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Network meta-analysis of randomized controlled trials comparing the effectiveness of different treatments in reducing amniocentesis-associated pain and anxiety



This network meta-analysis compared different methods to determine which is most efficient at lowering pain and anxiety in women undergoing amniocentesis.


We looked through all published randomized controlled trials in the databases PubMed, Scopus, Web of Science, Cochrane, and EM base. Anxiety and pain were the predominant results. We used the R software version 4.2.1 to analyze the data.


We included a total of 20 studies, with sample sizes ranging from 60 to 570. Virtual reality was the most effective strategy for lowering pain during AC [MD = -1.30, 95% CI (-2.11, -0.49)]. In addition, paracetamol use was the most successful approach for lowering pain following AC [MD = -1.68, 95% CI (-1.99, -1.37)]. The use of H7 acupressure, however, was the strategy that significantly reduced anxiety following AC [SMD = -15.46, 95% CI (-17.77, -13.15)].


The most effective method for reducing pain is the combination of virtual reality with paracetamol. Whereas, the most effective way to reduce anxiety is to combine an ice gel pack with H7 acupressure before applying AC.

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Prenatal diagnosis is an approach used by obstetricians to predict possible outcomes for each pregnancy such as congenital infections, alloimmunization, fetal genetic disorders, and fetal lung maturity. Receiving a prenatal diagnosis of congenital defects is momentous and emotionally challenging for women [1]. However, it provides a crucial opportunity for early intervention and informed decision-making regarding the management and care of the fetus [2].

The detection of fetal defects such as aneuploidy, a structural chromosome problem, requires invasive prenatal procedures such as amniocentesis (AC) and chorionic villus sampling (CVS) [1]. Over 190,000 AC procedures were carried out in the United States in 1997, making it a regularly used technique in obstetric practice [3]. The process is performed between 15 – 20 weeks after pregnancy, and the results are available in 7 to 14 days [4]. However, it carries risks such as membrane leakage, infection, and abortion with rates of 1.6%, 0.05%, and 1%, respectively [1, 5, 6]. Therefore, prenatal counseling is essential to prevent avoidable risks and costs for pregnant women [7].

High levels of anxiety have been reported in women undergoing AC [8], which may be due to fear of pain, fetal injury, and abortion, as well as concern about unfavorable results [9]. Moreover, anxiety might prolong the duration of the AC procedure, and contribute to procedure complications [10]. Studies have established a direct correlation between anxiety levels and pain intensity [11], with severe anxiety associated with increased pain during AC and chorionic villus sampling [11,12,13,14].

Even the smallest hint of pain could make the patient uncooperative and prevent a successful prenatal diagnosis. Therefore, several studies looked into various methods to help women getting AC to feel less pain and anxiety. While some of these studies found their method helpful [15,16,17], others did not [18,19,20].

Therefore, our network meta-analysis (NMA) aims to compare different pain and anxiety management strategies to identify the most effective approach for minimizing discomfort during AC procedures.


We followed the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” standards to carry out this study [21]. Additionally, we strictly followed the steps provided in the “Cochrane Handbook for Systematic Reviews of Interventions” [22].

Literature search strategy

From inception till August 2022, the following keywords were used to search PubMed, Scopus, Web of Science, and Cochrane Central: amniocentesis, amniocenteses, anesthesia, “local anesthesia”, lidocaine, “xylocaine”, EMLA, “lidocaine-prilocaine”, lignocaine, prilocaine, dalcaine, xylocitin, xylesthesin, xyloneural, otocaine, music, cryoanalgesia, “cold therapy”, “virtual reality”, “H7 acupressure”, “ethyl chloride”, “aromatic therapy”, “Light Pressure Effleurage”, education, paracetamol, Panadol, cryotherapy, “cold pack”, “Subfreezing room”, “Subfreezing”, “Light leg rubbing”, massage, analgesia, analgesic. Additionally, manual searches were conducted on Google Scholar, ResearchGate, and

Inclusion and exclusion criteria

We took included all randomized controlled trials (RCTs) that enrolled patients undergoing AC, compared various analgesics with one another, with a control, or with a placebo, and reported on pain perception, and anxiety. We excluded in vitro research, overlapping datasets, book chapters, reviews, cohort studies, case–control studies, and non-English articles. Using Endnote software, duplicates were eliminated, and then titles and abstracts of the retrieved references were checked. Eligible articles were then retrieved and underwent full-text screening. Additionally, we manually searched the reference lists of the papers that were included for other potentially qualifying studies.

Data extraction

We extracted the summary data, the population's baseline demographics, and the efficacy outcomes from the included studies.


Effective outcomes included anticipated pain, pain during the procedure, pain after the procedure, anxiety before the procedure, anxiety after the procedure, post-procedure pain, and anxiety, as well as willingness to undergo AC again if necessary.

