|Year : 2015 | Volume
| Issue : 2 | Page : 54-61
The effect of anesthetic technique for transvaginal ultrasound-guided oocyte retrieval on reproductive outcomes: A systematic review and meta-analysis
Bharatram Vasudevan, Anuradha Borle, Preet Moinder Singh, Rashmi Ramachandran, Vimi Rewari, Anjan Trikha
Department of Anaesthesia, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||11-Sep-2015|
Dr. Anuradha Borle
Department of Anaesthesia, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
The effects of various anesthetic techniques used for transvaginal ultrasound-guided oocyte retrieval (TUGOR) on reproductive outcomes remain controversial. Some studies have reported adverse effects due to nitrous oxide, propofol, and other general anesthetic drugs, whereas others have found them to be safe. The aim of the current meta-analysis is to pool the data available from studies comparing effects of a loco-regional technique against general anesthesia (GA)/intravenous sedation on reproductive outcomes when used for TUGOR. We searched PubMed, EMBASE, Cochrane Register, Google Scholar, and Scopus for studies that evaluated loco-regional anesthesia against GA and reported data on fertilization rate, cleavage rate, and pregnancy rate. A total of eight studies involving 1416 women undergoing TUGOR were identified. The risk of bias was high in most studies, and only two were randomized controlled trials. The loco-regional and the general anesthetic techniques used in these studies varied widely. Pooled odds ratio comparing general versus loco-regional groups for the fertilization rate was 0.939 (95% confidence interval [CI] 0.812-1.086; P > 0.05) and for the cleavage rate was 1.046 (95% CI 0.902-1.213; P > 0.05). Loco-regional anesthesia was found to be favorable to GA with regard to the pregnancy rate (pooled odds ratio was 0.701 (95% CI 0.543-0.905; P < 0.05). No serious complication was reported. Though the pregnancy rate was found to be higher in the loco-regional group, the superiority of one technique over the other cannot be confirmed based on the available quality of evidence and requires further well-conducted trials.
Keywords: Infertility anesthesia, ovum pickup anesthesia, sedation for in vitro fertilization
|How to cite this article:|
Vasudevan B, Borle A, Singh PM, Ramachandran R, Rewari V, Trikha A. The effect of anesthetic technique for transvaginal ultrasound-guided oocyte retrieval on reproductive outcomes: A systematic review and meta-analysis. J Obstet Anaesth Crit Care 2015;5:54-61
|How to cite this URL:|
Vasudevan B, Borle A, Singh PM, Ramachandran R, Rewari V, Trikha A. The effect of anesthetic technique for transvaginal ultrasound-guided oocyte retrieval on reproductive outcomes: A systematic review and meta-analysis. J Obstet Anaesth Crit Care [serial online] 2015 [cited 2019 Jun 16];5:54-61. Available from: http://www.joacc.com/text.asp?2015/5/2/54/165131
| Introduction|| |
In vitro fertilization (IVF) started more than 30 years ago and has undergone numerous advances leading to improved patient outcomes. Ovarian stimulation, oocyte retrieval, IVF after sperm processing, and embryo transfer constitute the major steps of IVF. Oocyte retrieval is an important step that requires an anesthesiologist's involvement. Though initially performed by laparoscopy, egg collection is now universally done by the transvaginal ultrasound-guided oocyte retrieval (TUGOR) technique. TUGOR is minimally invasive and requires shorter time compared to previous techniques. Yet, it is a potentially stressful and painful procedure and thus requires some form of analgesia with or without sedation. Anesthetic techniques have also undergone numerous advancements in the past 30 years, and various modalities have been used for oocyte retrieval. These include local anesthesia, regional anesthesia, general anesthesia (GA), conscious sedation, and even alternative techniques such as electro-acupuncture. The anesthetic agents used have been found in significant concentrations in the follicular fluid in animal and human studies and can influence the reproductive outcome. Clinical studies comparing the effect of different anesthetic techniques on reproductive outcome have yielded contradictory results. A meta-analysis published previously comparing the effects of GA and loco-regional anesthesia on reproductive outcomes found no significant difference in the cleavage rate or pregnancy rate using both techniques.  It included trials using both laparoscopy and TUGOR for oocyte retrieval. A recent Cochrane review evaluated randomized controlled trials (RCTs) comparing different methods of conscious sedation and analgesia and found no superior technique of providing conscious sedation and analgesia.  The current meta-analysis is updated with newer literature, evaluated studies which used only TUGOR for egg collection. The aim of the present study was to evaluate clinical trials that compared the effects of loco-regional anesthesia with GA or intravenous (IV) sedation on reproductive outcomes when used for TUGOR.
