI 3% - 16%), caesarean section (42%, 95% CI 26% 59%) and gestational diabetes (15%, 95% CI 7% - 30%) in upper-middle income countries, and spontaneous miscarriage (11%, 95% CI 7% - 15%) and induction of labour (30%, 95% CI 19% - 41%) in the high income and lower middle income countries respectively. There were no significant differences for fetal death or stillbirth, fetal growth restriction or admission to the NICU.
There were also no significant differences between the groups for antepartum haemorrhage, postpartum haemorrhage, hypertensive disorders or gestational diabetes when subgroup analysis was done based on decades of study conduct or risk of bias. There were significant differences between the groups based on decade of study conduct for induction of labour (p<0.001), caesarean section (p=0.012), fetal death or stillbirth (p=0.022), perinatal death (p<0.001), fetal growth restriction (p=0.006) and admission to the NICU (p<0.001); risk of bias for spontaneous miscarriage (p=0.008), caesarean section (p=0.034) and any preterm birth <37 weeks (p=0.013).The risk of stillbirths, perinatal deaths and admission to the neonatal intensive care units were lowering over time, while there was a worsening of the risk of caesarean sections with increasing decades. (Table 1b)
Funnel plot asymmetry was assessed for core outcomes with at least nine studies. There was evidence of small studies effect (Egger-test of asymmetry) for fetal growth restriction (p =
9
0.001), caesarean section (p = 0.01), any preterm birth (p = 0.017), fetal death or stillbirth (p = 0.036) and hypertensive disorders (p = 0.005).
Comment In pregnant women with epilepsy, caesarean section and admission to the neonatal intensive care unit are the commonest pregnancy complications. The rates of complications varied across geographical regions, with highest rates of caesarean section, miscarriage and preterm birth, and lowest rate of perinatal death in the Americas. There were no differences in risk of offspring outcomes between middle and high-income countries. Over time, there is a reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care units, and an increase in caesarean sections in women with epilepsy.
Strengths and limitations To our knowledge, ours is the first systematic review to provide global and temporal absolute risk estimates of adverse pregnancy outcomes in women with epilepsy, with variation in rates across different geographical and economic regions. This comprehensive review was conducted without language restrictions, and we used a prospective protocol to guide our methods. We pre-specified relevant sub-groups to allow us explore potential sources of heterogeneity and assessed the study quality in detail. We were able to include 22 more studies to provide estimates of rates, compared to our previous work published in Lancet, where the focus was on comparing reproductive outcomes in epileptic vs non-epileptic women.15 The large numbers of women included in this meta-analysis adds to the precision of our results.
10
We included core obstetric outcome sets, where available, for reporting as determined by Delphi consensus, 10 which were considered to be clinically relevant, and required to be minimally reported in studies involving women with epilepsy. Despite a systematic search of literature, we did not identify any studies involving mothers from Africa, or other low-income countries. We are unable to estimate the true burden of the condition in this region. The included studies varied in the characteristics of the population, aetiology of epilepsy and definition of outcomes. The reasons for infants admission to NICU is varied and with changing practice, advancement in medical care and higher detection rates of outcomes such as fetal growth restriction, gestational diabetes and preterm birth, this may explain the high prevalence rates in our findings. Access to neurologist and appropriate treatment, will have an effect on the diagnosis of epilepsy and care quality in some regions, thereby affecting obstetric outcomes.
Comparison to existing studies Previous studies have identified an increased risk of adverse maternal and fetal outcomes in pregnant women with epilepsy. 3,4,16-23 Those estimates were obtained across various geographical areas and over time, and were focussed on providing relative risks of complications. The regional estimates of risk provided by us should be considered when counselling women with epilepsy. The most common outcome of caesarean section has consistently high rates regardless of geographical region or countries economy. It is also the only outcome to have increased significantly over the past 20 years. This is parallel with current observations by the World Health Organisation (WHO), on the upward trend in caesarean section rates in both developing and developed countries.24-26 The effects of this rate increase on other outcomes such as maternal and perinatal morbidity is still unclear, however it 11
has been suggested that particularly in low resource settings, caesarean section can sometimes cause complications, disability or death. 25,27,28
Our review was able to include more data on admission to NICU, which showed that it is the most common neonatal outcome. However, this along with fetal death or stillbirth, perinatal death and fetal growth restriction, has seen a consistent reduction in rates over the last 2 decades. These improvements in the rates of fetal and neonatal outcomes over time could be attributed to an improvement in antiepileptic drugs administered to the mother as well as improvements in clinical care.
Although fetal growth restriction was shown to be significantly worse in women with epilepsy,4 our findings do not show a significant difference in its rates geographically. It is likely that the increased association of epilepsy and fetal growth restriction persists irrespective of regional variation. The rates of spontaneous miscarriage, antepartum haemorrhage, caesarean section and gestational diabetes in high and upper middle income countries like USA and China were much higher than is observed in the general population in these regions.29-32 The association of epilepsy with an increase in maternal and perinatal morbidity is well documented and may explain the increased rates of these outcomes in the current study in these regions.33-36
Relevance to clinical practice Vaginal delivery in women with epilepsy is recommended by the guidelines of the National Institute for Health and Clinical Excellence (NICE) in United Kingdom, the American Academy of Neurology (AAN) Practice Parameter update and the Italian Consensus Conference, with the exception of women with frequent seizures,19,37,38 however we noticed an 12
increase in the rates of caesarean section over time. This may suggest that clinicians might be under pressure to deliver early with caesarean section due to concerns about the wellbeing of the infant. It is also possible that clinicians may plan for induction of labour or caesarean section in women with epilepsy because of a worry that these women might have seizures during labour and delivery.39 Guidelines on the management of women with epilepsy have been developed only in the high-income country region. The most recent of these was published in the United Kingdom in 2016. Obstetricians caring for women with epilepsy will need to consider the potential impact of epilepsy on obstetric outcomes. Adequate facilities for maternal and neonatal care and resuscitation should be made available to women with epilepsy to try to mitigate these risks.
Research recommendations When developing prospective studies, it is important that identified core outcomes on the topic if available are considered for use as part of the study outcomes. This will improve the precision of meta-analyses and aid in drawing clinically useful conclusions from the findings. Research is needed in low income countries as well as in African region where the condition affects 10 million people.40 There is a need to improve research on the epidemiology, outcome and mortality of epilepsy in these regions, particularly in women of child bearing age especially since most countries in these regions have the highest fertility rates in the world.41
Conclusion The variation in maternal and offspring outcomes in pregnant women with epilepsy should be considered when counselling women with epilepsy. It is essential that women with epilepsy should have discussions with their health care provider prior to conception, with the focus on 13
the importance of a planned pregnancy and careful management to minimise their risks of adverse maternal or fetal outcomes.