Risk of bias

We used the Cochrane risk of bias instrument (version 2) as described in chapter 8.5 of the Cochrane Handbook to evaluate the risk of bias [23]. The randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported result, and overall bias were part of the quality assessment process.

Data analysis

We used the meta and netmeta tools in the R program version 4.2.1, to carry out network analysis. For pooling continuous outcomes, we used the mean difference (MD) or standardized mean difference (SMD), and for dichotomous outcomes, we used the risk ratio (RR), both with a 95% confidence interval (CI). Chi-square and I-square tests were used to determine how heterogeneous the pooled studies were, with a heterogeneous connection being defined as one where the I2 > 50% and the Chi-square P-value < 0.1. For pooling homogeneous data, we utilized a common effect model, and for heterogeneous data, we used random-effect model.


Data collection and characteristics of included studies

One thousand seven hundred three articles were found during database searches: 447 from PubMed, 280 from Web of Science, 640 from Scopus, 54 from CENTRAL, and 282 from other databases. We filtered 1019 items and deleted 684 duplicates. 983 were eliminated through the title and abstract screening process, and 20 [15,16,17,18,19,20, 24,25,26,27,28,29,30,31,32,33,34,35,36,37] acceptable studies were found after the full-text screening of the 36 publications that remained. A flowchart of the database search and study selection procedure is shown in Fig. 1.

Fig. 1
figure 1

Preferred reporting item for systematic review and meta-analysis

The sample sizes of the included RCTs ranged from 60 to 570 people. Different approaches were contrasted with one another, with a control group, or with a placebo. The included subjects' average age ranged from 31.3 to 37.7 years, their average gestational age was 15.9 to 21.95 weeks, and their average body mass index was 22.93 to 27 kg/m2. The summary and the baseline characteristics of the included subjects in each study are shown in Tables 1 and 2.

Table 1 Summary of the included studies
Table 2 Baseline characteristics of included participants

Risk of bias assessment

High to low-quality studies were included. The majority of the examined studies exhibited a high risk of bias across the board. In Supplementary Materials, Figs. S1 and S2 depict a risk of bias graph and a risk of bias summary, respectively.


Anticipated pain (See Supplementary materials)

Anticipated pain was reported by 10 studies [17, 19, 20, 25,26,27, 29, 31, 32, 34]. However, we removed WAX et al. [25], because their study resulted in two isolated networks. The most efficient method for reducing anticipated pain when compared to control was using an ice gel pack before AC; this method was significantly better [MD = -0.30, 95% CI (-0.54, -0.06)]. Figure 2 displays the NMA forest plot.

Fig. 2
figure 2

Network meta-analysis forest plot of anticipated pain

Pain during AC (See Supplementary materials)

Pain during AC was reported by six studies [15, 17, 18, 27, 34, 35]. However, we excluded Rekawek et al. [18], because their study resulted in two isolated networks. Virtual reality (VR) was the most effective approach for lowering pain during AC when compared to control [MD = -1.30, 95% CI (-2.11, -0.49)] after which ice gel pack before and after AC was the next most effective [MD = -0.93, 95% CI (-1.62, -0.23)]. Figure 3 displays the NMA forest plot.

Fig. 3
figure 3

Network meta-analysis forest plot of pain during amniocentesis

Pain after AC (See Supplementary materials)

Pain after AC was reported by 14 studies [17,18,19, 24,25,26,27,28,29,30, 33,34,35,36]. However, WAX et al. [25], was excluded because their study resulted in two isolated networks. Paracetamol was the most effective approach for lowering pain after AC when compared to control [MD = -1.68, 95% CI (-1.99, -1.37)] after which ice gel pack before and after AC was the next most effective [MD = -0.91, 95% CI (-1.30, -0.51)] Fig. 4 displays the NMA forest plot.

Fig. 4
figure 4

Network meta-analysis forest plot of pain after amniocentesis

Anxiety before AC (See Supplementary materials)

Eight studies reported anxiety before AC outcome [16, 19, 20, 29, 31, 32, 36, 37] Ice gel pack before AC was the most effective approach for lowering anxiety before AC when compared to control [SMD = -2.30, 95% CI (-2.43, -2.17)] after which menthol was the next most effective [SMD = -2.00, 95% CI (-2.37, -1.63)]. Figure 5 displays the NMA forest plot.

Fig. 5
figure 5

Network meta-analysis forest plot of anxiety before amniocentesis

Anxiety after AC (See supplementary materials)

Anxiety after AC was reported in five studies [16, 29, 33, 36, 37]. Katsogiannou et al. [33], were excluded because their study resulted in two isolated networks. H7-Acupressure was the most effective approach for lowering anxiety after AC when compared to control [SMD = -15.46, 95% CI (-17.77, -13.15)] after which psychological intervention was the next most effective [SMD = -6.78, 95% CI (-10.47, -3.09)]. Figure 6 displays the NMA forest plot.

