Corticosteroids for improving patient relevant outcomes in HELLP syndrome: a systematic review and meta-analysis

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Methods: CENTRAL, MEDLINE/PubMed, Web of Science, and Scopus, from the date of inception of the databases to September 20, 2023 were searched. Reference lists of included studies and systematic reviews were thoroughly searched. We included RCTs that enrolled women with HELLP syndrome, whether antepartum or postpartum, to receive any corticosteroid versus placebo or no treatment. No language or publication date restrictions were made. We used a dual independent approach for screening titles and abstracts, full text screening, data extraction, and risk of bias assessment. Pairwise meta-analyses were conducted, where two or more studies met methodological criteria for inclusion. GRADE approach was used to assess certainty of evidence for the pre-specified outcomes. Results : Fifteen trials (821 women) compared corticosteroids with placebo or no treatment. The effect of corticosteroids is uncertain for the primary outcome i.e., maternal death (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.25 to 2.38, very low certainty evidence). The effect of corticosteroids is also uncertain for other important outcomes including pulmonary edema, dialysis, liver morbidity (hematoma, rupture, and failure), or perinatal death because of very low certainty evidence. Low certainty evidence suggests that corticosteroids have little or no effect on the need for platelet transfusion and may result in a slight reduction in acute renal failure. Conclusions : In women with HELLP syndrome, the effect of corticosteroids vs placebo or no treatment is uncertain for patient-relevant outcomes including maternal death, maternal morbidity, and perinatal death. These uncertainties regarding this critical question should be addressed by adequately powered rigorous trials. Systematic review registration : Center for Open Science, osf.io/yzku5 HELLP Syndrome Corticosteroids Maternal Mortality Perinatal Mortality Figures Figure 1 Figure 2 Figure 3 Figure 4 Background The syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) has an incidence of 2.5 per 1000 singleton deliveries and it complicates 20% of women diagnosed with severe pre-eclampsia. [ 1 , 2 ] The pathophysiology of HELLP syndrome that is usually diagnosed between 27 and 37 weeks, is not completely understood. [ 3 ] The diagnosis depends on laboratory findings of microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes. Different investigators reported different threshold of hematologic and biochemical values for diagnosis of the syndrome or for determining the prognosis. [ 4 , 5 ] The presence of HELLP syndrome is associated with significant maternal mortality and morbidity including acute renal and liver failure. [ 1 ] Approximately 70% of pregnancies complicated by HELLP syndrome require preterm delivery, thus increasing perinatal morbidity and mortality. [ 5 ] Observational studies suggested that steroid treatment in HELLP syndrome may improve disordered maternal hematological and biochemical features and perhaps perinatal mortality and morbidity. Clinical trials examined the effects of corticosteroids for the treatment of maternal HELLP syndrome. Various regimens have been reported using prednisolone, dexamethasone, or betamethasone. [ 2 , 5 – 7 ] Current practice and clinical guidelines require an updated evidence synthesis because the latest available synthesis was published in 2010, [ 8 ] new studies have been published, and the clinical question remains relevant to decision makers. We conducted this systematic review to update the synthesized evidence regarding the effects of corticosteroids versus placebo or no treatment for improving outcomes in women with HELLP syndrome. Methods Protocol and registration This systematic review was conducted following the methodological standards of Cochrane Handbook. [ 9 ] We prospectively registered the protocol in Open Science Platform. The full text of the protocol is available in an open access registry and as an online as Supplemental file 1. We reported the review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) standards. [ 10 ] The full checklist is available as Supplemental file 2. Eligibility criteria We included published randomized controlled trials that recruited women with HELLP syndrome, confirmed by objective testing. We included studies comparing corticosteroids versus placebo or no treatment. The primary outcome measure was maternal death. Other outcomes included acute pulmonary edema; acute renal failure; dialysis, liver morbidity (hematoma, ruptured liver, and failure), need for platelet transfusion, and perinatal death. Information sources A comprehensive literature search was initially conducted on September 20, 2023. We did not impose language or other restrictions on any of the searches. We searched bibliographic databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed) and citation indexes (Web of Science and Scopus). We included the terms (HELLP Syndrome) AND (corticosteroids or glucocorticoids or Dexamethasone or Betamethasone or Prednisolone). The detailed exact strategy adapted for each database is provided in Supplemental file 3 and is available as an open access registry document. We peer-reviewed the search strategy and further tested it with a set of known relevant, ‘gold standard’, reports. We also searched clinical trial registries (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) to identify ongoing trials. We finally searched reference lists and explored the cited-by logs of identified studies and previously published reviews. Study selection All reports identified in the databases were imported to Bibtex library using Jabref version 5. After removing duplicates, two authors independently screened all titles and abstracts for eligibility. We retrieved and assessed the full text of all reports that potentially met our eligibility criteria during screening. Two authors (AFK, HBA, MAE, RHA) independently assessed each full-text article. Disagreements regarding trial eligibility was resolved by consensus and finally resolved by a third author (AFN). Data collection process For eligible studies, we extracted the data in duplicates using an offline electronic form. We resolved discrepancies through discussion. Extracted data were transcribed to a spreadsheet and checked for accuracy. We contacted authors of the original reports, if needed, to provide details regarding unclear or missing data. Data items Extracted data included study design, sample size, description of included participants, description of the intervention, outcomes, trial registration, and funding sources, and country. Study risk of bias assessment Two authors (AFK, HBA, MAE, RHA) independently used the Risk of Bias 2 (RoB 2) tool to assess the risk of bias of study results contributing information to each of the outcomes specified for inclusion in the Summary of Findings table. We assessed the following risk of bias domains as outlined in Cochrane Handbook for Systematic Reviews of Interventions: 1) risk of bias arising from the randomization process; 2) risk of bias due to deviations from the intended interventions (effect of assignment to intervention); 3) risk of bias due to missing outcome data; 4) risk of bias in measurement of the outcome; and 5) risk of bias in selection of the reported result. Each domain was judged as being at “low risk of bias”, “some concerns”, or “high risk of bias”. Trials with “low risk of bias” in all domains were classified as being at overall “low risk of bias”. RCTs with one domain judged to be at “some concerns”, but no domain judged to be at “high risk of bias”, were classified as being at overall “some concerns” of risk of bias. RCTs were classified as being at overall “high risk of bias” if at least one domain was judged as being at “high risk of bias”. However, if a trial was judged to be at “some concerns” due to risk of bias for multiple domains, it was judged as being at overall “high risk of bias” if the assessors judged that the multiple concerns amounted to a serious risk of bias. In case of discrepancies among their judgments and inability to reach consensus, we consulted the senior author (AFN) to reach a final decision. Effect measures For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI). None of the outcomes of interest were meta-analyzed as a continuous variable. The unit of analysis was the individual participant. We used a complete case approach for analysis. Data related to participants reported as not compliant was analyzed on an intention-to-treat basis. Synthesis methods Fixed-effect meta-analysis was performed to combine data of trials that are judged to be sufficiently similar in terms of intervention, populations, and methods. We planned to investigate substantial statistical heterogeneity, defined as I² statistic ≥ 50% or P < 0.1. We performed the planned subgroup analysis by gestational age at enrollment (ante- vs postpartum) and by type of corticosteroids. We assessed subgroup differences by interaction tests. Results of the subgroup analyses were reported by mentioning the Chi² statistic and P value, and the interaction test I² value. Sensitivity analysis was performed to explore robustness of pooled estimate using outcome data from trials with a low risk of bias. Synthesis was performed using RStudio 2023.06.1 Build 524 (MacOS, Apple Silicon version), R 4.3.1 (2023-06-16) [ 11 ] and R package meta version 6.5. [ 12 ] Reporting bias assessment We explored whether the study was included in a trial registry and whether a protocol was available. We planned to examine funnel plots to assess the potential for publication bias if we found 10 or more studies reporting on a particular outcome. Certainty assessment We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to create the Summary of Findings table. [ 13 ] Briefly, GRADE uses study limitations, consistency of effect, imprecision, indirectness, and publication bias to assess the certainty of evidence for each outcome. A summary of the intervention effect and a measure of certainty was produced using the GRADE Profiler Guideline Development Tool (GRADEpro GDT) software [ 14 ] for the prespecified important outcomes: maternal death, pulmonary edema, renal failure, dialysis, liver morbidity, need for platelet transfusion, and perinatal death. One author (A.N.) conducted GRADE assessments and the decisions on downgrading. This was discussed for final approval by all authors. Patient and public involvement We consulted with patients by asking