| Materials and Methods|| |
The current study was done in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines [Figure 1]. A Population Intervention Control and Outcome Study design protocol was used as the primary criterion to identify the studies [Table 1].
|Figure 1: Preferred reporting items for systematic reviews and meta-analyses flow diagram illustrating flow chart outlining retrieved, excluded, and included studies|
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Two authors conducted an independent search of online literature available on PubMed, EMBASE, Cochrane Center Register of Controlled trials, Google Scholar, and Scopus for published studies until May 2015. We also searched references in published meta-analyses on similar topics. The following terms were used for searching: "Anesthesia for, in vitro fertilization," "oocyte retrieval," "IVF," "general anesthesia," "local anesthesia," "regional anesthesia," "conscious sedation," "epidural," "spinal," "paracervical block," and "conscious sedation". Studies published in peer-reviewed journals comparing any local or regional anesthetic techniques with any type of GA or IV sedation and had reported the reproductive outcomes of fertilization rate or cleavage rate or pregnancy rate were considered. The decision to include a potential study was based on an independent assessment by two authors working independently. Disagreements were settled by consensus and arbitration by a third researcher, if necessary. A formal quality assessment for bias in studies was also carried out by an independent researcher.
Data extraction and statistical analysis
The following data were collected from each study - country, year of publication, study design, sample size, anesthetic techniques used and drug dosages, outcomes, and any reported complications. Fertilization rate, cleavage rate, and pregnancy rate were the reproductive outcomes studied. The odds ratio was calculated for each outcome. Statistical analysis of pooled data was performed using comprehensive meta-analysis, version 2 (Biostat Inc, USA). Results were expressed as a pooled odds ratio with 95% confidence interval (95% CI) for each outcome. P < 0.05 was considered statistically significant. Meta-analysis was initially performed with fixed-effect modeling and eventually with random-effect modeling after heterogeneity assessment. The extent of heterogeneity was quantified using the I2 value. Values of I2 <40% were considered unimportant, 40-60% were considered to represent moderate heterogeneity, 60-90% represented high heterogeneity, and values >90% represented considerable heterogeneity. Publication bias was evaluated using funnel plot.
| Results|| |
A total of 365 records were found by the search in the aforementioned databases. Duplicates were then removed electronically using endnote. After record screening and assessing full text articles for eligibility, eight studies fitted with the inclusion criteria and measured the desired outcomes [Table 2]. Of these, 3 were retrospective analyses, 2 were prospective RCTs, and 3 were prospective nonrandomized trials of which one was a matched case-controlled study. ,,,,,,, A total of 1416 women undergoing TUGOR were identified in these eight studies comparing a loco-regional anesthetic technique with a general anesthetic technique. One study by Piroli et al. compared four different anesthetic techniques (EMLA, propofol, thiopentone, and sevoflurane-based anesthesia) that led to three separate comparisons of local anesthesia versus GA.  The loco-regional techniques in the different studies varied and included two studies using epidural anesthesia, two using subarachnoid block, three using paracervical block (PCB), and one using local anesthesia with EMLA cream. The general anesthetic techniques varied widely between the studies and included both inhalational and IV agents, the most popular agent being propofol. One study just used IV remifentanil to induce sedation.  Majority of the studies had a high risk of bias as only two studies were RCTs. There were no serious side effects reported in the studies. The results of effects on reproductive outcomes are mentioned below.
