Dexamethasone and post-dural puncture headache in women who underwent cesarean delivery under spinal anesthesia: A systemic review and meta-analysis of randomized controlled trials

Background Post-dural puncture headache is a common complication after spinal anesthesia for women who undergo cesarean delivery. Intravenous (IV) dexamethasone has been used to reduce the incidence and severity of PDPH with controversial results. This Systemic review and meta-analysis aimed to assess the effects of IV dexamethasone on PDPH. Methods This study is reported as per Preferred Reporting Items for Systematic and Meta-analysis. The primary outcome was the incidence and severity of PDPH. The secondary outcome variables were the postoperative total analgesic requirement and incidence of nausea and/or vomiting. Twelve randomized controlled trials with a total of 1548 women were included. Results Intravenous (IV) dexamethasone had no effect on the incidence of PDPH (OR = 0.64; CI, 0.39 to 1.05; I2 = 71%, P = 0.08). Intravenous dexamethasone did not show a significant difference in the incidence of PDPH at 24 h at 48 h, and within one week postoperatively with p-values of less than 0.05. In a random-effect model, a pooled analysis showed that IV dexamethasone had no effect on the severity of PDPH in VAS (MD = 0.78; CI, −2.27 to 0.71; I2 = 98%, P = 0.30). Conclusion Intravenous dexamethasone failed to decrease the incidence and severity of PDPH in women who underwent cesarean delivery under spinal anesthesia.


Description of the condition
Spinal anesthesia has been the anesthetic technique of choice for cesarean delivery unless it is contraindicated [1][2][3][4]. Post-dural puncture headache (PDPH) is among common spinal anesthesia-related side effects for mothers who underwent cesarean delivery. It might appear several hours to a week after dural puncture, and could be a cause of poor patient outcome [5][6][7][8]. (see Table 1) Dural puncture and subsequent cerebrospinal fluid (CSF) leakage is the most accepted mechanism for the induction of headache [9][10][11][12]. CSF leakage through the dural hole and reduction in CSF pressure lessens the cushioning effect of the brain, allowing it to sag within the intracranial vault and stimulation of dural pain receptors especially in an upright position [13][14][15].
There were different techniques to prevent and treat PDPH like bed rest, hydration, non-opioid analgesics, caffeine, codeine, and steroids [16][17][18][19]. Different studies tried to show the effects of intravenous dexamethasone and found controversial results. Therefore, this study aims to find the pooled effects of intravenous dexamethasone on PDPH.

How the intervention might work
The exact mechanism of action of how dexamethasone helps in reducing the incidence and severity of PDPH and pain is not well established. Intravenous dexamethasone might reduce PDPH and pain by inhibiting the inflammatory process which is important in the pain cascading pathway [20][21][22][23][24][25].

Why it is important to do this SR and MA
There were controversial results regarding the effect of intravenous dexamethasone on reducing the occurrence and severity of PDPH, which necessitates this SR and MA. Some studies showed that dexamethasone increased significantly the frequency and severity of PDPH after cesarean delivery [26,27], other studies dexamethasone fail to reduce the incidence and severity of PDPH in different dosage [28,29], while other studies show that steroids decrease its incidence and severity [1,30,31]. There were SR and MA regarding the effects of IV dexamethasone on the incidence and severity of PDPH for women undergoing cesarean delivery under regional anesthesia. This SR and MA address the effectiveness of IV dexamethasone on PDPH occurrence and severity, and it might be supportive evidence for the scientific world. This Systemic review and meta-analysis aimed to assess the effects of IV dexamethasone administration on PDPH occurrence and severity.

Criteria for considering studies for this review
This study is reported as per Preferred Reporting Items for Systematic and Meta-analysis [32] and it is a high-quality systemic review based on AMSTAR 2 checklist self-evaluation [33]. Twelve randomized controlled trials with a total of 1548 patients were included. This SR and MA is registered in research registry with registration number revie-wregistry1063 available at https://www.researchregistry.com/browse -the-registry#registryofsystematicreviewsmeta-analyses/registryofsyste maticreviewsmeta-analysesdetails/5ff9a85073f73d001b5b2283/

Types of studies
Relevant articles were identified by four authors through their titles and abstracts from databases (Medline, Cochrane library, and Google scholar) and hand search. The clinical trials, free full texts, and human species were included.

Types of participants
The participants included in this SR and MA were women who underwent cesarean delivery under Spinal anesthesia.

Types of interventions
Intravenous dexamethasone is the intervention group in this SR and MA while normal saline is considered as a placebo group.

Types of outcome measures
The primary outcome in this SR and MA were the incidence of PDPH and severity of PDPH in VAS while the secondary outcomes were a total postoperative analgesic requirement and the incidence of postoperative nausea and/or vomiting.