a group to review and comment on an early draft of the manuscript. Results Study selection Bibliographic database search identified 154 records. After removing duplicates, 86 titles and abstracts were screened. Twenty-four titles required further assessment. One is an ongoing CTRI/2020/12/029730 and the full-text reports of 23 published reports were assessed using the predefined eligibility criteria. We excluded two reports identified in our search. One study did not meet our inclusion criteria for participants as it enrolled women with low platelets not HELLP syndrome. The other study was terminated because of the inability to recruit the required sample. Fifteen studies (21 reports published between 1994 and 2019) including 821 women were found eligible Fig. 1 . Figure 1 : PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses Study characteristics We summarized the characteristics of the included studies in Table 1 . The 15 included trials recruited 821 women with HELLP syndrome. Criteria for recruitment in five trials [ 15 – 20 ] were a diagnosis of HELLP class 1 or 2 on the Mississippi HELLP classification system. One trial exclusively recruited women with class 1. [ 21 ] One trial recruited women with class 2 and 3. [ 22 ] Three studies [ 23 – 25 ] recruited women with HELLP classes 1, 2, and 3. One study [ 26 ] included women with partial HELLP (1 or more parameters abnormal) (61/105 [58.1%]) and complete HELLP (all parameters abnormal) (44/105 [41.9%]); class 1 and 2 combined subset accounted for 85.7% of participants with complete HELLP. Three studies [ 27 , 28 , 29 ] did not report explicitly on the class of HELLP syndrome. Eleven trials administered dexamethasone vs placebo or no treatment, [ 16 – 18 , 20 – 22 , 25 – 29 ] two trials administered betamethasone, [ 23 , 24 ] and one trial administered prednisolone. [ 19 ] One multiple-arms trial compared dexamethasone vs betamethasone vs no treatment. [ 15 ] Corticosteroids administration commenced after delivery in eight trials, [ 15 , 16 , 18 , 20 , 25 – 27 , 29 ] before delivery in five trials, [ 19 , 22 – 24 , 28 ] and in two trials [ 17 , 21 ] treatment commenced according to timing of recruitment whether before or after delivery. Table 1 Characteristics of included studies Study ID (Country) Treatment commenced Sample size Corticosteroids HELLP syndrome class Corticosteroids regimen Bouchnak 2005 (Tunisia) Postpartum 20 Dexamethasone Not clearly defined Postpartum women in the experimental group received dexamethasone, 12 mg every 12h for 2 doses, started immediately following delivery. Fonseca 2005 (Colombia) Antepartum and Postpartum 132 Dexamethasone Class 1 (38%) and 2 (62%) Pregnant women in the experimental group received 10 mg doses of dexamethasone intravenously every 12 hours until delivery and 3 additional doses after delivery. Puerperal women received 3 10-mg doses after delivery. Fonseca 2019 (Colombia) Antepartum and Postpartum 87 Dexamethasone Class 1 Pregnant women in the experimental group received 10 mg doses of dexamethasone, intravenously, every 12 h until delivery; and 3 additional doses after delivery. Postpartum women received three 10 mg doses after delivery. Kadanali 1997 (Turkey) Antepartum 26 Dexamethasone Not clearly defined Pregnant women in the experimental group received a total of four doses of intravenous dexamethasone over 36 hours separated by 12-hour intervals. The first two doses were 10 mg each and the second two doses were 5 mg each. Katz 2008 (Brazil) Postpartum 105 Dexamethasone Partial HELLP and complete HELLP. Class 1 and 2 combined subsets of complete HELLP is 85.7% Postpartum women in the experimental group received 10 mg doses of dexamethasone every 12 hours for 4 days. Extra doses may have been administered to an undisclosed number of women with deteriorated status. Magann 1994 (USA) Antepartum 25 Dexamethasone Class 2 and 3 Pregnant women in the experimental group received 10-mg doses of dexamethasone intravenously every 12 hours until delivery. Magann 1994 (USA) Postpartum 40 Dexamethasone Class 1 and 2 Postpartum women in the experimental group received a total of four doses of dexamethasone separated by 12-hour intervals starting immediately after delivery and throughout the following 36 hours. The first two doses were 10-mg each and the second two doses were 5-mg each. Mould 2006 (South Africa) Postpartum 37 Dexamethasone Not clearly defined Postpartum women in the experimental group received 10 mg dexamethasone every 12 hours until platelets recovered (> 100,000 cells/mm3). Ozer 2009 (Turkey) Antepartum 60 Betamethasone Class 1, 2 and 3 Pregnant women in the Intervention group recieved 12 mg betamethasone IM every 12 hours until symptoms and signs in remission van Runnard 2006 (Netherlands) Antepartum 32 Prednisolone Class 1 and 2 Pregnant women in the interventions group recieved prednisolone IV, 50 mg over 12 hours in 100 ml of sodium chloride, for 2 days after delivery or for up to 14 days in antenatal period, then tapering off (4-day oral tapering protocol of 50, 20, 10 and 5 mg of medication). If women delivered during the tapering period, a stress dose was given during and after delivery every 12 hours for 48 hours) Vigil-De Gracia 1997 (Mexico) Postpartum 34 Dexamethasone Classes 1, 2, and 3 Postpartum women in the intervention group recieved 10 mg IV dexamethasone, repeated at 12 and 24 hrs (total 30 mg) Yalcin 1998 (Turkey) Postpartum 30 Dexamethasone Class 1 and 2 Postpartum women in the intervention group received 10 mg dexamethasone IV, then 10 mg at 12 hrs, and 5 mg at 24 and 36 hrs (total dose over 36 hrs = 30 mg) Du Plessis 2010 (South Africa) Postpartum 68 Dexamethasone Class 1 and 2 Postpartum women in the intervention group received dexamethasone 24 mg on day 1, 16 mg on day2 and 12 mg on day 3, intravenously Borekci 2008 (Turkey) Postpartum 60 Dexamethasone vs Betamethasone vs placebo Class 1 and 2 The first group was given 10 mg dexamethasone intravenously three times with a 12-hour interval for a total dose of 30 mg. The second group was given 12 mg betamethasone intramuscularly twice with a 24-hour interval. It was administered at a total dose of 24 mg. Caliskan 2010 (Turkey) Antepartum and Postpartum 65 Betamethasone Class 1, 2 and 3 Pregnant women in the Intervention group received 24 mg betamethasone intramuscularly before cesarean delivery and was repeated 24 hours later. Risk of bias in studies We assessed the risk of bias for the included RCTs contributing results to our outcomes using the RoB 2 tool. The overall risk of bias for all study results per outcome are available in Supplemental file 4. The results of risk of bias assessments for the primary outcome, maternal death are depicted in Supplemental file 4. Overall, 5 out of 6 studies were judged overall to be at “low risk” of bias. One study [ 25 ] was judged to be at “high risk” of bias. The main reasons for having “high risk” in domain 1 were lack of description in the randomization process with baseline differences in platelet count between intervention groups that suggest a problem with the randomization process. There were “some concerns” in two other domains. First, people delivering the interventions were probably aware of participants’ assigned intervention during the trial. Second, there were no information whether the data that produced this result were analyzed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis. Syntheses of results Maternal death Six trials (449 women) reported maternal death. The risk ratio (RR) was 0.77 (95% confidence intervals (CI) 0.25 to 2.38, Fig. 2 ). The effect of any corticosteroid vs placebo or no treatment is uncertain. We downgraded the certainty of the evidence to very low due to extremely serious imprecision, Table 2 . The subgroup analysis did not show significant differences among groups whether by the timing of corticosteroid administration (test for subgroup differences P = 0.79) or by the type of corticosteroid (test for subgroup differences P = 0.60) (Supplemental file 4). Sensitivity analysis to explore robustness of pooled estimate for maternal death, using outcome data from trials with a low risk of bias showed results similar to primary analysis with a RR 0.87 (95% CI 0.26 to 2.92) or by including studies with zero events with RR 0.79 (95% CI 0.27 to 2.32) (Supplemental file 4). Figure 2 : Maternal death: Corticosteroids vs placebo or no treatment Acute pulmonary edema The effect of any corticosteroid vs placebo or no treatment is very uncertain. Four trials (381 women) reported pulmonary edema. The risk ratio was 0.70 (95% confidence interval 0.23 to 2.09), Fig. 3 . We downgraded the certainty of the evidence to very low due to extremely serious imprecision. Figure 3 : Acute pulmonary edema: Corticosteroids vs placebo or no treatment Acute renal failure Five trials (406 women) reported acute renal failure. Corticosteroids may result in a slight reduction in acute renal failure. The risk ratio was 0.6658 (95% CI 0.3965 to 1.1179), Fig. 4 . The certainty of evidence was low due to very serious imprecision. Figure 4 : Acute renal failure: Corticosteroids vs placebo or no treatment Dialysis The evidence is very uncertain about the effect of corticosteroids on dialysis. The need for dialysis was reported in one study (60 women). The risk ratio was 3 (95% CI 0.1271 to 70.7833). The certainty of evidence was downgraded to very low due to extremely serious imprecision. Liver morbidity (hematoma, rupture, or failure) The evidence is very uncertain about the effect of corticosteroids on liver morbidity vs placebo or no treatment. Based on data from two studies (91 women), the risk ratio was 0.2171 (95% CI 0.0258 to 1.8257). We downgraded the certainty of evidence to very low due to extremely serious imprecision. Platelet transfusion Based on data from 219 women in two studies, corticosteroids have little or no difference in the need for platelet transfusion (RR 0.9821; 95% CI 0.6031 to 1.5994). We downgraded the certainty of evidence to low due to very serious imprecision. Perinatal death The evidence is very uncertain about the effect of corticosteroids on perinatal death. Based on data from two studies (58 women), the risk ratio was 0.6372 (95% CI 0.2062 to 1.9693). The certainty of evidence was very low due to extremely serious imprecision. Risk of reporting biases in syntheses The possibility of reporting bias could not be excluded, as not all trials reported all relevant outcomes. The planned funnel plots were not created because we did not include 10 or more studies reporting on any of the outcomes. Certainty of evidence The effect of corticosteroids, compared