The fertilization rate was available from five studies comprising a total of 620 patients leading to seven comparisons. ,,,, The pooled odds ratio was 0.939 (95% CI 0.812-1.086). The P value was not significant. The I2 value for heterogeneity was 0% [Figure 2].
|Figure 2: Forest plot showing pooled odds ratio for fertilization rate comparing general anesthesia/intravenous sedation with loco-regional anesthesia. No significant difference (P > 0.05)|
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The odds ratios for the cleavage rate could be obtained from only three studies comprising 450 patients leading to five comparisons. ,, The pooled odds ratio calculated was 1.046 (95% CI 0.902-1.213) and was not statistically favoring any of the two groups (P > 0.05). The value for heterogeneity was 0% [Figure 3].
|Figure 3: Forest plot showing pooled odds ratio for cleavage rate comparing general anesthesia/intravenous sedation with loco-regional anesthesia. No significant difference (P > 0.05)|
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Seven studies comprising 1316 patients gave the pregnancy rate. ,,,,,, The pooled odds ratio of the seven comparisons was 0.701 (95% CI 0.543-0.905) favoring loco-regional anesthesia over GA. The P value was significant at 0.006. There was moderate heterogeneity among the studies with an I2 value of 47.731% [Figure 4].
|Figure 4: Forest plot showing pooled odds ratio for pregnancy rate comparing general anesthesia/intravenous sedation with loco-regional anesthesia. Result favors loco-regional anesthesia (P < 0.05)|
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| Discussion|| |
Following the removal of the cumulus cells, all oocytes are examined for maturation, and matured oocytes were fertilized by the standard intracytoplasmic sperm. The proportion of ova that eventually became fertilized contributes to the fertilization rate. The rate of mitotic division in thus generated embryo determines the quality of embryo formed via IVF and the rate of division is estimated by the cleavage rate. In this study, we found that loco-regional techniques have been associated with significantly better pregnancy rate than GA though no difference could be demonstrated in fertilization and cleavage rates.
TUGOR is generally a short, day-care procedure, and different anesthetic techniques have been used for providing analgesia. The reproductive outcome is the most important concern in any IVF program and, therefore, the effect of different anesthetics on these outcomes is a subject of major debate. All anesthetic drugs have been found in the follicular fluid and thus can influence fertilization and embryo development. ,,, Drugs used for GA are of more concern, as local anesthetics used usually do not reach follicular fluid in significant concentrations. But local anesthetic techniques can lead to decreased comfort levels of the patient and the gynecologist and have been associated with a lesser number of retrieved oocytes. Conscious sedation with or without loco-regional anesthesia is increasingly being used now. 
Of the drugs used for GA, the role of nitrous oxide (N 2 O) remains controversial. Two older studies included in this meta-analysis have used N 2 O. , While Botta et al. found no significant difference when comparing epidural anesthesia with propofol and N 2 O-based GA, Gonen et al. reported decreased pregnancy and delivery rates with N 2 O-and halothane-based GA. However, they found no difference in embryo yield or quality of embryos. They concluded that the deleterious effects of N 2 O-based GA manifests late after embryo transfer in their retrospective analysis.  This is consistent with the pooled results of this meta-analysis. On the contrary, other studies using N 2 O by Rosen et al., Matt et al., and Hadimioglu et al. found it to be safe. ,,
Halogenated inhalational agent-based GA used in studies by Azmude et al. and Aghaamoo et al., which were included in this review, also report decreased pregnancy rates. , The duration of anesthesia in these two studies were, however, longer compared to other studies. In a study by Piroli et al., Sevoflurane group had the lowest number of good embryos compared to EMLA, propofol, and thiopentone. 