Funding: None
Role of funding source: None obtained
Author Contributions: ST was involved in conceptualizing the research question and designed the protocol. JA, PL and LV undertook literature search, study selection and data extraction. DA, JA and JZ did statistical analysis. The tables, figures and appendices were designed by JA, DA and JZ. The initial drafts of the manuscript were prepared by JA and ST, with additional input from KK. All authors contributed to the drafts and final version of the manuscript.
Ethical approval: Not required.
Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been disclosed.
Data sharing: No additional data available.
Acknowledgement 14
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19. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009; 73(2): 126-32. 20. Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an obstetric perspective. American Journal of Obstetrics & Gynecology 2004; 190(2): 371-9. 21. Sabers A, aRogvi-Hansen B, Dam M, et al. Pregnancy and epilepsy: a retrospective study of 151 pregnancies. Acta Neurologica Scandinavica 1998; 97(3): 164-70. 22. Thomas SV, Sindhu K, Ajaykumar B, Sulekha Devi PB, Sujamol J. Maternal and obstetric outcome of women with epilepsy. Seizure 2009; 18(3): 163-6. 23. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 2009; 50(9): 2130-9. 24. Vogel JP, Betrán AP, Vindevoghel N, et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. The Lancet Global Health 2015; 3(5): e260-e70. 25. Ye J, Betran AP, Guerrero Vela M, Souza JP, Zhang J. Searching for the optimal rate of medically necessary cesarean delivery. Birth 2014; 41(3): 237-44. 26. Betran AP, Torloni MR, Zhang JJ, Gulmezoglu AM, Section WHOWGoC. WHO Statement on Caesarean Section Rates. BJOG : an international journal of obstetrics and gynaecology 2016; 123(5): 667-70. 27. Ye J, Zhang J, Mikolajczyk R, Torloni MR, Gulmezoglu AM, Betran AP. Association between rates of caesarean section and maternal and neonatal mortality in the 21st century: a worldwide population-based ecological study with longitudinal data. BJOG : an international journal of obstetrics and gynaecology 2016; 123(5): 745-53. 28. Althabe F, Sosa C, Belizan JM, Gibbons L, Jacquerioz F, Bergel E. Cesarean section rates and maternal and neonatal mortality in low-, medium-, and high-income countries: an ecological study. Birth 2006; 33(4): 270-7. 29. Katz VL. Spontaneous and recurrent abortion: etiology, diagnosis, treatment. In: Katz VL, Lentz GM, Lobo RA, Gershenson DM, eds. Comprehensive Gynecology. 6th ed. Philadelphia, PA: Elsevier Mosby; 2012:chap 16. 30. Royal College of Obstetricians and Gynaecologists. Antepartum Haemorrhage Greentop Guideline No. 63 London: RCOG; November 2011. 31. Giordano R, Cacciatore A, Cignini P, Vigna R, Romano M. Antepartum haemorrhage. J Prenat Med 2010; 4(1): 12-6. 32. DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010. Prev Chronic Dis 2014; 11: E104. 33. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. The Lancet Global Health 2014; 2(6): e323-e33. 34. Kadir RA, Aledort LM. Obstetrical and gynaecological bleeding: a common presenting symptom. Clinical and Laboratory Haematology 2000; 22(s1): 12-6. 35. Wendland EM, Torloni MR, Falavigna M, et al. Gestational diabetes and pregnancy outcomes--a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) diagnostic criteria. BMC pregnancy and childbirth 2012; 12: 23. 16
36. Shah A, Fawole B, M'Imunya J M, et al. Cesarean delivery outcomes from the WHO global survey on maternal and perinatal health in Africa. Int J Gynaecol Obstet 2009; 107(3): 191-7. 37. Aguglia U, Barboni G, Battino D, et al. Italian consensus conference on epilepsy and pregnancy, labor and puerperium. Epilepsia 2009; 50 Suppl 1: 7-23. 38. NICE. Epilepsies, diagnosis and management. In: Clinical guideline [CG137]. London: National Institute for Clinical Excellence; 2016. 39. Katz JM, Devinsky O. Primary generalized epilepsy: a risk factor for seizures in labor and delivery? Seizure 2003; 12(4): 217-9. 40. World Health Organization, author. Epilepsy in the WHO African region: bridging the gap. Geneva: WHO; 2004. 41. The World's Women 2015. Trends and Statistics. Department of Economic and Social Affairs United Nations. New York, 2015. ST/ESA/STAT/SER.K/20.
17
Figure 1. Study selection process in the systematic review of prevalence of adverse obstetric core outcomes in epilepsy
Total number of citations identified (n =7420)
-
Electronic databases (n=7389) From reference lists (n=31)
Articles excluded (n=7307)
-
Duplicates (n=770) Exclusion criteria (n=6537)
Articles retrieved for full evaluation (n=113)
Articles excluded (n=51)
-
Reviews ( n=9) Data cannot be extracted (n=20) Inappropriate outcome (n= 6) Inappropriate population (n= 16)
Articles included in the review n=62 (n=60 studies**, 116,105 pregnancies)
** Outcomes reported in Borthen 2009; Borthen 2010 and Bozhinov 2016; Bozhinov 2016 were from the same populationbased cohort study 18
Fig 2: Quality assessment for risk of bias of studies included in the systematic review on the prevalence of adverse maternal and fetal core outcomes in pregnant women with epilepsy
Sample size 0 calculation
60
Validated assessment tool
60
Response rate
0
56
Adequacy of sampling
6
38
Study design
22
28
0%
20%
32
40%
60% Yes
19
No
80%
100%
Fig 3: Rates of complications of maternal and fetal core outcomes in pregnant women with epilepsy Outcome
Studies (n)
Events (n)
Pregnancies (N)
Spontaneous miscarriage
20
2,138
19,003
Antepartum haemorrhage
14
1,579
74,449
Postpartum haemorrhage
12
3,251
76,860
Induction of labour
12
15,112
73,686
Caesarean section
35
34,513
92,282