Fig. 6
figure 6

Network meta-analysis forest plot of anxiety after amniocentesis

Post-procedure pain and anxiety (See Supplementary materials)

Post-procedure pain and anxiety were reported in three studies [20, 31, 32]. The use of Ice gel pack before AC was the most effective method for reducing post-procedure pain and anxiety when compared to the control [MD = -0.60, 95% CI (-0.92, -0.28)]. Figure 7 displays the NMA forest plot.

Fig. 7
figure 7

Network meta-analysis forest plot of post-procedure pain and anxiety

Undergoing AC again if indicated (See Supplementary materials)

This outcome was reported in three studies [20, 24, 26]. Compared to the control group, the available strategies were not significant. Figure 8 displays the NMA forest plot.

Fig. 8
figure 8

Network meta-analysis forest plot of Undergoing amniocentesis again if indicated

Table 3 Summarizes the findings of the main outcomes.

Table 3 Summary of the main findings of the NMA


The present network meta-analysis compared different strategies to reduce pain and anxiety in prenatal diagnostic procedures. The VR intervention was the most successful in reducing pain during AC. The literature reported that paying attention to pain might affect the pain experience, can be used to explain this. It implies that deflecting attention away from pain can lower perceived pain levels [38]. Distraction is to make a painful stimulus seem less intense since people can’t focus on several sensory inputs at once [39]. Additionally, the VR’s multiple senses may impede nociception flow and lessen pain perception [40]. With a VR headset on, patients can leave the clinical setting and visit another world unconnected to the treatment and any potential pain [41]. Although the exact method by which VR relieves pain is yet unknown, given the well-known connection between pain and emotions, the analgesic impact of VR may be mediated by brain systems [40]. Additionally, VR is simple to use, reasonably priced, and has the benefit of no negative side effects.

The popular pain reliever paracetamol is safe for use during pregnancy [42]. It was successful in lowering pain following AC; however, it was ineffective during AC. The timing of drug intake before the surgery may help to explain this [17]. Further research is needed to determine the ideal premedication period. However, paracetamol has a number of benefits including broad therapeutic applicability, good tolerability, and good absorption after oral administration [43].

The anti-swelling and analgesic effects of cold therapy are widely established for treating soft tissue injuries [44], postoperative pain from gynecologic surgery [45], and perineal pain following vaginal delivery [46]. Reduced soft tissue temperature can have an analgesic effect by slowing the speed at which pain is transmitted. Therefore, applying an ice gel pack before and after receiving AC was useful in lowering pain only after receiving AC, not during receiving AC. Additionally, applying an ice gel pack prior to the AC helped to lower anxiousness. However, a prolonged or excessive exposure might have negative effects like burns and ulcers [46].

H7 Acupressure proved to be successful in lowering anxiety after AC. The results can be explained by a number of various mechanisms. Cortisol and stress are associated in that as stress rises, cortisol also rises. In the hypothalamic–pituitary–adrenal axis, the stimulation of acupressure points alters hormonal-neuronal responses, which in turn controls cortisol output and induces calm. Additionally, by activating the anterior pituitary, acupressure can boost serotonin and dopamine release [47]. Serotonin and dopamine levels in the plasma rise, which reduces cortisol synthesis [48]. In addition, the stimulation of the acupressure point releases endorphins, which peak 30 min after the stimulation begins and remain elevated for 10 h. Similarly, serotonin levels are raised, and endorphins are released when the H7 acupoint is stimulated vigorously and repeatedly [49]. However, other factors must be taken into account while using this method as they may have an impact on the outcomes, such as the target population, the acupressure points employed, and the length of the acupressure.


The majority of the included studies had a high overall risk of bias, which could have an impact on the study’s findings. We exclude some trials to conduct a single network meta-analysis.


VR was the most effective method for reducing pain during AC, whereas paracetamol was the best method for reducing pain following AC. Additionally, H7 Acupressure was the most effective for reducing anxiety after AC, while an ice gel pack was the best for reducing anxiety before AC. By combining and integrating these methods, healthcare workers will have the potential to significantly aid women who are having AC.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.



Network meta-analysis




Visual reality


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A.M.M. conceptualized the research idea, coordinated the resources, performed data extraction, performed the quality assessment, conducted the network meta-analysis, and participated in writing and editing the final manuscript. A.R.A. performed data extraction, performed the quality assessment, conducted the network meta-analysis, and participated in writing and editing the final manuscript.

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Correspondence to Abdallah R. Allam.

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Mahmoud, A.M., Allam, A.R. Network meta-analysis of randomized controlled trials comparing the effectiveness of different treatments in reducing amniocentesis-associated pain and anxiety. BMC Pregnancy Childbirth 23, 807 (2023).

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