with placebo or no treatment, is uncertain for maternal death, acute pulmonary edema, dialysis, and perinatal death. We downgraded the certainty of the evidence three levels to very low due to extremely serious imprecision. The 95% CI is very wide and includes both large benefit and large harm. The two boundaries of CI suggest very different inferences. Corticosteroids, compared with placebo or no treatment, may result in a slight reduction in acute renal failure. We downgraded the certainty of the evidence two levels to low due to very serious imprecision. The 95% CI overlaps no effect and includes large benefit. Corticosteroids, compared with placebo or no treatment, have little or no difference in the need for platelet transfusion. We downgraded the certainty of evidence two levels to low due to very serious imprecision. The pooled estimate of the risk ratio suggests no difference and the CI includes appreciable benefit and harm. A Summary of Findings table presents the same information as the text above, with footnotes explaining judgments, Table 2 . Table 2 Summary of Findings: Corticosteroids compared to placebo for women with HELLP syndrome. Outcomes Number of participants (studies) Follow-up Certainty of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with placebo Risk difference with Corticosteroid Maternal death 449 (6 RCTs) ⨁◯◯◯ Very low a RR 0.7700 (0.2492 to 2.3799) 31 per 1,000 7 fewer per 1,000 (24 fewer to 43 more) Acute renal failure 406 (5 RCTs) ⨁⨁◯◯ Low b RR 0.6658 (0.3965 to 1.1179) 144 per 1,000 48 fewer per 1,000 (87 fewer to 17 more) Acute Pulmonary edema 381 (4 RCTs) ⨁◯◯◯ Very low a RR 0.6975 (0.2323 to 2.0944) 43 per 1,000 13 fewer per 1,000 (33 fewer to 47 more) Dialysis 60 (1 RCT) ⨁◯◯◯ Very low a RR 3.0000 (0.1271 to 70.7833) 0 per 1,000 0 fewer per 1,000 (0 fewer to 0 fewer) Liver morbidity 91 (2 RCTs) ⨁◯◯◯ Very low a RR 0.2171 (0.0258 to 1.8257) 87 per 1,000 68 fewer per 1,000 (85 fewer to 72 more) Platelet transfusion 219 (2 RCTs) ⨁⨁◯◯ Low c RR 0.9821 (0.6031 to 1.5994) 225 per 1,000 4 fewer per 1,000 (89 fewer to 135 more) Perinatal death 58 (2 RCTs) ⨁◯◯◯ Very low a RR 0.6372 (0.2062 to 1.9693) 233 per 1,000 85 fewer per 1,000 (185 fewer to 226 more) The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets GRADE Working Group grades of evidence: High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. Explanations CI is very wide and includes both large benefit and large harm. The two boundaries of CI suggest very different inferences. We rated down three levels for imprecision. CI overlaps no effect and includes both large benefit and small harm. We rated down two levels for imprecision. The pooled estimate of the risk ratio suggests no difference and the CI includes appreciable benefit and harm. Discussion We conducted this systematic review and meta-analysis to assess the effects of corticosteroids for improving outcomes in women with HELLP syndrome. This updated evidence synthesis is mandatory for the development of the Egyptian National Guideline for the management of severe preeclampsia, commissioned by the Egyptian Health Council. Summary of the evidence There was no clear evidence of a treatment effect of corticosteroids on substantive clinical outcomes. The effect of corticosteroids, compared with placebo or no treatment, is uncertain for maternal death, acute pulmonary edema, dialysis, and perinatal death. Corticosteroids, compared with placebo or no treatment, have little or no difference in the need for platelet transfusion but may result in a slight reduction in acute renal failure. The results of this up-to-date review are consistent with the findings reported previously [ 8 ] that there was insufficient evidence to support the administration of corticosteroids to women with HELLP syndrome. In this review, we only included randomized trials for the meta-analysis. A major issue of observational evidence is that it is known to have limited internal validity as it is subject to both bias and confounding, therefore observational studies were excluded to ensure reliability of the results by minimizing the risk of bias due to unmeasured confounders. Overall, observational study designs are not the most appropriate to assess the causal relationship between an intervention and an outcome as several characteristics might differ or might change over time between the different intervention groups. So, the inclusion of observational studies in a meta-analysis might introduce bias in the summary effect. Potential biases are likely to be greater for observational studies compared with randomized trials when evaluating the effects of interventions. Observational studies of interventions vary in their ability to estimate a causal effect. Biases affecting observational studies of interventions vary depending on the features of the studies. Published reviews [ 30 ] that included observational studies have not adequately addressed potential confounders and the likelihood of increased heterogeneity resulting from residual confounding and from other biases that vary across studies. Our strategy aimed to study the effectiveness of corticosteroids in HELLP syndrome for improving critical maternal and perinatal outcomes rather than surrogate outcomes. While surrogate outcome measures, such as platelet count and liver enzymes laboratory results, may provide insights into how a treatment might work, yet they do not necessarily reflect clinical benefits relevant to decision making. Some interventions that reduce the risk for a surrogate outcome may have no or harmful effects on clinically relevant outcomes, and other interventions having no effect on surrogate measures may improve clinical outcomes. [ 31 , 32 ] As such, and despite their potential appeal, superiority on a surrogate end point, for example the change in platelet count and liver enzymes, may not reflect actual benefits that corticosteroids have on critical outcomes of women with HELLP syndrome. Furthermore, surrogate end points are potentially misleading and should be avoided, or at least interpreted with caution, as decision makers are required to extrapolate the findings to estimate true patient benefits, resulting in uncertainty about the effect of corticosteroids in HELLP syndrome. Published synthesized evidence [ 30 ] that included surrogate outcomes without downgrading the certainty of evidence for indirectness would provide misleading implications for practice. In the presence of patient-relevant outcomes, the use of surrogate outcomes in a synthesis of evidence to inform practice cannot be justified. [ 33 ] We focused on studies that compared corticosteroids to placebo or standard care. Various types of corticosteroids differ in their relative potency and duration of action. It would, therefore, be counter-intuitive, and not clinically useful, to compare one corticosteroid to another when evidence fails to show a difference between any corticosteroid vs placebo or no treatment. Investigators [ 34 ] raised serious concerns regarding the credibility of the subgroup analysis results of the Cochrane Review [ 8 ] and the application of these subgroup results into clinical practice. A recently published review [ 35 ] had serious concerns that stakeholders must be aware of. The review included a trial that enrolled women without HELLP syndrome, [ 36 ] while it did not include nine eligible published trials. [ 15 , 16 , 18 , 20 , 23 , 25 , 27 – 29 ] The meta-analyses suffered from incorrect data entry both in the number of events and in the total number of participants in several outcomes leading to incorrect estimates of the effects that have serious implications when interpreting the results. [ 35 ] Further, the review indicated that the revised Cochrane Risk of Bias tool (RoB 2) was used. RoB 2 is a “results-based” tool because it is used to assess bias for a specific result reported in an individual study. The original risk of bias tool, and most other tools, assess bias across all outcomes and results for an entire study. However, the review incorrectly reported the risk of bias for each entire trial while the RoB table headings and the citation refer to RoB-2. The review did not report any subgroup or sensitivity analyses. The review did not rate the certainty of evidence using any approach such as GRADE. [ 35 ] In summary, our methodology minimized bias through strict inclusion of randomized controlled trials, established the class effect first before agent comparisons, and emphasized outcomes of greatest clinical relevance. This approach provided the most robust and applicable evidence for clinical decision making. The results of our up-to-date synthesis of available evidence provide a rigorous evidence base for trustworthy clinical practice guidelines for the management of HELLP syndrome. [ 37 – 43 ] Limitations A limitation of the evidence was the restricted number of outcomes reported in the included trials. Most included trials reported surrogate laboratory results. The possibility of reporting bias could not be excluded, given that not all trials reported all relevant outcomes. In the case of HELLP syndrome, patient-relevant outcomes do not require exceptional training, expensive tools, or long follow up. It would be implausible to conduct a trial in such a critical condition without reporting maternal death or morbidity. Conclusions In women with HELLP syndrome, the effect of corticosteroids versus placebo or no treatment is uncertain for critical patient-relevant outcomes. The currently available evidence does not support or refute the practice of corticosteroid administration for treating HELLP syndrome. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials All data relevant to this study are publicly available. Data, analysis script and materials related to this study are publicly available on the Open Science Framework at https://osf.io/9vwdq. The study protocol and materials were registered on 18 September 2023 at https://osf.io/yzku5. To facilitate reproducibility, this manuscript was written by interleaving regular prose and analysis code using R Markdown. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Authors' contributions AFN conceived the idea for this review and designed the review methods. AFK, HBA coordinated the research activities. All authors collaborated in searching, screening, selecting studies, data extraction and synthesis. AFN, AFK, HBA wrote the first draft of the manuscript. All authors revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript. AFN is the guarantor for this manuscript. Acknowledgments We acknowledge the contribution and the spirit of goodwill of Dr. Maha Khalifa, the healthcare advocate for her valuable insights. References Lisonkova S, Razaz N, Sabr Y, et al. Maternal risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study. BJOG: An International Journal of Obstetrics & Gynaecology. 