Any preterm birth (< 37 weeks)
39
9,449
93,568
Hypertensive disorders
32
7,930
80,313
Gestational diabetes
10
4,061
72,006
Fetal death or stillbirth
18
746
82,352
Perinatal death
9
70
7,643
Fetal growth restriction
38
4,706
88,090
Admission to NICU
5
437
3,423
Prevalence (95% CI)
p value
I2 (%)
9.1 (6.3, 12.3)
<0.001
96.87%
3.8 (2.4, 5.6)
<0.001
91.48%
4.6 (1.3, 9.3)
<0.001
99.18%
19.9 (16.8, 23.2)
<0.001
90.19%
29.2 (25.4, 33.1)
<0.001
98.44%
7.6 (6.4, 8.9)
<0.001
93.73%
6.0 (4.5, 7.5)
<0.001
93.33%
4.1 (2.2, 6.5)
<0.001
91.81%
0.8 (0.5, 1.1)
<0.001
71.60%
1.3 (0.6, 2.2)
0.001
69.36%
9.8 (7.6, 12.3)
<0.001
97.86%
12.5 (9.6, 15.8)
0.038
60.63%
Maternal outcome
Fetal and neonatal outcome
0
10.0
Rates (x100 pregnancies)
20
20.0
30.0
Table 1a: Sub-group analysis according to WHO regions and income groupings for rates of maternal and fetal complications in women with Economies income
WHO region
Outcome
P value
P value
Lower-middle
Upper-middle
High
<0.001
3.6 (2.3; 5.2)
6.4 (2.2; 12.2)
10.8 (7.3; 14.9)
0.002
9.6 (1.6; 22.4)
<0.001
0.0 (0.0; 0.3)
8.9 (3.4; 16.1)
3.9 (2.4; 5.8)
0.000
3.8 (0.7; 8.6)
9.3 (6.8; 12.3)
<0.001
1.7 (0.0; 10.8)
3.8 (1.0; 12.8) #
5.7 (1.5; 12.2)
0.226
16.8 (13.1; 20.8)
17.0 (9.2; 29.2) #
-
0.013
29.7 (19.3; 41.3)
18.3 (11.4; 28.0) #
19.3 (16.0; 22.8)
0.003
34.9 (25.8; 44.7)
28.2 (23.1; 33.5)
22.3 (4.3; 48.4)
20.6 (13.8; 28.4)
0.008
34.9 (25.8; 44.7)
42.3 (26.4; 59.0)
24.4 (20.1; 29.0)
0.020
10.1 (8.3; 12.2)
7.5 (0.5; 19.8)
6.1 (5.0; 7.3)
9.1 (2.4; 19.2)
9.4 (6.1; 13.3)
0.007
7.5 (0.5; 19.8)
16.9 (6.1; 31.3)
7.3 (6.1; 8.5)
0.207
Hypertensive disorders
5.9 (3.3; 9.3)
7.8 (0.7; 19.9)
5.3 (4.2; 6.5)
2.6 (0.3; 6.6)
14.3 (8.1; 21.7)
0.017
7.8 (0.7; 20.0)
3.5 (1.5; 6.1)
6.5 (4.9; 8.3)
0.181
Gestational diabetes
2.9 (0.8; 6.2)
0.8 (0.2; 1.8)
5.4 (1.9; 10.5)
13.2 (6.6; 24.8) #
15.2 (6.7; 30.9) #
0.137
0.8 (0.2; 1.8)
15.2 (6.7; 30.9) #
4.4 (2.4; 6.9)
0.009
Americas
South East Asia
European
Eastern Mediterranean
Western Pacific
Spontaneous miscarriage
39.2 (34.5; 44.0)
3.6 (2.3; 5.2)
8.1 (5.4; 11.3)
8.8 (5.2; 13.2)
7.3 (4.5; 11.7) #
Antepartum haemorrhage
2.1 (2.0; 2.2)
0.0 (0.0; 0.3)
3.3 (0.7; 7.4)
10.1 (4.8; 16.8)
Postpartum haemorrhage
3.2 (3.1; 3.4) #
1.7 (0.0; 10.8)
6.3 (1.7; 13.4)
Induction of labour
24.0 (15.7; 33.3)
29.7 (19.3; 41.3)
Caesarean section
37.0 (32.0; 42.3)
Any preterm birth (< 37 weeks)
Maternal outcome
Fetal and neonatal outcome Fetal death or stillbirth
0.9 (0.5; 1.4)
1.2 (0.2; 2.9)
0.6 (0.2; 1.1)
0.7 (0.1; 3.6) #
7.0 (2.4; 18.6) #
0.863
1.2 (0.2; 2.9)
1.0 (0.2; 5.5) #
0.7 (0.4; 1.1)
0.655
Perinatal death
0.5 (0.1; 1.7) #
-
1.4 (0.5; 2.7)
-
2.0 (0.5; 6.9) #
0.013
-
-
1.3 (0.6; 2.2)
-
Fetal growth restriction
8.6 (4.8; 13.4)
8.8 (6.5; 11.3)
9.7 (7.3; 12.4)
8.2 (4.0; 13.6)
12.0 (7.2; 17.6)
0.806
8.7 (6.5; 11.3)
10.2 (4.9; 17.1)
9.8 (7.2; 12.7)
0.878
-
13.3 (10.4; 16.6)
5.7 (1.9; 15.4) #
-
0.092
-
-
12.5 (9.6; 15.8)
-
Admission to NICU* 3.6 (2.3; 5.2)
epilepsy (Numbers are rates per hundred pregnancies and [95% CI]) 21 NICU* - Neonatal Intensive Care Unit
Table 1b: Sub-group analysis according to decades and study quality for rates of maternal and fetal complications in women with epilepsy (Numbers are rates per hundred pregnancies and [95% CI])
Outcome
Decades 1990s
P value
2000s
2010s
Spontaneous miscarriage 9.9 (4.9; 16.3)
6.1 (4.2; 8.2)
10.7 (5.4; 17.5)
Antepartum haemorrhage
9.4 (2.9; 18.9)
2.2 (0.7; 4.4)
Postpartum haemorrhage
4.2 (0.0; 14.4)
Induction of labour
Quality
P value
Low
High
0.170
5.2 (3.8; 6.9)
10.3 (6.9; 14.1)
0.008
6.4 (0.2; 18.6)
0.098
6.4 (2.7; 11.4)
3.6 (2.1; 5.4)
0.117
2.8 (0.0; 13.2)
9.5 (1.1; 23.8)
0.583
6.5 (1.9; 13.1)
4.2 (1.0; 9.2)
0.394
8.0 (4.5; 13.7) #
23.1 (15.3; 31.9)
19.6 (16.2; 23.2)
<0.001
24.6 (17.0; 33.1)
19.2 (16.0; 22.6)
0.183
Caesarean section
20.3 (12.5; 29.5)
26.9 (22.3; 31.9)
35.3 (29.6; 41.2)
0.012
43.2 (27.6; 59.5)
25.8 (21.2; 30.6)
0.034
Any preterm birth (< 37 weeks)
5.5 (3.1; 8.5)
7.8 (6.1; 9.6)
8.3 (6.4; 10.4)
0.247
14.7 (8.2; 22.7)
7.0 (5.8; 8.3)
0.013
Hypertensive disorders
9.2 (2.9; 18.4)
5.0 (3.5; 6.7)
5.4 (3.6; 7.6)
0.583
5.1 (2.0; 9.2)
6.2 (4.7; 8.0)
0.800
Gestational diabetes
-
4.4 (1.5; 8.5)
4.1 (1.5; 7.7)
0.873
15.2 (6.7; 30.9) #
3.8 (2.0; 6.1)
0.510
Maternal outcome
Fetal and neonatal outcome
Fetal death or stillbirth
1.7 (0.0; 5.0)
1.0 (0.6; 1.6)
0.7 (0.6; 0.8)
0.022
0.6 (0.2; 2.0) #
0.8 (0.5; 1.2)
0.231
Perinatal death
2.4 (1.5; 3.6)
0.6 (0.2; 1.0)
-
<0.001
3.2 (1.8; 5.6) #
1.0 (0.4; 1.7)
0.072
Fetal growth restriction
6.1 (4.2; 8.4)
12.1 (8.7; 16.0)
10.4 (7.0; 14.5)
0.006
12.1 (9.0; 15.5)
9.4 (6.9; 12.1)
0.129
NICU* - Neonatal Intensive Care Unit # - derived from one study
22
Admission to NICU*
19.9 (14.3; 26.9) #
12.0 (9.6; 14.7)
10.0 (6.7; 14.5) #
23
<0.001
-
12.5 (9.6; 15.8)
-
S0301-2115(17)30251-8 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.05.016 EURO 9908
To appear in:
EURO
Received date: Accepted date:
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Please cite this article as: Allotey John, Aroyo-Manzano David, Lopez Patricia, Viale Luz, Zamora Javier, Thangaratinam Shakila.Global variation in pregnancy complications in women with epilepsy: A metaanalysis.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.05.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Global variation in pregnancy complications in women with epilepsy: A meta-analysis
John Allotey, MSc1,2, David Aroyo-Manzano, MSc3,4, Patricia Lopez, MD3,4, Luz Viale, MD5, Prof Javier Zamora, PhD1,3,4, Prof Shakila Thangaratinam, PhD1,2
Affiliation: Women’s Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 1
2
Multidisciplinary Evidence Synthesis Hub (MESH), Queen Mary University of London London, UK 3