Propofol was reported to have adverse effects on the cleavage rate in earlier animal studies. , Various studies have found a follicular accumulation of propofol with increasing dose and duration of usage. , Christiaens et al. compared propofol with PCB and noted a lower implantation rate with propofol though it was not statistically significant. However, embryological data were not impaired with propofol.  Piroli et al. observed lower fertilization rate with propofol when compared with EMLA and thiopentone. They also observed the highest rate of anomalous fertilization in the propofol group.  Whereas Bümen et al., in his RCT, observed a higher number of retrieved oocytes and pregnancy rate in the propofol group, though it was not statistically significant.  Various other studies not included in this meta-analysis have also found propofol to be safe.
Opioid-based conscious sedation alone was compared with PCB in the RCT by Öztürk et al. which found higher pregnancy rates in remifentanil group, while no difference was found in fertilization rates. 
Different modalities of conscious sedation were compared in a recent Cochrane review which also included studies using electro-acupuncture. It was concluded that there was no significant difference in the pregnancy rate using these techniques.  Studies using electro-acupuncture were not included in the present review, as we aimed to compare only loco-regional anesthesia with GA. Though loco-regional anesthesia was favored in the present analysis with regard to the pregnancy rate, the results should be interpreted with caution as only two trials were randomized control studies, the rest being retrospective analysis or prospective observational/nonrandomized trials leading to doubtful quality of evidence. Also, two studies favoring regional anesthesia by Azmude et al. and Aghaamoo et al. were from the same center comparing similar techniques with the author overlap between the two studies, thereby increasing the risk of bias. , The other drawback is that the anesthetic drugs and techniques used in the included studies varied widely. There was a paucity of suitable studies comparing loco-regional anesthesia with conscious sedation alone, which is the most commonly used technique presently in many centers. From the available evidence, it may be logical to avoid inhalational anesthetics and also decrease the dosage and duration of IV induction agents such as propofol. Further multicenter RCTs are needed for further clarity on the results.
Funnel plot analysis was conducted for each of the three outcomes analyzed [Figure 5], [Figure 6], [Figure 7]. The funnel plot for the fertilization rate and pregnancy rate was symmetrical with egger regression test intercept value of -0.559 (P = 0.138) and 2.219 (P = 0.347), respectively, eliminating the possibility of any publication bias. The intercept value for the cleavage rate was 0.565 (P = 0.002) with an asymmetrical funnel plot. The cleavage rate was reported in only three studies leading to five comparisons and funnel plot tests on such a less number of studies can be spurious and misleading.
| Conclusion|| |
A higher pregnancy rate was associated with loco-regional anesthetic techniques used in the included studies, whereas the fertilization rate and cleavage rate were comparable with general anesthetic techniques. In conclusion, the superiority of loco-regional anesthesia over GA could not be concluded with confidence and requires further well-conducted RCTs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kim WO, Kil HK, Koh SO, Kim JI. Effects of general and locoregional anesthesia on the reproductive outcome for in vitro
fertilization: A meta-analysis. J Korean Med Sci 2000;15:68-72.
Kwan I, Bhattacharya S, Knox F, McNeil A. Pain relief for women undergoing oocyte retrieval for assisted reproduction. Cochrane Database Syst Rev 2013;1:CD004829.
Botta G, D′Angelo A, D′Ari G, Merlino G, Chapman M, Grudzinskas G. Epidural anesthesia in an in vitro
fertilization and embryo transfer program. J Assist Reprod Genet 1995;12:187-90.
Gonen O, Shulman A, Ghetler Y, Shapiro A, Judeiken R, Beyth Y, et al.
The impact of different types of anesthesia on in vitro
fertilization-embryo transfer treatment outcome. J Assist Reprod Genet 1995;12:678-82.
Christiaens F, Janssenswillen C, Van Steirteghem AC, Devroey P, Verborgh C, Camu F. Comparison of assisted reproductive technology performance after oocyte retrieval under general anaesthesia (propofol) versus paracervical local anaesthetic block: A case-controlled study. Hum Reprod 1998;13:2456-60.
