Quality assessment is shown in Appendices 2 and 3, available online at http://links.lww.com/AOG/B534. None of the studies were considered low risk for bias or applicability. The retrospective and case–control design of many of the studies created a high risk of bias across the patient-selection domain; additionally, 5 of 11 studies did not state or clearly define a diagnosis of eclampsia, creating potential risk of bias across the reference standard domain. Furthermore, two studies did not define the control population well, that is, only randomly selected noneclamptic women and a control group of women of the same age and parity. Of the 11 studies, only two assessed the signs and symptoms of interest without knowledge of the diagnosis of eclampsia, creating a potential high risk of bias owing to the knowledge of diagnosis before recording of signs and symptoms. Overall, there was significant potential for risk of bias across all domains as assessed using the QUADAS-2 tool.
A total of 28 different signs and symptoms were identified. The sensitivity, specificity, and LRs for each were largely inconsistent, as shown in Appendix 4, available online at http://links.lww.com/AOG/B534. Pooled test characteristics of signs and symptoms are shown in Table 2; however, owing to significant heterogeneity between studies, with differing designs, participants, settings, and signs and symptoms, pooled estimates were not possible for all reported signs and symptoms.
Symptoms that are commonly associated with eclampsia and preeclampsia where those most investigated within the studies, including visual disturbances and epigastric pain, which were reported by six studies (three cohort and three case–control), and headache and edema, which were reported by five and four studies, respectively. However, none of the pooled estimates for these symptoms was able to conclusively diagnose or rule out imminent eclampsia, with moderate specificity (83–94%) and poor sensitivity between (29% and 56%) (Table 2).
Headache had the highest sensitivity at 56% (95% CI 41–69%), that is, the lowest degree of false-negative results, but also had among the poorest specificity (83%; 95% CI 50–96%), that is, the greatest number of false-positive results. Additionally, the LRs for headache were modest, +LR 3.25 (95% CI 0.96–11.03) and −LR 0.54 (95% CI 0.39–0.74). Even though sensitivity for headache was the best among the different tests, headache still captured only half of the women who went on to develop eclampsia and thus cannot be used as a rule-out test when deciding on which women are at risk for eclampsia. Subgroup analysis of high-risk populations (preeclampsia with severe features or HELLP syndrome; n=4) modestly changed the sensitivity (57%) and reduced the specificity to 64% (95% CI 52–74%). Findings were similar for both visual disturbances and epigastric pain. Visual disturbances had the highest +LR at 5.81 (95% 1.74–19.42), and, although the pooled specificity was high (94%; 95% CI 80–98%), sensitivity was poor (35%; 95% CI 24–47%). Epigastric pain had the lowest sensitivity at 29% (95% CI 21–40%) and poor LRs (+LR 3.40 [95% CI 1.02–11.3], −LR 0.77 [95% CI 0.67–0.89]).
Other commonly reported (three studies) symptoms and signs included nausea and vomiting, proteinuria (dipstick greater than +1), and systolic blood pressure 160 mm Hg or higher or diastolic blood pressure 110 mm Hg or higher or both (Appendix 4, http://links.lww.com/AOG/B534). Owing to heterogeneity in design, participants, and setting, pooled estimates were not calculated.
Individual signs and symptoms yielded poor predictive test characteristics. Of those reported, diastolic blood pressure 110 mm Hg or higher performed the best, with a positive LR of 18 (95% CI 8.43–38.45); yet, as with the majority of individual signs and symptoms, the negative LR was modest, which suggests that this may be a poor indicator for ruling out eclampsia in its absence. However, it is important to note that this estimate is based on a single, small case–control study and thus potentially unreliable. Additionally, the majority of 95% CIs for both pooled and individual positive and negative LRs approached or crossed the null value, suggesting these are of little or no value in identifying women with impending eclampsia.
Eclampsia is a rare but life-threatening pregnancy complication, occurring in women with preeclampsia as well as in normotensive women.11 It is perhaps a result of the rarity of this condition that only a small number of studies exist investigating the clinical prediction of eclampsia. We identified 11 largely retrospective studies, almost all of which had significant methodologic limitations and were at high risk for bias. Additionally, heterogeneity was high between the studies, with varied study designs, populations, and settings. A total of 28 signs and symptoms were reported. Because meta-analyses generally require more than two studies, we deemed it inappropriate to provide pooled estimates for the majority of signs and symptoms.
The retrospective design of the majority of studies makes it impossible to evaluate symptoms other than those asked or actively reported; this potentially limits the discovery of any symptoms not already commonly associated with eclampsia. Our findings reflect this, with visual disturbances, epigastric pain, and headache most frequently reported across the studies. These symptoms moderately increased the likelihood of eclampsia when present. However, as indicated by high negative LRs, the absence of any of these symptoms did not reduce the likelihood of eclampsia in a clinically significant manner. Similar results were found for individual symptoms, such as diastolic blood pressure 110 mm Hg or higher and nausea and vomiting, with high positive LRs and corresponding high negative LRs and similar results for sensitivity and specificity. None of the included studies explored the possibility of combining different signs and symptoms to improve the overall predictive value. It is important to note that combining very few studies with differing characteristics makes any kind of synthesis weak; thus, the pooled estimates for even the more commonly reported signs and symptoms are unable to provide accurate estimates of the true diagnostic and predictive value.
Our findings highlight the challenges faced in synthesizing accurate estimates for rare diseases, specifically those occurring in low-resource settings.12,13 Meaningful research in these settings is hampered by inadequate antenatal care,14 leaving women unaware of the warning signs and symptoms of eclampsia, which can result in convulsions occurring in the home without a diagnosis. Improved education and awareness of the importance of antenatal care may not only improve maternal and neonatal outcomes, but also assist in the improved characterization of eclampsia and, in turn, increased detection and thus appropriate prophylactic management.
The present analysis is significantly limited by lacking research and the poor quality of the available studies. Additionally, some eligible studies appeared to gather the relevant data but did not report those data in a way that allowed for sensitivity and specificity calculations; therefore, these studies were not included. Together, these factors significantly limit the current review, making it inappropriate and not possible to calculate the area under the receiver operating characteristic curves or conclusively determine the diagnostic accuracy of prodromal signs and symptoms of eclampsia. Our search strategy did not include the individual signs and symptoms that are often thought to be associated with eclampsia (headache, blurred vision, changes in blood pressure), because this may have excluded any new or underreported predictors. Although this does broaden our search, it may, too, have resulted in excluded relevant articles; however, given that bibliographies were also screened for additional references, this is unlikely. Additionally, our search strategy may have also been limited by the exclusion of studies not available in English. The risk of differential treatment bias due to unreported medication use, such as antihypertensives, is unlikely. A Cochrane review evaluating the use of any antihypertensive drug and critical outcomes of preeclampsia found, among five trials, that there was no significant difference in the overall risk of eclampsia (RR 0.34 95% CI 0.01–8.15).
Symptoms frequently associated with severe preeclampsia were those most common across the studies, including visual disturbances, epigastric pain, and headache. However, none were accurate predictors of eclampsia, with poor-to-modest test characteristics. Improved prediction of eclampsia is vital in reducing the maternal morbidity and mortality related to this life-threatening complication. Predictors with improved sensitivity would reduce the number of eclamptic convulsions, and improved specificity would allow appropriate treatment and resources to be directed to those most in need; together this would reduce the variability of magnesium sulphate prophylaxis. Our findings highlight the need for large, prospective, high-quality studies investigating the accuracy of signs and symptoms in predicting eclampsia.
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