Hospital Ramón y Cajal (IRYCIS), Madrid, Spain
4
CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain
5
Centro Rosarino de Estudios Perinatales, Rosario, Argentina
Corresponding author John Allotey Women’s Health Research Unit, Multidisciplinary Evidence Synthesis Hub (MESH) Barts and the London School of Medicine and Dentistry Queen Mary University of London, London Tel: +44 2078826048, E-mail: [email protected]
Structured abstract Objective: Women with epilepsy are at risk of pregnancy complications. Whether these vary globally is unknown. We undertook a systematic review to assess the overall rates of obstetric outcomes in
1
women with epilepsy, and variations in estimates across geographical region, economic status of country, and over time. Study design: We searched Medline, Embase, Cochrane, AMED and CINAHL, (January 1, 1990 and November 29, 2016), without any language restrictions for studies reporting core maternal and fetal outcomes in women with epilepsy. We pooled the results using Freeman-Tukey Transformation random effects meta-analysis, and reported our findings as rates of complications per 100 pregnancies with 95% confidence intervals (CI). We assessed for differences in risk across World Health Organisation (WHO) regions, income status, and year of publication. Results: From the 7,420 articles screened, we included 60 studies (62 articles). In women with epilepsy (116,105 pregnancies), the commonest complications were caesarean section (29.2 per 100 pregnancies; 95% CI 25.4 – 33.1, I2=98.44%), and admission to the neonatal intensive care unit (12.5 per 100 pregnancies; 95% CI 9.6 – 15.8, I2=60.63%). There were significant differences across the WHO regions, with the highest rates of caesarean section (37%, 95% CI 32% 42%); spontaneous miscarriage (39%, 95% CI 35% - 44%) and preterm birth (10%, 95% CI 8% - 12%) in the Americas; postpartum haemorrhage (9%, 95% CI 7% - 12%), hypertensive disorders (14%, 95% CI 8% - 21%) and perinatal death (2%, 95% CI 1% - 7%) in the Western Pacific; induction of labour (30%, 95% CI 19% - 41%) in South East Asia and antepartum haemorrhage (10%,95% CI 5% - 17%) in the Eastern Mediterranean . The reported rates of antepartum haemorrhage, caesarean section, gestational diabetes and spontaneous miscarriage 2
were highest in high income and high-middle income countries. Over time, there was a significant increase in caesarean section, and reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care unit in women with epilepsy.
Conclusion: There is significant variation in reported maternal and offspring outcomes in pregnant women with epilepsy across geographical regions, economic status of country and over time, which needs to be considered in setting priorities for clinical management and research.
Keywords: Epilepsy, pregnancy; maternal, fetal, core outcomes
Word Count: 359
Introduction Epilepsy is one of the commonest neurological conditions affecting women of reproductive age.1-3 Risk of maternal death is ten-fold higher in women with epilepsy than those without the condition,3 with increase in rates of obstetric complications. 4 In UK, successive confidential enquires have highlighted the need to manage mothers with epilepsy as a high-risk condition, and for provision of information on risk status.5 However, in the absence of robust information on the rates of various maternal and fetal complications in women with epilepsy, counselling during pre-conception and in pregnancy is limited.
3
Numerous studies have reported on risks of seizure deterioration in pregnancy. Our systematic review on association of epilepsy with obstetric complications was limited to data from comparative cohorts.4 Studies have not assessed if there are any variations in risks of core obstetric outcomes required for reporting in clinical studies 6 on women with epilepsy across geographical regions, countries grouped by income status, and variation in risk over time are not known. Disparities in geographical distribution of health care resources and clinical practice, as well as advances in medical care, are factors expected to contribute to variations in the reported obstetric outcomes in women with epilepsy.
We undertook a systematic review of the literature to obtain precise estimates of the rates of obstetric outcomes in women with epilepsy, and assessing global variation in core pregnancy outcome rates in women with epilepsy.
Methods We undertook our systematic review using a prospective protocol in line with current recommendations, and reported using PRISMA guidelines (Appendix 1).7,8
Search strategy and study selection We searched the electronic databases Medline, Embase, Cochrane, AMED and CINAHL from January 1, 1990 without language restrictions for comparative studies on pregnant women with epilepsy and complications, as part of our previous meta-analysis.4 We updated this search to November 29, 2016, and additionally included studies that provided risk estimates of various complications. We only included studies that provided data on reproductive outcomes in women and excluded abstracts, case reports, case series, in vitro and animal studies. We 4
included outcomes that are considered relevant to clinical practice such as spontaneous miscarriage, induction of labour (IOL), caesarean section, antepartum haemorrhage (APH), postpartum haemorrhage (PPH), any preterm birth (<37 weeks), hypertensive disorders and gestational diabetes. The fetal and neonatal outcomes assessed were fetal death, fetal growth restriction that included both low birth weight and small for gestational age babies, admission to the neonatal intensive care unit (NICU) and perinatal death.
