ABSTRACT

To evaluate the efficacy of lidocaine local analgesia on maternal pain reduction during amniocentesis. Web of Science, Scopus, PubMed, and CENTRAL databases were screened from inception and updated in July 2022. The included randomized controlled trials (RCTs) were evaluated for the risk of bias via the Cochrane tool. The primary outcome was pain perception using the 10 cm visual analog scale, and was summarized as mean difference (MD) with 95% confidence interval (CI) in a random-effects model. Subgroup analysis was performed according to the mode of administration. Meta-analysis was done via Review Manager software. We included five RCTs totaling 1004 women (lidocaine arm n=502 patients and control arm n=502 patients). Overall, there was no significant difference between both arms [MD=-0.21, 95% CI (-0.48, 0.07), p=0.80]. The pooled analysis showed homogeneity (p=0.13, I²=43%). Subgroup analysis according to the mode of administration showed that pain perception did not significantly differ between both arms when lidocaine was employed as injection [n=3 RCTs, MD=-0.26, 95% CI (-0.76, 0.23), p=0.29] or non-injection [n=2 RCTs, MD=-0.18, 95% CI (-0.55, 0.18), p=0.33]. The pooled analyses showed heterogeneity (p=0.05, I²=66%) and homogeneity (p=0.27, I²=19%), respectively. There was no noteworthy change concerning maternal pain perception between the lidocaine and control arms. Most women reported just minimal discomfort during amniocentesis. Counseling should educate patients that the pain they might experience during amniocentesis is comparable to venous blood sampling.

Introduction

Amniocentesis is an invasive procedure employed primarily in prenatal diagnosis⁽¹⁾. Pain is a common concern among pregnant women undergoing amniocentesis⁽²⁾. The most popular approach for evaluating pain perception with high reliability during and after procedures is the visual analog scale (VAS)^(2,3).

Currently, there are two main approaches for pain relief during amniocentesis, namely, pharmacological agents and non-pharmacological methods⁽²⁾. Among the pharmacological agents, lidocaine is a common local anesthetic agent for pain relief⁽⁴⁾.

Several randomized controlled trials (RCTs) explored the capacity of lidocaine-mediated pain relief among pregnant women undergoing amniocentesis^(5,6,7,8,9). However, the findings of these RCTs were limited by various shortcomings, such as small sample sizes, relatively poor quality of studies, different routes of administration, and inconsistent reported results. All in all, the analgesic efficacy of lidocaine among pregnant women undergoing amniocentesis remains poorly delineated. Moreover, no meta-analysis report has been published to assess the clinical utility of lidocaine during amniocentesis. Such research is enormously imperative to generate evidence-based recommendations that will inform obstetric practice.

Therefore, the purpose of this contemporary investigation is to determine whether lidocaine administration has any analgesic effect on reducing maternal pain during amniocentesis when contrasted with a control treatment. The hypothesis is that the lidocaine administration will correlate with better maternal analgesia than the control treatment during amniocentesis.

In this study, we followed the steps of the Cochrane Handbook for Systematic Reviews of Interventions⁽¹⁰⁾ as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses⁽¹¹⁾. Ethical approval was exempted.

Search Approach

Web of Science, Scopus, PubMed and Cochrane Central Register of Controlled Trials were searched until July 2022. The search approach comprised (amniocentesis OR amniocenteses) AND (anesthesia OR “local anesthesia” OR lidocaine OR xylocaine OR EMLA OR “lidocaine-prilocaine” OR lignocaine OR prilocaine OR dalcaine OR xylocitin OR xylesthesin OR xyloneural OR “2-2EtN-2MePhAcN” OR otocaine).

Inclusion and Exclusion Criteria

The inclusion criteria comprised (a) patients: Females undergoing amniocentesis, (b) intervention: Local analgesia using lidocaine, (c) comparison: Placebo or no treatment, (d) outcome: Pain perception, (e) study design: RCTs. The exclusion criteria comprised non-RCT study designs and studies published in languages other than English.

Screening and Study Selection

The retrieved citations were sequentially subjected to removal of duplicates, title/abstract examination, and lastly full-text inspection to determine final eligibility. Two independent authors completed the task and resolved the conflicts.

Quality Assessment

Quality assessment was completed using the revised version of the Cochrane Risk of Bias assessment tool⁽¹²⁾. Two authors performed the quality assessment independently for all RCTs to assess the risk of bias of the included studies according to the second version of the Cochrane Risk of Bias assessment tool⁽¹²⁾. “Low,” “some concerns,” or “high” risk of bias judgments were assigned to each domain. Two independent authors completed the task and resolved the conflicts.

Data Extraction and Outcome

Data extraction of studies comprised country, trial period, total number of patients, the intervention arm, the control arm, and type of administration. Data extraction of patients comprised the number of patients per arm, age, gestational age (weeks), parity, body mass index (kg/m²), weight (kg), and height (in). The primary outcome included pain perception by using the 10 cm VAS. Two independent authors completed the task and resolved the conflicts.

Meta-analysis

The primary outcome was analyzed via the Inverse-Variance method and reported as mean difference (MD) with 95% confidence interval (CI). The random-effects model of statistical analysis was employed.  I² values of more than 50% and the chi-square test (p<0.1) were indicative of high heterogeneity. Forest plots were generated through the Review Manager software, version 5.4.

Results

Literature Search

Overall, 203 citations were retrieved after the omission of duplicates. Additionally, nine articles progressed to full-text screening, of which five studies met the eligibility criteria and were included in the quantitative synthesis (Figure 1)^(5,6,7,8,9).