2020;127:1189–98. 10.1111/1471-0528.16225 . Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: Clinical issues and management. A Review. BMC Pregnancy Childbirth. 2009;9. 10.1186/1471-2393-9-8 . Wallace K, Harris S, Addison A, et al. 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Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane database of systematic reviews. 2010;9:CD008148. 10.1002/14651858.CD008148.pub2 . Higgins JPT, Thomas J, Chandler J, et al. editors. Cochrane handbook for systematic reviews of interventions version 6.4 (updated august 2023). Cochrane 2023. http://www.training.cochrane.org/handbook . Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol. 2021;134:178–89. 10.1016/j.jclinepi.2021.03.001 . R Core Team. R: A language and environment for statistical computing. Published Online First: 2023. https://www.R-project.org/ . Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with r: A practical tutorial. 2019. Schünemann H, Brożek J, Guyatt G et al. GRADE handbook for grading quality of evidence and strength of recommendations. 2013.guidelinedevelopment.org/handbook. GRADEpro GDT. GRADEpro Guideline Development Tool [software]. McMaster University and Evidence Prime Published Online First: 2022.gradepro.org. Börekçi B, Bebek Z, Ingeç M, et al. Effects of postpartum corticosteroids in patients with HELLP syndrome. J Turkish German Gynecol Association. 2008;9:79–83. Du Plessis J, Van Soest J, Joubert G. HELLP syndrome: Does postpartum dexamethasone improve maternal outcome? Pregnancy Hypertens. 2010;1:26. 10.1016/S2210-7789(10)60109-2 . Fonseca JE, Méndez F, Cataño C, et al. Dexamethasone treatment does not improve the outcome of women with HELLP syndrome: A double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol. 2005;193:1591–8. 10.1016/j.ajog.2005.07.037 . Magann EF, Perry KGJ, Meydrech EF, et al. Postpartum corticosteroids: Accelerated recovery from the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol. 1994;171:1154–8. 10.1016/0002-9378(94)90055-8 . van Runnard Heimel PJ, Huisjes AJM, Franx A, et al. A randomised placebo-controlled trial of prolonged prednisolone administration to patients with HELLP syndrome remote from term. Eur J Obstet Gynecol Reproductive Biology. 2006;128:187–93. https://doi.org/10.1016/j.ejogrb.2005.11.041 . Yalcin OT, Sener T, Hassa H, et al. Effects of postpartum corticosteroids in patients with HELLP syndrome. Int J Gynecol Obstet. 1998;61:141–8. 10.1016/S0020-7292(98)00036-8 . Fonseca JE, Otero JC, Messa C. Dexamethasone for the treatment of class i HELLP syndrome: A double-blind, placebo-controlled, multicenter, randomized clinical trial. Pregnancy Hypertens. 2019;17:158–64. 10.1016/j.preghy.2019.06.003 . Magann EF, Bass D, Chauhan SP, et al. Antepartum corticosteroids: Disease stabilization in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol. 1994;171:1148–53. 10.1016/0002-9378(94)90054-x . Çalişkan E, Çakiroǧlu Y, Doǧer E, et al. The effects of high dose betamethasone applications on HELLP syndrome. Turkiye Klinikleri Journal of Medical Sciences. 2010;30:1134–42. 10.5336/medsci.2008-9788 . Ozer A, Kanat-Pektas M, Ozer S, et al. The effects of betamethasone treatment on clinical and laboratory features of pregnant women with HELLP syndrome. Arch Gynecol Obstet. 2009;280:65–70. 10.1007/s00404-008-0865-3 . Vigil-De Gracia P, García-Cáceres E. Dexamethasone in the post-partum treatment of HELLP syndrome. Int J Gynaecol Obstet. 1997;59:217–21. 10.1016/s0020-7292(97)00214-2 . Katz L, de Amorim MMR, Figueiroa JN, et al. Postpartum dexamethasone for women with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: A double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol. 2008;198:283e1–8. 10.1016/j.ajog.2007.10.797 . Bouchnak M, Souissi K, Ouragini H, et al. [Maternal benefit of postpartum corticosteroid therapy in patients with HELLP (hemolysis elevated liver enzymes low platelets count) syndrome]. Tunis Med. 2005;83:473–6. Kadanali S, Kucukozkan T, Bukam B. Helpful effect of high-dose corticosteroid use on hellp syndrome. Jinekoloji Ve Obstetrik Dergisi. 1997;11:55–8. Mould S, Paruk F, Moodley J. High-dose dexamethasone in the treatment of HELLP syndrome. Int J Gynecol Obstet. 2006;93:140–1. 10.1016/j.ijgo.2006.01.017 . Mao M, Chen C. Corticosteroid Therapy for Management of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (HELLP) Syndrome: A Meta-Analysis. Med Sci Monit. 2015;21:3777–83. 10.12659/msm.895220 . Bucher HC, Cook DJ, Holbrook AM et al. Surrogate outcomes. In: Guyatt G, Rennie D, Meade MO, eds. Users’ guides to the medical literature: A manual for evidence-based clinical practice, 3rd ed. New York, NY:: McGraw-Hill Education 2015. jamaevidence.mhmedical.com/content.aspx?aid = 1183876702 . McKenzie JE, Brennan SE, Ryan RE et al. Defining the criteria for including studies and how they will be grouped for the synthesis. In: Higgins JPT, Thomas J, Chandler J, eds. Cochrane handbook for systematic reviews of interventions version 6.4 (updated august 2023). Cochrane 2023. http://www.training.cochrane.org/handbook . Tufanaru C. Surrogate outcomes. JBI Database of Systematic Reviews and Implementation Reports. 2016;14:1–2. 10.11124/jbisrir-2016-003172 . Basaran A, Basaran M, Sen C. Choice of glucocorticoid in HELLP syndrome dexamethasone versus betamethasone: revisiting the dilemma. J Maternal-Fetal Neonatal Med. 2012;25:2597–600. 10.3109/14767058.2012.712571 . Sun W-J, Hu J, Zhang Q, et al. Administration of corticosteroid therapy for HELLP syndrome in pregnant women: evidences from seven randomized controlled trials. Hypertens Pregnancy. 2023;42:2276726. 10.1080/10641955.2023.2276726 . Barrilleaux PS, Martin JN, Klauser CK, et al. Postpartum intravenous dexamethasone for severely preeclamptic patients without hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome: a randomized trial. Obstet Gynecol. 2005;105:843–8. 10.1097/01.AOG.0000154887.57440.d1 . Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2020;135:e237–60. 10.1097/aog.0000000000003891 . Bonnet M-P, Garnier M, Keita H, et al. Guidelines for the management of women with severe pre-eclampsia. Anaesth Crit Care Pain Med. 2021;40:100901. 10.1016/j.accpm.2021.100901 . WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Published Online First: 2011. https://www.ncbi.nlm.nih.gov/books/NBK140561 . WHO recommendations. : Drug treatment for severe hypertension in pregnancy. Published Online First: 2018. https://www.ncbi.nlm.nih.gov/books/NBK535778 . National Institute for Health and Care Excellence. Hypertension in pregnancy: diagnosis and management NICE guideline (NG133). 2019. https://www.nice.org.uk/guidance/ng133 . Magee LA, Pels A, Helewa M, et al. Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary. J Obstet Gynecol Can. 2014;36:416–38. 10.1016/s1701-2163(15)30588-0 . Lowe SA, Bowyer L, Lust K, et al. SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. Aust N Z J Obstet Gynaecol. 2015;55. 10.1111/ajo.12399 . Additional Declarations No competing interests reported. Supplementary Files Supp1Protocol.pdf Supplemental file 1: Protocol Supp2PRISMAchecklist.pdf Supplemental file 2: PRISMA checklist Supp3Searchstrategy.pdf Supplemental file 3: Search strategy Supp4Dataandsynthesisscript.pdf Supplemental file 4: Data and synthesis script Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2024 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted Editorial decision: Revision requested 02 Feb, 2024 Reviewers agreed at journal 08 Jan, 2024 Reviews received at journal 25 Dec, 2023 Reviewers agreed at journal 11 Dec, 2023 Reviewers invited by journal 08 Dec, 2023 Editor assigned by journal 03 Dec, 2023 Editor invited by journal 03 Dec, 2023 Submission checks completed at journal 03 Dec, 2023 First submitted to journal 25 Nov, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe pathophysiology of HELLP syndrome that is usually diagnosed between 27 and 37 weeks, is not completely understood. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe diagnosis depends on laboratory findings of microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes. Different investigators reported different threshold of hematologic and biochemical values for diagnosis of the syndrome or for determining the prognosis. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe presence of HELLP syndrome is associated with significant maternal mortality and morbidity including acute renal and liver failure. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Approximately 70% of pregnancies complicated by HELLP syndrome require preterm delivery, thus increasing perinatal morbidity and mortality. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eObservational studies suggested that steroid treatment in HELLP syndrome may improve disordered maternal hematological and biochemical features and perhaps perinatal mortality and morbidity. Clinical trials examined the effects of corticosteroids for the treatment of maternal HELLP syndrome. Various regimens have been reported using prednisolone, dexamethasone, or betamethasone. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCurrent practice and clinical guidelines require an updated evidence synthesis because the latest available synthesis was published in 2010, [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] new studies have been published, and the clinical question remains relevant to decision makers.\u003c/p\u003e \u003cp\u003e We conducted this systematic review to update the synthesized evidence regarding the effects of corticosteroids versus placebo or no treatment for improving outcomes in women with HELLP syndrome.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eProtocol and registration\u003c/p\u003e \u003cp\u003e This systematic review was conducted following the methodological standards of Cochrane Handbook. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] We prospectively registered the protocol in Open Science Platform. The full text of the protocol is available in an open access registry and as an online as Supplemental file 1. We reported the review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) standards. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The full checklist is available as Supplemental file 2.