Quality assessment and data extraction Two independent reviewers (JA and LV/PL) undertook quality assessment, with any disagreements resolved after discussion with a different reviewer (JZ). We assessed the methodological quality of included studies for internal validity.9 Characteristics of study design, adequacy of sampling, sufficiently high response rate, assessment of outcome, and sample size calculation were evaluated to determine the quality of studies. Prospective studies were given one point for study design, while random or consecutive sampling methods received a point as an adequate method of participant sampling. 9 Studies with a response rate of at least 80% were given a point and the use of a validated tool for assessing the outcome during the study also received a point. Appropriate sample size calculation had to be undertaken before the start of the study for a point to be scored on this criterion. Studies were ranked as high or low quality, with high quality studies scoring at least 3 of the 5 possible points.9
Data were extracted in duplicates (JA and LV/PL) with pre-designed data extraction forms. The estimates of overall rates of adverse maternal and fetal outcomes in pregnant women with epilepsy were reported with 95% CI. When the same cohort was reported twice, we extracted data from the most recent study with the largest sample size for relevant outcomes. For regional 5
prevalence estimates, countries were grouped into six WHO world regions of African, Americas, South East Asia, European, Eastern Mediterranean and Western Pacific. Countries were also separated based on their WHO income levels of Low, Lower-middle, Upper-middle and High-income economies. We reported on the core obstetric outcomes determined by Delphi consensus. 10
Statistical analysis We computed rates of complications with pregnancy as the unit of analysis. We reported the results obtained after pooling individual study estimates using Freeman-Tukey Transformation random effects meta-analysis as outcomes per 100 pregnancies with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic. Rates were calculated for three time periods: 1990s, 2000s and 2010s and further a priori planned subgroup analysis was done based on quality of the study (low or high). We assessed publication bias and the effect of small studies using funnel plots and Begg’s11 and Egger’s tests.12 All analysis were done with Stata (version 14).13
Results From the 7,420 citations identified, we selected 113 articles for detailed assessment (Figure 1). Sixty studies published in 62 articles, including 116,105 pregnancies met our inclusion criteria. Of the 51 excluded articles, nine were reviews, 20 did not have extractable data and 22 had inappropriate populations or outcomes.
6
Characteristics and quality of the included studies Sixty studies (116,105pregnancies) provided data on rates of obstetric maternal and fetal core outcomes in pregnant women with epilepsy. Of the 60 primary studies, 28 were prospectively conducted and 32 studies had a retrospective design. According to the WHO regional groupings of Member states,14 half (30/60) of the included studies were conducted in the European region and 11 were conducted in the Americas. Eight studies were carried out in the Western Pacific region, 6 in the Eastern Mediterranean and 5 studies were carried out in the South-East Asian region. There were no studies conducted in the African region and more than three quarters (47/60) of included studies were published after 2000. Based on the income level of their economies, 78.3% (47/60) of studies were conducted in countries classed as high-income, 8 (13.3%) were upper-middle-income and 5 (8.3%) were in lower-middle-income economies. None of the studies were carried out in a low-income country. (Appendix 2)
Most studies (80%, 48/60) included in the review had an overall low risk of bias. Twenty-eight studies (28/60, 47%) had a low risk of bias for study design, while 63% (38/60) had a low risk for method of sampling. For response rate, 93% (56/60) had a low risk of bias; all the studies used a validated method to assess outcomes. None of the studies reported whether a sample size calculation was carried out before the start of the study (Figure 2, Appendix 3).
Maternal and fetal complications in mothers with epilepsy Fifty-seven studies reported maternal core outcomes in women with epilepsy. Overall, the rates of complications were as follows: spontaneous miscarriage 9.1 per 100 pregnancies (95% CI 6.3 – 12.3, I2=96.87%), antepartum haemorrhage 3.8 per 100 pregnancies (95% CI 2.4 – 5.6, I2=91.48%), post-partum haemorrhage 4.6 per 100 pregnancies (95% CI 1.3 – 9.3, I2=99.18%), 7
induction of labour 19.9 per 100 pregnancies (95% CI 16.8 – 23.2, I2=90.19%), caesarean section 29.2 per 100 pregnancies (95% CI 25.4 – 33.1, I2=98.44%), any preterm birth 7.6 per 100 pregnancies (95% CI 6.4 – 8.8, I2=93.73%), hypertensive disorders 6.0 per 100 pregnancies (95% CI 4.5 – 7.5, I2=93.33%) and gestational diabetes 4.1 per 100 pregnancies (95% CI 2.2 – 6.5, I2=91.81%). (Figure 3)
Rates of fetal and neonatal complications were evaluated in 45 studies. The risks included fetal death or stillbirth 0.8 per 100 pregnancies (95% CI 0.5 – 1.1, I2=71.60%), perinatal death 1.3 per 100 pregnancies (95% CI 0.6 – 2.2, I2=69.36%), fetal growth restriction 9.8 per 100 pregnancies (95% CI 7.6 – 12.3, I2=97.86%) and admission to Neonatal Intensive Care Unit (NICU) 12.5 per 100 pregnancies (95% CI 9.6 – 15.8, I2=60.63%). (Figure 3)
Variation in maternal and offspring risks Subgroup analysis based on WHO regions showed significant differences between the groups for spontaneous miscarriage (p<0.001), antepartum haemorrhage (p<0.001), postpartum haemorrhage (p<0.001), induction of labour (p=0.013), caesarean section (p=0.008), any preterm birth <37 weeks (p=0.007), hypertensive disorders (p=0.017) and perinatal death (p=0.013). The highest rates of caesarean section (37%, 95% CI 32% - 42%), spontaneous miscarriage (39%, 95% CI 35% - 44%) and preterm birth (10%, 95% CI 8% - 12%) were in the Americas, postpartum haemorrhage (9%, 95% CI 7% - 12%), hypertensive disorders (14%, 95% CI 8% - 21%) and perinatal death (2%, 95% CI 1% - 7%) in the Western Pacific, induction of labour (30%, 95% CI 19% - 41%) and antepartum haemorrhage (10%, 95% CI 5% - 17%) in South East Asia and Eastern Mediterranean regions respectively. (Table 1a)
8
We observed significant variations in risks when grouped by country economy income for spontaneous miscarriage (p=0.002), antepartum haemorrhage (p=0.000), induction of labour (p=0.003), caesarean section (p=0.02) and gestational diabetes (p=0.009), with the highest rates of antepartum haemorrhage (9%, 95% CI 3% - 16%), caesarean section (42%, 95% CI 26% 59%) and gestational diabetes (15%, 95% CI 7% - 30%) in upper-middle income countries, and spontaneous miscarriage (11%, 95% CI 7% - 15%) and induction of labour (30%, 95% CI 19% - 41%) in the high income and lower middle income countries respectively. There were no significant differences for fetal death or stillbirth, fetal growth restriction or admission to the NICU.