Electronic searches
The MEDLINE, Cochrane library, and google scholar from inception to October 2020, were searched for clinical trials comparing the effectiveness of intravenous dexamethasone versus placebo on the effect of PDPH.
We searched the following databases for the literature of the English language by using the following terms: (

Searching other sources
The hand search was applied to studies to identify additional literature by using key terms and via cross-references, links, and citations in google scholar and PubMed.

Exclusion criteria
Studies that compared IV dexamethasone with other interventions of PDPH without a control group, IV dexamethasone without spinal anesthesia, IV dexamethasone with other additives.

Data extraction and management
Authors' names with a year of publication, study characteristics, type of surgery, type of anesthesia, a dose of dexamethasone, normal saline dose, and outcomes were extracted.
The titles and abstracts of all references identified in the searches were reviewed by four authors. Studies that are not met inclusion criteria were excluded. Full paper copies of included studies will be reviewed by four authors independently, and decisions made regarding selection/rejection. The disagreements arising were resolved by the discussion of all the reviewers.

Assessment of risk of bias in included studies
The risk of bias was assessed by using the Cochrane risk of bias tool and noted as being low, unclear, or high risk by the four researchers independently. Trials were rated according to random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. The disagreements arising were considered and resolved by discussion. Concerning incomplete outcome data, studies were classified as low risk of bias if the follow-up rate was ≥80%. For selective outcome reporting bias, studies were classified as low risk of bias if trials were preregistered and their protocols were available for full review [32].

Statistical analysis
Analyses were done with Review Manager version 5.4.1; Cochrane Library, Oxford, UK. Dichotomous variables (incidence of PDPH and incidence of PONV), and continuous variables (severity of PDPH in VAS and analgesic requirement in mg) were reported as odds ratio and mean differences with 95% CIs respectively. The I 2 test was used to assess the Heterogeneity of the outcomes. A fixed-effect model and a randomeffect model were used when I 2 <50% and I 2 >50% respectively. The funnel-plot analysis was used to assess potential publication biases [46].

Description of studies
The primary literature search initially identified 3247 articles. After duplicates were removed 2567 were left for further screening by abstract and title which gave us 52 full text available clinical trials of human studies for inclusion. Then 12 studies were used for qualitative (SR) while 10 studies were used for quantitative (MA) (Fig. 1).
The risks of bias for included studies were evaluated by four authors and discussed as low risk, high risk, and unclear risk. Hamzei et al. [38] high risk of bias in blinding of participants and personnel, and blinding of outcome assessment. Motaghi et al. [43] low risk of bias in random sequence generation, and reporting bias, while the unclear risk of bias in allocation concealment, blinding of participants and personnel, and blinding of outcome assessment and in other biases (Fig. 2).

Assessment of publication bias
A funnel plot was created for the primary outcome and visually inspected to assess publication bias. A symmetrical inverted funnel plot shows no publication bias.

Incidence of nausea and/or vomiting
The incidence of PDPH was reported by three RCTs [37,39,41]. In a random-effect model, a pooled analysis showed that intravenous dexamethasone has no statistically significant effect on the prevalence of nausea and/or vomiting (OR = 0.39; CI, 0.09 to 1.69; I 2 = 82%, P = 0.21) (Fig. 6).

Discussion
Intravenous dexamethasone might reduce the incidence and severity of PDPH and pain through glucocorticoid steroid receptors that cause vasoconstriction and reduce the absorption of administered local anesthetic, inhibiting the production of inflammatory mediators [21,25]. There were controversial results regarding the effect of intravenous dexamethasone on reducing the occurrence and severity of PDPH, which necessitates this SR and MA.
The results of our systemic review and meta-analysis revealed that intravenous dexamethasone failed to decrease the occurrence and the severity of PDPH in women who underwent cesarean delivery under spinal anesthesia. Contrary to this SR and MA researches done by Ona   Fig. 3. Effects of intravenous dexamethasone on the incidence of PDPH. et al., Yousefshahi et al., showed that IV dexamethasone increases the occurrence of PDPH [26,27]. In agreement with this SR and MA studies done by Yang et al., and Mahmoud et al. found that the use of IV dexamethasone has no statistically significant benefit to the occurrence and severity of PDPH [28,29], while some studies showed that steroids decrease its incidence and severity [1,30,31]. There were SR and MA regarding the effects of IV dexamethasone on the incidence and severity of PDPH for women undergoing cesarean delivery under regional anesthesia.
This SR and MA address the effectiveness of IV dexamethasone on PDPH occurrence and severity, and it might be supportive evidence for the scientific world. This Systemic review and meta-analysis aimed to  assess the effects of IV dexamethasone administration on PDPH occurrence and severity.

Conclusions
Intravenous dexamethasone failed to decrease the incidence and severity of PDPH in women who underwent cesarean delivery under spinal anesthesia.

Limits and challenges
During this study, we have encountered the difficulty of found freely available studies and we tried to search them by using different databases.