Figure 1

Summary of the Included Studies

We included five RCTs^(5,6,7,8,9) with 1004 patients (lidocaine arm n=502 patients and control arm n=502 patients). Three RCTs used lidocaine as injection^(5,6,7) and two RCTs used it as non-injection [spray⁽⁸⁾ and cream⁽⁹⁾]. Table 1 and Table 2, respectively, summarize the major features of the included studies and participants.

Table 1

Table 2

Quality Assessment

Three RCTs achieved an overall low risk of bias^(6,8,9). One RCT⁽⁷⁾ was evaluated as “some concerns” in the domain of randomization because it provided no information about the randomization process and allocation concealment. Lastly, one RCT⁽⁵⁾ was judged as high risk of bias in the domain of randomization because it provided no information about the randomization process and allocation concealment, and baseline imbalance suggested a problem in the randomization process (Figure 2).

Figure 2

Meta-Analysis of Pain Perception (VAS)

All RCTs reported pain perception^(5,6,7,8,9). Overall, there was no significant difference between both arms [MD=-0.21, 95% CI (-0.48, 0.07), p=0.80]. The pooled analysis showed homogeneity (p=0.13, I²=43%). Subgroup analysis according to the mode of administration showed that pain perception did not significantly differ between both arms when lidocaine was employed as injection [n=3 RCTs, MD=-0.26, 95% CI (-0.76, 0.23), p=0.29] or non-injection [n=2 RCTs, MD=-0.18, 95% CI (-0.55, 0.18), p=0.33]. The pooled analyses showed heterogeneity (p=0.05, I²=66%) and homogeneity (p=0.27, I²=19%), respectively (Figure 3).

Figure 3

Discussion

Summary of the Main Findings

During amniocentesis, this meta-analysis of five RCTs showed no significant difference concerning maternal pain perception between the local analgesia group with lidocaine and the control group.

Interpretation of Findings

Lidocaine is among the most potent anesthetic substances frequently used in medical procedures⁽⁴⁾. Lidocaine spray is a practical approach that is simple to employ in clinical practice for relieving pain in the skin or mucosa. A previous study showed that women who received lidocaine spray experienced less pain than those who received a placebo⁽⁸⁾. Women who are highly fearful of the procedure or have low pain tolerance may be given the option of lidocaine spray⁽⁸⁾. Some restrictions apply to this investigation; although the lidocaine spray starts immediately, the one-minute wait before the procedure may not have been long enough to provide the required anesthetic effect⁽⁸⁾. However, waiting for just a minute would prevent any intervening fetal movement that would change the targeted puncture site on the mother’s abdomen⁽⁸⁾.

In another trial on lidocaine cream⁽⁹⁾, the results showed that patients’ perceptions of worry and pain were mild before amniocentesis. There were no discernible variations in the VAS values between the two arms for anxiety (before procedure), anticipated pain, and pain (after procedure). Based on the distinction between the VAS pain levels before and after the procedure, the findings showed that lidocaine-prilocaine cream did not significantly reduce amniocentesis-related pain⁽⁸⁾. The local anesthetic effect can explain this result as it lowers cutaneous pain but not peritoneal discomfort. The peritoneum and uterus are the primary sources of pain during the procedure⁽⁸⁾.

According to data from a previous study by Van Schoubroeck and Verhaeghe⁽⁵⁾, most patients (59%) believed that the pain induced by amniocentesis was analogous to that induced by venipuncture. After injecting a local anesthetic into the dermis and subcutaneous tissues, they noticed no variance in pain or distress during amniocentesis⁽⁵⁾. This finding is crucial since skipping local anesthetics saves both time and money. It takes time to aspirate the local anesthesia, slowly inject it and wait for it to take effect. Also, it is possible to avoid paying 3.26 EUR ($3.41) for each patient for a single syringe, two needles, and local anesthesia material (lidocaine)⁽⁵⁾.

In the investigations by Van Schoubroeck and Verhaeghe⁽⁵⁾ and Gordon et al.⁽⁶⁾, lidocaine was locally injected before amniocentesis, but neither group reported that this technique reduced pain. The verbal rating scale of 1 to 4 was employed in the study by Van Schoubroeck and Verhaeghe⁽⁵⁾, however without blinding. In the study by Gordon et al.⁽⁶⁾, 66% of the local anesthetic arm and 53% of the control arm had the procedure performed by maternal-fetal medicine staff. They also discovered that women felt less discomfort when staff members performed the procedure. This result might be confusing since the women experienced pain due to local penetration. Although the study by Van Schoubroeck and Verhaeghe⁽⁵⁾ was a quasi-randomized trial, the results of the investigation by Gordon et al.⁽⁶⁾ showed no evidence of considerable heterogeneity. The amniocentesis procedures were not wholly carried out by doctors with the exact clinical expertise. Still, because in the Gordon et al.⁽⁶⁾ study, maternal-fetal medicine staff carried out more operations involving an anesthetic, this might have influenced the study in favor of an affirmative conclusion regarding the utility of local anesthesia.

Study Limitations

The usage of LA for pain management is not yet supported by sufficient evidence (i.e., small number of trials and sample sizes). Our study only evaluated post-procedural pain and did not analyze post-procedural anxiety. Also, publication bias was not explored secondary to the few studies included.

Conclusion

There was no noteworthy change concerning maternal pain perception between the lidocaine and control arms. Most women reported just minimal discomfort during amniocentesis. Counseling should educate patients that the pain they might experience throughout the procedure is comparable to discomfort during venipuncture.