\u003c/p\u003e \u003cp\u003eEligibility criteria\u003c/p\u003e \u003cp\u003eWe included published randomized controlled trials that recruited women with HELLP syndrome, confirmed by objective testing. We included studies comparing corticosteroids versus placebo or no treatment. The primary outcome measure was maternal death. Other outcomes included acute pulmonary edema; acute renal failure; dialysis, liver morbidity (hematoma, ruptured liver, and failure), need for platelet transfusion, and perinatal death.\u003c/p\u003e \u003cp\u003eInformation sources\u003c/p\u003e \u003cp\u003eA comprehensive literature search was initially conducted on September 20, 2023. We did not impose language or other restrictions on any of the searches. We searched bibliographic databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed) and citation indexes (Web of Science and Scopus). We included the terms (HELLP Syndrome) AND (corticosteroids or glucocorticoids or Dexamethasone or Betamethasone or Prednisolone). The detailed exact strategy adapted for each database is provided in Supplemental file 3 and is available as an open access registry document. We peer-reviewed the search strategy and further tested it with a set of known relevant, \u0026lsquo;gold standard\u0026rsquo;, reports. We also searched clinical trial registries (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) to identify ongoing trials. We finally searched reference lists and explored the cited-by logs of identified studies and previously published reviews.\u003c/p\u003e \u003cp\u003eStudy selection\u003c/p\u003e \u003cp\u003eAll reports identified in the databases were imported to Bibtex library using Jabref version 5. After removing duplicates, two authors independently screened all titles and abstracts for eligibility. We retrieved and assessed the full text of all reports that potentially met our eligibility criteria during screening. Two authors (AFK, HBA, MAE, RHA) independently assessed each full-text article. Disagreements regarding trial eligibility was resolved by consensus and finally resolved by a third author (AFN).\u003c/p\u003e \u003cp\u003eData collection process\u003c/p\u003e \u003cp\u003eFor eligible studies, we extracted the data in duplicates using an offline electronic form. We resolved discrepancies through discussion. Extracted data were transcribed to a spreadsheet and checked for accuracy. We contacted authors of the original reports, if needed, to provide details regarding unclear or missing data.\u003c/p\u003e \u003cp\u003eData items\u003c/p\u003e \u003cp\u003eExtracted data included study design, sample size, description of included participants, description of the intervention, outcomes, trial registration, and funding sources, and country.\u003c/p\u003e \u003cp\u003eStudy risk of bias assessment\u003c/p\u003e \u003cp\u003eTwo authors (AFK, HBA, MAE, RHA) independently used the Risk of Bias 2 (RoB 2) tool to assess the risk of bias of study results contributing information to each of the outcomes specified for inclusion in the Summary of Findings table.\u003c/p\u003e \u003cp\u003eWe assessed the following risk of bias domains as outlined in Cochrane Handbook for Systematic Reviews of Interventions: 1) risk of bias arising from the randomization process; 2) risk of bias due to deviations from the intended interventions (effect of assignment to intervention); 3) risk of bias due to missing outcome data; 4) risk of bias in measurement of the outcome; and 5) risk of bias in selection of the reported result. Each domain was judged as being at \u0026ldquo;low risk of bias\u0026rdquo;, \u0026ldquo;some concerns\u0026rdquo;, or \u0026ldquo;high risk of bias\u0026rdquo;. Trials with \u0026ldquo;low risk of bias\u0026rdquo; in all domains were classified as being at overall \u0026ldquo;low risk of bias\u0026rdquo;. RCTs with one domain judged to be at \u0026ldquo;some concerns\u0026rdquo;, but no domain judged to be at \u0026ldquo;high risk of bias\u0026rdquo;, were classified as being at overall \u0026ldquo;some concerns\u0026rdquo; of risk of bias. RCTs were classified as being at overall \u0026ldquo;high risk of bias\u0026rdquo; if at least one domain was judged as being at \u0026ldquo;high risk of bias\u0026rdquo;. However, if a trial was judged to be at \u0026ldquo;some concerns\u0026rdquo; due to risk of bias for multiple domains, it was judged as being at overall \u0026ldquo;high risk of bias\u0026rdquo; if the assessors judged that the multiple concerns amounted to a serious risk of bias. In case of discrepancies among their judgments and inability to reach consensus, we consulted the senior author (AFN) to reach a final decision.\u003c/p\u003e \u003cp\u003eEffect measures\u003c/p\u003e \u003cp\u003eFor dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI). None of the outcomes of interest were meta-analyzed as a continuous variable. The unit of analysis was the individual participant. We used a complete case approach for analysis. Data related to participants reported as not compliant was analyzed on an intention-to-treat basis.\u003c/p\u003e \u003cp\u003eSynthesis methods\u003c/p\u003e \u003cp\u003eFixed-effect meta-analysis was performed to combine data of trials that are judged to be sufficiently similar in terms of intervention, populations, and methods. We planned to investigate substantial statistical heterogeneity, defined as I\u0026sup2; statistic\u0026thinsp;\u0026ge;\u0026thinsp;50% or P\u0026thinsp;\u0026lt;\u0026thinsp;0.1.\u003c/p\u003e \u003cp\u003eWe performed the planned subgroup analysis by gestational age at enrollment (ante- vs postpartum) and by type of corticosteroids. We assessed subgroup differences by interaction tests. Results of the subgroup analyses were reported by mentioning the Chi\u0026sup2; statistic and P value, and the interaction test I\u0026sup2; value.\u003c/p\u003e \u003cp\u003eSensitivity analysis was performed to explore robustness of pooled estimate using outcome data from trials with a low risk of bias.\u003c/p\u003e \u003cp\u003eSynthesis was performed using RStudio 2023.06.1 Build 524 (MacOS, Apple Silicon version), R 4.3.1 (2023-06-16) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and R package meta version 6.5. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eReporting bias assessment\u003c/p\u003e \u003cp\u003eWe explored whether the study was included in a trial registry and whether a protocol was available. We planned to examine funnel plots to assess the potential for publication bias if we found 10 or more studies reporting on a particular outcome.\u003c/p\u003e \u003cp\u003eCertainty assessment\u003c/p\u003e \u003cp\u003eWe used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to create the Summary of Findings table. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Briefly, GRADE uses study limitations, consistency of effect, imprecision, indirectness, and publication bias to assess the certainty of evidence for each outcome. A summary of the intervention effect and a measure of certainty was produced using the GRADE Profiler Guideline Development Tool (GRADEpro GDT) software [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] for the prespecified important outcomes: maternal death, pulmonary edema, renal failure, dialysis, liver morbidity, need for platelet transfusion, and perinatal death. One author (A.N.) conducted GRADE assessments and the decisions on downgrading. This was discussed for final approval by all authors.\u003c/p\u003e \u003cp\u003ePatient and public involvement\u003c/p\u003e \u003cp\u003eWe consulted with patients by asking a group to review and comment on an early draft of the manuscript.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eStudy selection\u003c/p\u003e \u003cp\u003eBibliographic database search identified 154 records. After removing duplicates, 86 titles and abstracts were screened. Twenty-four titles required further assessment. One is an ongoing CTRI/2020/12/029730 and the full-text reports of 23 published reports were assessed using the predefined eligibility criteria. We excluded two reports identified in our search. One study did not meet our inclusion criteria for participants as it enrolled women with low platelets not HELLP syndrome. The other study was terminated because of the inability to recruit the required sample. Fifteen studies (21 reports published between 1994 and 2019) including 821 women were found eligible Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStudy characteristics\u003c/p\u003e \u003cp\u003eWe summarized the characteristics of the included studies in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe 15 included trials recruited 821 women with HELLP syndrome. Criteria for recruitment in five trials [\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] were a diagnosis of HELLP class 1 or 2 on the Mississippi HELLP classification system. One trial exclusively recruited women with class 1. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] One trial recruited women with class 2 and 3. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Three studies [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] recruited women with HELLP classes 1, 2, and 3. One study [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] included women with partial HELLP (1 or more parameters abnormal) (61/105 [58.1%]) and complete HELLP (all parameters abnormal) (44/105 [41.9%]); class 1 and 2 combined subset accounted for 85.7% of participants with complete HELLP. Three studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] did not report explicitly on the class of HELLP syndrome.\u003c/p\u003e \u003cp\u003eEleven trials administered dexamethasone vs placebo or no treatment, [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26 CR27 CR28\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] two trials administered betamethasone, [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and one trial administered prednisolone. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] One multiple-arms trial compared dexamethasone vs betamethasone vs no treatment. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCorticosteroids administration commenced after delivery in eight trials, [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] before delivery in five trials, [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and in two trials [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] treatment commenced according to timing of recruitment whether before or after delivery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy ID (Country)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTreatment commenced\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCorticosteroids\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHELLP syndrome class\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCorticosteroids regimen\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBouchnak 2005 (Tunisia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNot clearly defined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the experimental group received dexamethasone, 12 mg every 12h for 2 doses, started immediately following delivery.