Öztürk E, Günaydin B, Karabacak O, Tuncer B, Erdem M, Erdem A, et al
. Remifentanil infusion and paracervical block combination versus remifentanil infusion alone during in vitro
fertilisation (IVF). Turk J Med Sci 2006;32:33-5.
Bümen S, Günüşen Ý, Firat V, Karaman S, Akdoğan A, Göker EN. A comparison of intravenous general anesthesia and paracervical block for in vitro
fertilization: Effects on oocytes using the transvaginal technique. Turk J Med Sci 2011;41:801-8.
Piroli A, Marci R, Marinangeli F, Paladini A, Di Emidio G, Giovanni Artini P, et al.
Comparison of different anaesthetic methodologies for sedation during in vitro
fertilization procedures: Effects on patient physiology and oocyte competence. Gynecol Endocrinol 2012;28:796-9.
Azmude A, Agha′amou S, Yousefshahi F, Berjis K, Mirmohammad′khani M, Sadaat′ahmadi F, et al.
Pregnancy outcome using general anesthesia versus spinal anesthesia for in vitro
fertilization. Anesth Pain Med 2013;3:239-42.
Aghaamoo S, Azmoodeh A, Yousefshahi F, Berjis K, Ahmady F, Qods K, et al.
Does spinal analgesia have advantage over general anesthesia for achieving success in in vitro
fertilization? Oman Med J 2014;29:97-101.
Bailey-Pridham DD, Reshef E, Drury K, Cook CL, Hurst HE, Yussman MA. Follicular fluid lidocaine levels during transvaginal oocyte retrieval. Fertil Steril 1990;53:171-3.
Christiaens F, Janssenswillen C, Verborgh C, Moerman I, Devroey P, Van Steirteghem A, et al.
Propofol concentrations in follicular fluid during general anaesthesia for transvaginal oocyte retrieval. Hum Reprod 1999;14:345-8.
Soussis I, Boyd O, Paraschos T, Duffy S, Bower S, Troughton P, et al.
Follicular fluid levels of midazolam, fentanyl, and alfentanil during transvaginal oocyte retrieval. Fertil Steril 1995;64:1003-7.
Coetsier T, Dhont M, De Sutter P, Merchiers E, Versichelen L, Rosseel MT. Propofol anaesthesia for ultrasound guided oocyte retrieval: Accumulation of the anaesthetic agent in follicular fluid. Hum Reprod 1992;7:1422-4.
Ditkoff EC, Plumb J, Selick A, Sauer MV. Anesthesia practices in the United States common to in vitro
fertilization (IVF) centers. J Assist Reprod Genet 1997;14:145-7.
Rosen MA, Roizen MF, Eger EI 2 nd
, Glass RH, Martin M, Dandekar PV, et al.
The effect of nitrous oxide on in vitro
fertilization success rate. Anesthesiology 1987;67:42-4.
Matt DW, Steingold KA, Dastvan CM, James CA, Dunwiddie W. Effects of sera from patients given various anesthetics on preimplantation mouse embryo development in vitro
. J In Vitro
Fert Embryo Transf 1991;8:191-7.
Hadimioglu N, Aydogdu Titiz T, Dosemeci L, Erman M. Comparison of various sedation regimens for transvaginal oocyte retrieval. Fertil Steril 2002;78:648-9.
Janssenswillen C, Christiaens F, Camu F, Van Steirteghem A. The effect of propofol on parthenogenetic activation, in vitro
fertilization and early development of mouse oocytes. Fertil Steril 1997;67:769-74.
Tatone C, Francione A, Marinangeli F, Lottan M, Varrassi G, Colonna R. An evaluation of propofol toxicity on mouse oocytes and preimplantation embryos. Hum Reprod 1998;13:430-5.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]