There were also no significant differences between the groups for antepartum haemorrhage, postpartum haemorrhage, hypertensive disorders or gestational diabetes when subgroup analysis was done based on decades of study conduct or risk of bias. There were significant differences between the groups based on decade of study conduct for induction of labour (p<0.001), caesarean section (p=0.012), fetal death or stillbirth (p=0.022), perinatal death (p<0.001), fetal growth restriction (p=0.006) and admission to the NICU (p<0.001); risk of bias for spontaneous miscarriage (p=0.008), caesarean section (p=0.034) and any preterm birth <37 weeks (p=0.013).The risk of stillbirths, perinatal deaths and admission to the neonatal intensive care units were lowering over time, while there was a worsening of the risk of caesarean sections with increasing decades. (Table 1b)
Funnel plot asymmetry was assessed for core outcomes with at least nine studies. There was evidence of small studies effect (Egger-test of asymmetry) for fetal growth restriction (p =
9
0.001), caesarean section (p = 0.01), any preterm birth (p = 0.017), fetal death or stillbirth (p = 0.036) and hypertensive disorders (p = 0.005).
Comment In pregnant women with epilepsy, caesarean section and admission to the neonatal intensive care unit are the commonest pregnancy complications. The rates of complications varied across geographical regions, with highest rates of caesarean section, miscarriage and preterm birth, and lowest rate of perinatal death in the Americas. There were no differences in risk of offspring outcomes between middle and high-income countries. Over time, there is a reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care units, and an increase in caesarean sections in women with epilepsy.
Strengths and limitations To our knowledge, ours is the first systematic review to provide global and temporal absolute risk estimates of adverse pregnancy outcomes in women with epilepsy, with variation in rates across different geographical and economic regions. This comprehensive review was conducted without language restrictions, and we used a prospective protocol to guide our methods. We pre-specified relevant sub-groups to allow us explore potential sources of heterogeneity and assessed the study quality in detail. We were able to include 22 more studies to provide estimates of rates, compared to our previous work published in Lancet, where the focus was on comparing reproductive outcomes in epileptic vs non-epileptic women.15 The large numbers of women included in this meta-analysis adds to the precision of our results.
10
We included core obstetric outcome sets, where available, for reporting as determined by Delphi consensus, 10 which were considered to be clinically relevant, and required to be minimally reported in studies involving women with epilepsy. Despite a systematic search of literature, we did not identify any studies involving mothers from Africa, or other low-income countries. We are unable to estimate the true burden of the condition in this region. The included studies varied in the characteristics of the population, aetiology of epilepsy and definition of outcomes. The reasons for infants admission to NICU is varied and with changing practice, advancement in medical care and higher detection rates of outcomes such as fetal growth restriction, gestational diabetes and preterm birth, this may explain the high prevalence rates in our findings. Access to neurologist and appropriate treatment, will have an effect on the diagnosis of epilepsy and care quality in some regions, thereby affecting obstetric outcomes.
Comparison to existing studies Previous studies have identified an increased risk of adverse maternal and fetal outcomes in pregnant women with epilepsy. 3,4,16-23 Those estimates were obtained across various geographical areas and over time, and were focussed on providing relative risks of complications. The regional estimates of risk provided by us should be considered when counselling women with epilepsy. The most common outcome of caesarean section has consistently high rates regardless of geographical region or countries economy. It is also the only outcome to have increased significantly over the past 20 years. This is parallel with current observations by the World Health Organisation (WHO), on the upward trend in caesarean section rates in both developing and developed countries.24-26 The effects of this rate increase on other outcomes such as maternal and perinatal morbidity is still unclear, however it 11
has been suggested that particularly in low resource settings, caesarean section can sometimes cause complications, disability or death. 25,27,28
Our review was able to include more data on admission to NICU, which showed that it is the most common neonatal outcome. However, this along with fetal death or stillbirth, perinatal death and fetal growth restriction, has seen a consistent reduction in rates over the last 2 decades. These improvements in the rates of fetal and neonatal outcomes over time could be attributed to an improvement in antiepileptic drugs administered to the mother as well as improvements in clinical care.
Although fetal growth restriction was shown to be significantly worse in women with epilepsy,4 our findings do not show a significant difference in its rates geographically. It is likely that the increased association of epilepsy and fetal growth restriction persists irrespective of regional variation. The rates of spontaneous miscarriage, antepartum haemorrhage, caesarean section and gestational diabetes in high and upper middle income countries like USA and China were much higher than is observed in the general population in these regions.29-32 The association of epilepsy with an increase in maternal and perinatal morbidity is well documented and may explain the increased rates of these outcomes in the current study in these regions.33-36
Relevance to clinical practice Vaginal delivery in women with epilepsy is recommended by the guidelines of the National Institute for Health and Clinical Excellence (NICE) in United Kingdom, the American Academy of Neurology (AAN) Practice Parameter update and the Italian Consensus Conference, with the exception of women with frequent seizures,19,37,38 however we noticed an 12
increase in the rates of caesarean section over time. This may suggest that clinicians might be under pressure to deliver early with caesarean section due to concerns about the wellbeing of the infant. It is also possible that clinicians may plan for induction of labour or caesarean section in women with epilepsy because of a worry that these women might have seizures during labour and delivery.39 Guidelines on the management of women with epilepsy have been developed only in the high-income country region. The most recent of these was published in the United Kingdom in 2016. Obstetricians caring for women with epilepsy will need to consider the potential impact of epilepsy on obstetric outcomes. Adequate facilities for maternal and neonatal care and resuscitation should be made available to women with epilepsy to try to mitigate these risks.
Research recommendations When developing prospective studies, it is important that identified core outcomes on the topic if available are considered for use as part of the study outcomes. This will improve the precision of meta-analyses and aid in drawing clinically useful conclusions from the findings. Research is needed in low income countries as well as in African region where the condition affects 10 million people.40 There is a need to improve research on the epidemiology, outcome and mortality of epilepsy in these regions, particularly in women of child bearing age especially since most countries in these regions have the highest fertility rates in the world.41
Conclusion The variation in maternal and offspring outcomes in pregnant women with epilepsy should be considered when counselling women with epilepsy. It is essential that women with epilepsy should have discussions with their health care provider prior to conception, with the focus on 13
the importance of a planned pregnancy and careful management to minimise their risks of adverse maternal or fetal outcomes.
Funding: None
Role of funding source: None obtained
Author Contributions: ST was involved in conceptualizing the research question and designed the protocol. JA, PL and LV undertook literature search, study selection and data extraction. DA, JA and JZ did statistical analysis. The tables, figures and appendices were designed by JA, DA and JZ. The initial drafts of the manuscript were prepared by JA and ST, with additional input from KK. All authors contributed to the drafts and final version of the manuscript.
Ethical approval: Not required.
Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been disclosed.
Data sharing: No additional data available.