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFonseca 2005 (Colombia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum and Postpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 (38%) and 2 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the experimental group received 10 mg doses of dexamethasone intravenously every 12 hours until delivery and 3 additional doses after delivery. Puerperal women received 3 10-mg doses after delivery.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFonseca 2019 (Colombia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum and Postpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the experimental group received 10 mg doses of dexamethasone, intravenously, every 12 h until delivery; and 3 additional doses after delivery. Postpartum women received three 10 mg doses after delivery.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKadanali 1997 (Turkey)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNot clearly defined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the experimental group received a total of four doses of intravenous dexamethasone over 36 hours separated by 12-hour intervals. The first two doses were 10 mg each and the second two doses were 5 mg each.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKatz 2008 (Brazil)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePartial HELLP and complete HELLP. Class 1 and 2 combined subsets of complete HELLP is 85.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the experimental group received 10 mg doses of dexamethasone every 12 hours for 4 days. Extra doses may have been administered to an undisclosed number of women with deteriorated status.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagann 1994 (USA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 2 and 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the experimental group received 10-mg doses of dexamethasone intravenously every 12 hours until delivery.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagann 1994 (USA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 and 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the experimental group received a total of four doses of dexamethasone separated by 12-hour intervals starting immediately after delivery and throughout the following 36 hours. The first two doses were 10-mg each and the second two doses were 5-mg each.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMould 2006 (South Africa)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNot clearly defined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the experimental group received 10 mg dexamethasone every 12 hours until platelets recovered (\u0026gt;\u0026thinsp;100,000 cells/mm3).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOzer 2009 (Turkey)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBetamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1, 2 and 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the Intervention group recieved 12 mg betamethasone IM every 12 hours until symptoms and signs in remission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evan Runnard 2006 (Netherlands)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePrednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 and 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the interventions group recieved prednisolone IV, 50 mg over 12 hours in 100 ml of sodium chloride, for 2 days after delivery or for up to 14 days in antenatal period, then tapering off (4-day oral tapering protocol of 50, 20, 10 and 5 mg of medication). If women delivered during the tapering period, a stress dose was given during and after delivery every 12 hours for 48 hours)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVigil-De Gracia 1997 (Mexico)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClasses 1, 2, and 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the intervention group recieved 10 mg IV dexamethasone, repeated at 12 and 24 hrs (total 30 mg)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYalcin 1998 (Turkey)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 and 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the intervention group received 10 mg dexamethasone IV, then 10 mg at 12 hrs, and 5 mg at 24 and 36 hrs (total dose over 36 hrs\u0026thinsp;=\u0026thinsp;30 mg)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDu Plessis 2010 (South Africa)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 and 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePostpartum women in the intervention group received dexamethasone 24 mg on day 1, 16 mg on day2 and 12 mg on day 3, intravenously\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBorekci 2008 (Turkey)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDexamethasone vs Betamethasone vs placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1 and 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThe first group was given 10 mg dexamethasone intravenously three times with a 12-hour interval for a total dose of 30 mg. The second group was given 12 mg betamethasone intramuscularly twice with a 24-hour interval. It was administered at a total dose of 24 mg.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaliskan 2010 (Turkey)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntepartum and Postpartum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBetamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 1, 2 and 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePregnant women in the Intervention group received 24 mg betamethasone intramuscularly\u0026nbsp;before cesarean delivery and was repeated 24 hours later.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eRisk of bias in studies\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe assessed the risk of bias for the included RCTs contributing results to our outcomes using the RoB 2 tool. The overall risk of bias for all study results per outcome are available in Supplemental file 4.\u003c/p\u003e \u003cp\u003eThe results of risk of bias assessments for the primary outcome, maternal death are depicted in Supplemental file 4. Overall, 5 out of 6 studies were judged overall to be at \u0026ldquo;low risk\u0026rdquo; of bias. One study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] was judged to be at \u0026ldquo;high risk\u0026rdquo; of bias. The main reasons for having \u0026ldquo;high risk\u0026rdquo; in domain 1 were lack of description in the randomization process with baseline differences in platelet count between intervention groups that suggest a problem with the randomization process. There were \u0026ldquo;some concerns\u0026rdquo; in two other domains. First, people delivering the interventions were probably aware of participants\u0026rsquo; assigned intervention during the trial. Second, there were no information whether the data that produced this result were analyzed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis.\u003c/p\u003e \u003cp\u003eSyntheses of results\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMaternal death\u003c/h2\u003e \u003cp\u003eSix trials (449 women) reported maternal death. The risk ratio (RR) was 0.77 (95% confidence intervals (CI) 0.25 to 2.38, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The effect of any corticosteroid vs placebo or no treatment is uncertain. We downgraded the certainty of the evidence to very low due to extremely serious imprecision, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe subgroup analysis did not show significant differences among groups whether by the timing of corticosteroid administration (test for subgroup differences P\u0026thinsp;=\u0026thinsp;0.79) or by the type of corticosteroid (test for subgroup differences P\u0026thinsp;=\u0026thinsp;0.60) (Supplemental file 4).\u003c/p\u003e \u003cp\u003eSensitivity analysis to explore robustness of pooled estimate for maternal death, using outcome data from trials with a low risk of bias showed results similar to primary analysis with a RR 0.87 (95% CI 0.26 to 2.92) or by including studies with zero events with RR 0.79 (95% CI 0.27 to 2.32) (Supplemental file 4).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: Maternal death: Corticosteroids vs placebo or no treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAcute pulmonary edema\u003c/h2\u003e \u003cp\u003eThe effect of any corticosteroid vs placebo or no treatment is very uncertain. Four trials (381 women) reported pulmonary edema. The risk ratio was 0.70 (95% confidence interval 0.23 to 2.09), Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. We downgraded the certainty of the evidence to very low due to extremely serious imprecision.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e: Acute pulmonary edema: Corticosteroids vs placebo or no treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAcute renal failure\u003c/h2\u003e \u003cp\u003eFive trials (406 women) reported acute renal failure. Corticosteroids may result in a slight reduction in acute renal failure. The risk ratio was 0.6658 (95% CI 0.3965 to 1.1179), Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The certainty of evidence was low due to very serious imprecision.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e: Acute renal failure: Corticosteroids vs placebo or no treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDialysis\u003c/h2\u003e \u003cp\u003eThe evidence is very uncertain about the effect of corticosteroids on dialysis. The need for dialysis was reported in one study (60 women). The risk ratio was 3 (95% CI 0.1271 to 70.7833). The certainty of evidence was downgraded to very low due to extremely serious imprecision.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eLiver morbidity (hematoma, rupture, or failure)\u003c/h2\u003e \u003cp\u003eThe evidence is very uncertain about the effect of corticosteroids on liver morbidity vs placebo or no treatment. Based on data from two studies (91 women), the risk ratio was 0.2171 (95% CI 0.0258 to 1.8257). We downgraded the certainty of evidence to very low due to extremely serious imprecision.