Acknowledgement 14
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19. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009; 73(2): 126-32. 20. Richmond JR, Krishnamoorthy P, Andermann E, Benjamin A. Epilepsy and pregnancy: an obstetric perspective. American Journal of Obstetrics & Gynecology 2004; 190(2): 371-9. 21. Sabers A, aRogvi-Hansen B, Dam M, et al. Pregnancy and epilepsy: a retrospective study of 151 pregnancies. Acta Neurologica Scandinavica 1998; 97(3): 164-70. 22. Thomas SV, Sindhu K, Ajaykumar B, Sulekha Devi PB, Sujamol J. Maternal and obstetric outcome of women with epilepsy. Seizure 2009; 18(3): 163-6. 23. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 2009; 50(9): 2130-9. 24. Vogel JP, Betrán AP, Vindevoghel N, et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. The Lancet Global Health 2015; 3(5): e260-e70. 25. Ye J, Betran AP, Guerrero Vela M, Souza JP, Zhang J. Searching for the optimal rate of medically necessary cesarean delivery. Birth 2014; 41(3): 237-44. 26. Betran AP, Torloni MR, Zhang JJ, Gulmezoglu AM, Section WHOWGoC. WHO Statement on Caesarean Section Rates. BJOG : an international journal of obstetrics and gynaecology 2016; 123(5): 667-70. 27. Ye J, Zhang J, Mikolajczyk R, Torloni MR, Gulmezoglu AM, Betran AP. Association between rates of caesarean section and maternal and neonatal mortality in the 21st century: a worldwide population-based ecological study with longitudinal data. BJOG : an international journal of obstetrics and gynaecology 2016; 123(5): 745-53. 28. Althabe F, Sosa C, Belizan JM, Gibbons L, Jacquerioz F, Bergel E. Cesarean section rates and maternal and neonatal mortality in low-, medium-, and high-income countries: an ecological study. Birth 2006; 33(4): 270-7. 29. Katz VL. Spontaneous and recurrent abortion: etiology, diagnosis, treatment. In: Katz VL, Lentz GM, Lobo RA, Gershenson DM, eds. Comprehensive Gynecology. 6th ed. Philadelphia, PA: Elsevier Mosby; 2012:chap 16. 30. Royal College of Obstetricians and Gynaecologists. Antepartum Haemorrhage Greentop Guideline No. 63 London: RCOG; November 2011. 31. Giordano R, Cacciatore A, Cignini P, Vigna R, Romano M. Antepartum haemorrhage. J Prenat Med 2010; 4(1): 12-6. 32. DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010. Prev Chronic Dis 2014; 11: E104. 33. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. The Lancet Global Health 2014; 2(6): e323-e33. 34. Kadir RA, Aledort LM. Obstetrical and gynaecological bleeding: a common presenting symptom. Clinical and Laboratory Haematology 2000; 22(s1): 12-6. 35. Wendland EM, Torloni MR, Falavigna M, et al. Gestational diabetes and pregnancy outcomes--a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) diagnostic criteria. BMC pregnancy and childbirth 2012; 12: 23. 16
36. Shah A, Fawole B, M'Imunya J M, et al. Cesarean delivery outcomes from the WHO global survey on maternal and perinatal health in Africa. Int J Gynaecol Obstet 2009; 107(3): 191-7. 37. Aguglia U, Barboni G, Battino D, et al. Italian consensus conference on epilepsy and pregnancy, labor and puerperium. Epilepsia 2009; 50 Suppl 1: 7-23. 38. NICE. Epilepsies, diagnosis and management. In: Clinical guideline [CG137]. London: National Institute for Clinical Excellence; 2016. 39. Katz JM, Devinsky O. Primary generalized epilepsy: a risk factor for seizures in labor and delivery? Seizure 2003; 12(4): 217-9. 40. World Health Organization, author. Epilepsy in the WHO African region: bridging the gap. Geneva: WHO; 2004. 41. The World's Women 2015. Trends and Statistics. Department of Economic and Social Affairs United Nations. New York, 2015. ST/ESA/STAT/SER.K/20.
17
Figure 1. Study selection process in the systematic review of prevalence of adverse obstetric core outcomes in epilepsy
Total number of citations identified (n =7420)
-
Electronic databases (n=7389) From reference lists (n=31)
Articles excluded (n=7307)
-
Duplicates (n=770) Exclusion criteria (n=6537)
Articles retrieved for full evaluation (n=113)
Articles excluded (n=51)
-
Reviews ( n=9) Data cannot be extracted (n=20) Inappropriate outcome (n= 6) Inappropriate population (n= 16)
Articles included in the review n=62 (n=60 studies**, 116,105 pregnancies)
** Outcomes reported in Borthen 2009; Borthen 2010 and Bozhinov 2016; Bozhinov 2016 were from the same populationbased cohort study 18
Fig 2: Quality assessment for risk of bias of studies included in the systematic review on the prevalence of adverse maternal and fetal core outcomes in pregnant women with epilepsy
Sample size 0 calculation
60
Validated assessment tool
60
Response rate
0
56
Adequacy of sampling
6
38
Study design
22
28
0%
20%
32
40%
60% Yes
19
No
80%
100%
Fig 3: Rates of complications of maternal and fetal core outcomes in pregnant women with epilepsy Outcome
Studies (n)
Events (n)
Pregnancies (N)
Spontaneous miscarriage
20
2,138
19,003