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePlatelet transfusion\u003c/h2\u003e \u003cp\u003eBased on data from 219 women in two studies, corticosteroids have little or no difference in the need for platelet transfusion (RR 0.9821; 95% CI 0.6031 to 1.5994). We downgraded the certainty of evidence to low due to very serious imprecision.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePerinatal death\u003c/h3\u003e\n\u003cp\u003eThe evidence is very uncertain about the effect of corticosteroids on perinatal death. Based on data from two studies (58 women), the risk ratio was 0.6372 (95% CI 0.2062 to 1.9693). The certainty of evidence was very low due to extremely serious imprecision.\u003c/p\u003e \u003cp\u003eRisk of reporting biases in syntheses\u003c/p\u003e \u003cp\u003eThe possibility of reporting bias could not be excluded, as not all trials reported all relevant outcomes. The planned funnel plots were not created because we did not include 10 or more studies reporting on any of the outcomes.\u003c/p\u003e \u003cp\u003eCertainty of evidence\u003c/p\u003e \u003cp\u003eThe effect of corticosteroids, compared with placebo or no treatment, is uncertain for maternal death, acute pulmonary edema, dialysis, and perinatal death. We downgraded the certainty of the evidence three levels to very low due to extremely serious imprecision. The 95% CI is very wide and includes both large benefit and large harm. The two boundaries of CI suggest very different inferences.\u003c/p\u003e \u003cp\u003eCorticosteroids, compared with placebo or no treatment, may result in a slight reduction in acute renal failure. We downgraded the certainty of the evidence two levels to low due to very serious imprecision. The 95% CI overlaps no effect and includes large benefit.\u003c/p\u003e \u003cp\u003eCorticosteroids, compared with placebo or no treatment, have little or no difference in the need for platelet transfusion. We downgraded the certainty of evidence two levels to low due to very serious imprecision. The pooled estimate of the risk ratio suggests no difference and the CI includes appreciable benefit and harm.\u003c/p\u003e \u003cp\u003eA Summary of Findings table presents the same information as the text above, with footnotes explaining judgments, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Findings: Corticosteroids compared to placebo for women with HELLP syndrome.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of participants\u003c/p\u003e \u003cp\u003e(studies)\u003c/p\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCertainty of the evidence\u003c/p\u003e \u003cp\u003e(GRADE)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRelative effect\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAnticipated absolute effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRisk with placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRisk difference with Corticosteroid\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e449\u003c/p\u003e \u003cp\u003e(6 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁◯◯◯\u003c/p\u003e \u003cp\u003eVery low\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.7700\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.2492 to 2.3799)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e7 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(24 fewer to 43 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute renal failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e406\u003c/p\u003e \u003cp\u003e(5 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.6658\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.3965 to 1.1179)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e144 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e48 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(87 fewer to 17 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Pulmonary edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e381\u003c/p\u003e \u003cp\u003e(4 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁◯◯◯\u003c/p\u003e \u003cp\u003eVery low\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.6975\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.2323 to 2.0944)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e13 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(33 fewer to 47 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60\u003c/p\u003e \u003cp\u003e(1 RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁◯◯◯\u003c/p\u003e \u003cp\u003eVery low\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 3.0000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.1271 to 70.7833)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0 fewer to 0 fewer)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver morbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91\u003c/p\u003e \u003cp\u003e(2 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁◯◯◯\u003c/p\u003e \u003cp\u003eVery low\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.2171\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.0258 to 1.8257)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e87 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e68 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(85 fewer to 72 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet transfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e219\u003c/p\u003e \u003cp\u003e(2 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eLow\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.9821\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.6031 to 1.5994)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e225 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e4 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(89 fewer to 135 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerinatal death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003cp\u003e(2 RCTs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁◯◯◯\u003c/p\u003e \u003cp\u003eVery low\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eRR 0.6372\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(0.2062 to 1.9693)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e233 per 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e85 fewer per 1,000\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(185 fewer to 226 more)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).\u003c/p\u003e \u003cp\u003eCI: confidence interval; RR: risk ratio; HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets\u003c/p\u003e \u003cp\u003eGRADE Working Group grades of evidence:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effect.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eModerate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLow certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVery low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eExplanations\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCI is very wide and includes both large benefit and large harm. The two boundaries of CI suggest very different inferences. We rated down three levels for imprecision.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCI overlaps no effect and includes both large benefit and small harm. We rated down two levels for imprecision.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe pooled estimate of the risk ratio suggests no difference and the CI includes appreciable benefit and harm.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e We conducted this systematic review and meta-analysis to assess the effects of corticosteroids for improving outcomes in women with HELLP syndrome. This updated evidence synthesis is mandatory for the development of the Egyptian National Guideline for the management of severe preeclampsia, commissioned by the Egyptian Health Council.\u003c/p\u003e \u003cp\u003eSummary of the evidence\u003c/p\u003e \u003cp\u003eThere was no clear evidence of a treatment effect of corticosteroids on substantive clinical outcomes. The effect of corticosteroids, compared with placebo or no treatment, is uncertain for maternal death, acute pulmonary edema, dialysis, and perinatal death. Corticosteroids, compared with placebo or no treatment, have little or no difference in the need for platelet transfusion but may result in a slight reduction in acute renal failure.\u003c/p\u003e \u003cp\u003eThe results of this up-to-date review are consistent with the findings reported previously [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] that there was insufficient evidence to support the administration of corticosteroids to women with HELLP syndrome.\u003c/p\u003e \u003cp\u003e In this review, we only included randomized trials for the meta-analysis. A major issue of observational evidence is that it is known to have limited internal validity as it is subject to both bias and confounding, therefore observational studies were excluded to ensure reliability of the results by minimizing the risk of bias due to unmeasured confounders. Overall, observational study designs are not the most appropriate to assess the causal relationship between an intervention and an outcome as several characteristics might differ or might change over time between the different intervention groups. So, the inclusion of observational studies in a meta-analysis might introduce bias in the summary effect. Potential biases are likely to be greater for observational studies compared with randomized trials when evaluating the effects of interventions. Observational studies of interventions vary in their ability to estimate a causal effect. Biases affecting observational studies of interventions vary depending on the features of the studies. Published reviews [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] that included observational studies have not adequately addressed potential confounders and the likelihood of increased heterogeneity resulting from residual confounding and from other biases that vary across studies.\u003c/p\u003e \u003cp\u003eOur strategy aimed to study the effectiveness of corticosteroids in HELLP syndrome for improving critical maternal and perinatal outcomes rather than surrogate outcomes. While surrogate outcome measures, such as platelet count and liver enzymes laboratory results, may provide insights into how a treatment might work, yet they do not necessarily reflect clinical benefits relevant to decision making. Some interventions that reduce the risk for a surrogate outcome may have no or harmful effects on clinically relevant outcomes, and other interventions having no effect on surrogate measures may improve clinical outcomes. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] As such, and despite their potential appeal, superiority on a surrogate end point, for example the change in platelet count and liver enzymes, may not reflect actual benefits that corticosteroids have on critical outcomes of women with HELLP syndrome. Furthermore, surrogate end points are potentially misleading and should be avoided, or at least interpreted with caution, as decision makers are required to extrapolate the findings to estimate true patient benefits, resulting in uncertainty about the effect of corticosteroids in HELLP syndrome. Published synthesized evidence [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] that included surrogate outcomes without downgrading the certainty of evidence for indirectness would provide misleading implications for practice. In the presence of patient-relevant outcomes, the use of surrogate outcomes in a synthesis of evidence to inform practice cannot be justified. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWe focused on studies that compared corticosteroids to placebo or standard care. Various types of corticosteroids differ in their relative potency and duration of action. It would, therefore, be counter-intuitive, and not clinically useful, to compare one corticosteroid to another when evidence fails to show a difference between any corticosteroid vs placebo or no treatment. Investigators [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] raised serious concerns regarding the credibility of the subgroup analysis results of the Cochrane Review [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and the application of these subgroup results into clinical practice.\u003c/p\u003e \u003cp\u003eA recently published review [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] had serious concerns that stakeholders must be aware of. The review included a trial that enrolled women without HELLP syndrome, [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] while it did not include nine eligible published trials. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] The meta-analyses suffered from incorrect data entry both in the number of events and in the total number of participants in several outcomes leading to incorrect estimates of the effects that have serious implications when interpreting the results. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] Further, the review indicated that the revised Cochrane Risk of Bias tool (RoB 2) was used. RoB 2 is a \u0026ldquo;results-based\u0026rdquo; tool because it is used to assess bias for a specific result reported in an individual study. The original risk of bias tool, and most other tools, assess bias across all outcomes and results for an entire study. However, the review incorrectly reported the risk of bias for each entire trial while the RoB table headings and the citation refer to RoB-2. The review did not report any subgroup or sensitivity analyses. The review did not rate the certainty of evidence using any approach such as GRADE. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn summary, our methodology minimized bias through strict inclusion of randomized controlled trials, established the class effect first before agent comparisons, and emphasized outcomes of greatest clinical relevance. This approach provided the most robust and applicable evidence for clinical decision making.\u003c/p\u003e \u003cp\u003e The results of our up-to-date synthesis of available evidence provide a rigorous evidence base for trustworthy clinical practice guidelines for the management of HELLP syndrome. [\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eA limitation of the evidence was the restricted number of outcomes reported in the included trials. Most included trials reported surrogate laboratory results. The possibility of reporting bias could not be excluded, given that not all trials reported all relevant outcomes. In the case of HELLP syndrome, patient-relevant outcomes do not require exceptional training, expensive tools, or long follow up. It would be implausible to conduct a trial in such a critical condition without reporting maternal death or morbidity.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn women with HELLP syndrome, the effect of corticosteroids versus placebo or no treatment is uncertain for critical patient-relevant outcomes. The currently available evidence does not support or refute the practice of corticosteroid administration for treating HELLP syndrome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eAll data relevant to this study are publicly available. Data, analysis script and materials related to this study are publicly available on the Open Science Framework at https://osf.io/9vwdq. The study protocol and materials were registered on 18 September 2023 at https://osf.io/yzku5. To facilitate reproducibility, this manuscript was written by interleaving regular prose and analysis code using R Markdown.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions\u003c/h2\u003e\n\u003cp\u003eAFN conceived the idea for this review and designed the review methods. AFK, HBA coordinated the research activities. All authors collaborated in searching, screening, selecting studies, data extraction and synthesis. AFN, AFK, HBA wrote the first draft of the manuscript. All authors revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript. AFN is the guarantor for this manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eWe acknowledge the contribution and the spirit of goodwill of Dr. Maha Khalifa, the healthcare advocate for her valuable insights.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLisonkova S, Razaz N, Sabr Y, et al. Maternal risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study. BJOG: An International Journal of Obstetrics \u0026amp; Gynaecology. 2020;127:1189\u0026ndash;98. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/1471-0528.16225\u003c/span\u003e\u003cspan address=\"10.1111/1471-0528.16225\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaram K, Svendsen E, Abildgaard U. 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J Obstet Gynecol Can. 2014;36:416\u0026ndash;38. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1701-2163(15)30588-0\u003c/span\u003e\u003cspan address=\"10.1016/s1701-2163(15)30588-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLowe SA, Bowyer L, Lust K, et al. SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. Aust N Z J Obstet Gynaecol. 2015;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ajo.12399\u003c/span\u003e\u003cspan address=\"10.1111/ajo.12399\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HELLP Syndrome, Corticosteroids, Maternal Mortality, Perinatal Mortality","lastPublishedDoi":"10.21203/rs.3.rs-3663675/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3663675/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e We conducted this updated systematic review to assess the effects of corticosteroids vs placebo or no treatment for improving patient-relevant outcomes in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e CENTRAL, MEDLINE/PubMed, Web of Science, and Scopus, from the date of inception of the databases to September 20, 2023 were searched. Reference lists of included studies and systematic reviews were thoroughly searched. We included RCTs that enrolled women with HELLP syndrome, whether antepartum or postpartum, to receive any corticosteroid versus placebo or no treatment. No language or publication date restrictions were made. We used a dual independent approach for screening titles and abstracts, full text screening, data extraction, and risk of bias assessment. Pairwise meta-analyses were conducted, where two or more studies met methodological criteria for inclusion. GRADE approach was used to assess certainty of evidence for the pre-specified outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Fifteen trials (821 women) compared corticosteroids with placebo or no treatment. The effect of corticosteroids is uncertain for the primary outcome i.e., maternal death (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.25 to 2.38, very low certainty evidence). The effect of corticosteroids is also uncertain for other important outcomes including pulmonary edema, dialysis, liver morbidity (hematoma, rupture, and failure), or perinatal death because of very low certainty evidence. Low certainty evidence suggests that corticosteroids have little or no effect on the need for platelet transfusion and may result in a slight reduction in acute renal failure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: In women with HELLP syndrome, the effect of corticosteroids vs placebo or no treatment is uncertain for patient-relevant outcomes including maternal death, maternal morbidity, and perinatal death. These uncertainties regarding this critical question should be addressed by adequately powered rigorous trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic review registration\u003c/strong\u003e: Center for Open Science, osf.io/yzku5\u003c/p\u003e","manuscriptTitle":"Corticosteroids for improving patient relevant outcomes in HELLP syndrome: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-06 13:48:53","doi":"10.21203/rs.3.rs-3663675/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-02-02T13:22:23+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"beaf04b6-84d8-49e5-a04c-365fe005eea7","date":"2024-01-08T14:56:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-12-25T21:10:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57496999-24d8-4f3b-af5a-ae60d9e34be0","date":"2023-12-11T15:02:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-12-09T04:22:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-03T13:43:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-12-03T13:34:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-03T13:30:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2023-11-25T13:05:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cbf1799e-4dbf-4bcc-9024-8d21545d3b40","owner":[],"postedDate":"December 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-01T16:19:27+00:00","versionOfRecord":{"articleIdentity":"rs-3663675","link":"https://doi.org/10.1186/s12884-024-06665-y","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2024-07-18 16:13:07","publishedOnDateReadable":"July 18th, 2024"},"versionCreatedAt":"2023-12-06 13:48:53","video":"","vorDoi":"10.1186/s12884-024-06665-y","vorDoiUrl":"https://doi.org/10.1186/s12884-024-06665-y","workflowStages":[]},"version":"v1","identity":"rs-3663675","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3663675","identity":"rs-3663675","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}