Antepartum haemorrhage
14
1,579
74,449
Postpartum haemorrhage
12
3,251
76,860
Induction of labour
12
15,112
73,686
Caesarean section
35
34,513
92,282
Any preterm birth (< 37 weeks)
39
9,449
93,568
Hypertensive disorders
32
7,930
80,313
Gestational diabetes
10
4,061
72,006
Fetal death or stillbirth
18
746
82,352
Perinatal death
9
70
7,643
Fetal growth restriction
38
4,706
88,090
Admission to NICU
5
437
3,423
Prevalence (95% CI)
p value
I2 (%)
9.1 (6.3, 12.3)
<0.001
96.87%
3.8 (2.4, 5.6)
<0.001
91.48%
4.6 (1.3, 9.3)
<0.001
99.18%
19.9 (16.8, 23.2)
<0.001
90.19%
29.2 (25.4, 33.1)
<0.001
98.44%
7.6 (6.4, 8.9)
<0.001
93.73%
6.0 (4.5, 7.5)
<0.001
93.33%
4.1 (2.2, 6.5)
<0.001
91.81%
0.8 (0.5, 1.1)
<0.001
71.60%
1.3 (0.6, 2.2)
0.001
69.36%
9.8 (7.6, 12.3)
<0.001
97.86%
12.5 (9.6, 15.8)
0.038
60.63%
Maternal outcome
Fetal and neonatal outcome
0
10.0
Rates (x100 pregnancies)
20
20.0
30.0
Table 1a: Sub-group analysis according to WHO regions and income groupings for rates of maternal and fetal complications in women with Economies income
WHO region
Outcome
P value
P value
Lower-middle
Upper-middle
High
<0.001
3.6 (2.3; 5.2)
6.4 (2.2; 12.2)
10.8 (7.3; 14.9)
0.002
9.6 (1.6; 22.4)
<0.001
0.0 (0.0; 0.3)
8.9 (3.4; 16.1)
3.9 (2.4; 5.8)
0.000
3.8 (0.7; 8.6)
9.3 (6.8; 12.3)
<0.001
1.7 (0.0; 10.8)
3.8 (1.0; 12.8) #
5.7 (1.5; 12.2)
0.226
16.8 (13.1; 20.8)
17.0 (9.2; 29.2) #
-
0.013
29.7 (19.3; 41.3)
18.3 (11.4; 28.0) #
19.3 (16.0; 22.8)
0.003
34.9 (25.8; 44.7)
28.2 (23.1; 33.5)
22.3 (4.3; 48.4)
20.6 (13.8; 28.4)
0.008
34.9 (25.8; 44.7)
42.3 (26.4; 59.0)
24.4 (20.1; 29.0)
0.020
10.1 (8.3; 12.2)
7.5 (0.5; 19.8)
6.1 (5.0; 7.3)
9.1 (2.4; 19.2)
9.4 (6.1; 13.3)
0.007
7.5 (0.5; 19.8)
16.9 (6.1; 31.3)
7.3 (6.1; 8.5)
0.207
Hypertensive disorders
5.9 (3.3; 9.3)
7.8 (0.7; 19.9)
5.3 (4.2; 6.5)
2.6 (0.3; 6.6)
14.3 (8.1; 21.7)
0.017
7.8 (0.7; 20.0)
3.5 (1.5; 6.1)
6.5 (4.9; 8.3)
0.181
Gestational diabetes
2.9 (0.8; 6.2)
0.8 (0.2; 1.8)
5.4 (1.9; 10.5)
13.2 (6.6; 24.8) #
15.2 (6.7; 30.9) #
0.137
0.8 (0.2; 1.8)
15.2 (6.7; 30.9) #
4.4 (2.4; 6.9)
0.009
Americas
South East Asia
European
Eastern Mediterranean
Western Pacific
Spontaneous miscarriage
39.2 (34.5; 44.0)
3.6 (2.3; 5.2)
8.1 (5.4; 11.3)
8.8 (5.2; 13.2)
7.3 (4.5; 11.7) #
Antepartum haemorrhage
2.1 (2.0; 2.2)
0.0 (0.0; 0.3)
3.3 (0.7; 7.4)
10.1 (4.8; 16.8)
Postpartum haemorrhage
3.2 (3.1; 3.4) #
1.7 (0.0; 10.8)
6.3 (1.7; 13.4)
Induction of labour
24.0 (15.7; 33.3)
29.7 (19.3; 41.3)
Caesarean section
37.0 (32.0; 42.3)
Any preterm birth (< 37 weeks)
Maternal outcome
Fetal and neonatal outcome Fetal death or stillbirth
0.9 (0.5; 1.4)
1.2 (0.2; 2.9)
0.6 (0.2; 1.1)
0.7 (0.1; 3.6) #
7.0 (2.4; 18.6) #
0.863
1.2 (0.2; 2.9)
1.0 (0.2; 5.5) #
0.7 (0.4; 1.1)
0.655
Perinatal death
0.5 (0.1; 1.7) #
-
1.4 (0.5; 2.7)
-
2.0 (0.5; 6.9) #
0.013
-
-
1.3 (0.6; 2.2)
-
Fetal growth restriction
8.6 (4.8; 13.4)
8.8 (6.5; 11.3)
9.7 (7.3; 12.4)
8.2 (4.0; 13.6)
12.0 (7.2; 17.6)
0.806
8.7 (6.5; 11.3)
10.2 (4.9; 17.1)
9.8 (7.2; 12.7)
0.878
-
13.3 (10.4; 16.6)
5.7 (1.9; 15.4) #
-
0.092
-
-
12.5 (9.6; 15.8)
-
Admission to NICU* 3.6 (2.3; 5.2)
epilepsy (Numbers are rates per hundred pregnancies and [95% CI]) 21 NICU* - Neonatal Intensive Care Unit
Table 1b: Sub-group analysis according to decades and study quality for rates of maternal and fetal complications in women with epilepsy (Numbers are rates per hundred pregnancies and [95% CI])
Outcome
Decades 1990s
P value
2000s
2010s
Spontaneous miscarriage 9.9 (4.9; 16.3)
6.1 (4.2; 8.2)
10.7 (5.4; 17.5)
Antepartum haemorrhage
9.4 (2.9; 18.9)
2.2 (0.7; 4.4)
Postpartum haemorrhage
4.2 (0.0; 14.4)
Induction of labour
Quality
P value
Low
High
0.170
5.2 (3.8; 6.9)
10.3 (6.9; 14.1)
0.008
6.4 (0.2; 18.6)
0.098
6.4 (2.7; 11.4)
3.6 (2.1; 5.4)
0.117
2.8 (0.0; 13.2)
9.5 (1.1; 23.8)
0.583
6.5 (1.9; 13.1)
4.2 (1.0; 9.2)
0.394
8.0 (4.5; 13.7) #
23.1 (15.3; 31.9)
19.6 (16.2; 23.2)
<0.001
24.6 (17.0; 33.1)
19.2 (16.0; 22.6)
0.183
Caesarean section
20.3 (12.5; 29.5)
26.9 (22.3; 31.9)
35.3 (29.6; 41.2)
0.012
43.2 (27.6; 59.5)
25.8 (21.2; 30.6)
0.034
Any preterm birth (< 37 weeks)
5.5 (3.1; 8.5)
7.8 (6.1; 9.6)
8.3 (6.4; 10.4)
0.247
14.7 (8.2; 22.7)
7.0 (5.8; 8.3)
0.013
Hypertensive disorders
9.2 (2.9; 18.4)
5.0 (3.5; 6.7)
5.4 (3.6; 7.6)
0.583
5.1 (2.0; 9.2)
6.2 (4.7; 8.0)
0.800
Gestational diabetes
-
4.4 (1.5; 8.5)
4.1 (1.5; 7.7)
0.873
15.2 (6.7; 30.9) #
3.8 (2.0; 6.1)
0.510
Maternal outcome
Fetal and neonatal outcome
Fetal death or stillbirth
1.7 (0.0; 5.0)
1.0 (0.6; 1.6)
0.7 (0.6; 0.8)
0.022
0.6 (0.2; 2.0) #
0.8 (0.5; 1.2)
0.231
Perinatal death
2.4 (1.5; 3.6)
0.6 (0.2; 1.0)
-
<0.001
3.2 (1.8; 5.6) #
1.0 (0.4; 1.7)
0.072
Fetal growth restriction
6.1 (4.2; 8.4)
12.1 (8.7; 16.0)
10.4 (7.0; 14.5)
0.006
12.1 (9.0; 15.5)
9.4 (6.9; 12.1)
0.129
NICU* - Neonatal Intensive Care Unit # - derived from one study
22
Admission to NICU*
19.9 (14.3; 26.9) #
12.0 (9.6; 14.7)
10.0 (6.7; 14.5) #
23
<0.001
-
12.5 (9.6; 15.8)
-