Pain Management during Ultrasound Guided Transvaginal Oocyte Retrieval – A Narrative Review

ABSTRACT

Transvaginal oocyte retrieval (TVOR), done for the purpose of assisted reproduction can instigate enormous pain and therefore requires adequate analgesia with the least adverse effects. As the procedure involves retrieving oocytes for in vitro fertilisation, the effect of the anaesthetic drugs on the oocyte quality should also be considered. This review focuses on the various modes of anaesthesia and the anaesthetic drugs which can be administered safely to provide effective analgesia in normal and in special conditions such as women with pre-existing comorbidities. Medline, Embase, PubMed and Cochrane electronic databases were searched according to modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. According to this review, conscious sedation appears to be the most preferred mode of anaesthesia in women undergoing TVOR owing to fewer adverse effects, faster recovery, better patient and specialist comfort and the least effect on oocyte quality and embryo development. Combining it with paracervical block resulted in lesser consumption of the anaesthetic drug, which may have a beneficial effect on the oocyte quality.

INTRODUCTION

Assisted reproductive techniques (ARTs) in the form of in vitro fertilisation (IVF) or intracytoplasmic sperm injection are interventions that include in vitro handling of gametes or embryos for the purpose of reproduction. It is either the final recourse in many couples with unexplained infertility of long duration or the only option in women with bilateral tubal block and men with azoospermia who undergo surgical sperm retrieval. With increasing awareness and improvised techniques, the number of patients who opt for these treatment modalities is constantly on the rise. Women undergoing ART require ovarian stimulation with gonadotropins followed by oocyte retrieval. During the earlier stages of ART, oocyte retrieval was done laparoscopically. Dr. Subas Mukherjee created India's first IVF baby and the world's second IVF baby (born just 67 days after the world's first IVF baby on 3^rd October 1978) by retrieving oocytes through the transvaginal approach. His great contribution was not recognised and the first reported transvaginal oocyte retrieval (TVOR) was many years later in the year 1984.[1] At present, the ultrasound-guided transvaginal approach is widely practiced for oocyte retrieval. Although the procedure is less invasive when compared to the transabdominal or laparoscopic approach, the women can experience significant pain during the procedure which demands the need for anaesthesia. This review discusses the various available methods for pain management during TVOR in women with and without associated comorbidities. The outcomes that were focused on, were pain relief during the procedure, physician and patient satisfaction, adverse effects, effect on the oocyte quality and embryo development and ART outcome. The review was written to provide insight into the methods that provide adequate pain relief with fewer side effects and the least impact on oocyte quality and embryo development.

TRANSVAGINAL OOCYTE RETRIEVAL AND ANAESTHETIC IMPLICATIONS

Pain experienced during oocyte retrieval is due to the needle piercing the vaginal wall and stretching and piercing of the ovarian capsule. At present, conscious sedation is the most preferred method while the other practiced techniques are general anaesthesia (GA), regional or local anaesthesia.[2] Apart from providing safe analgesia with fewer adverse effects, the other major concern when it comes to anaesthesia for assisted reproduction is the presence of the anaesthetic drug in the follicular fluid and its possible effects on the oocyte quality and thereby the pregnancy rates. Follicular fluid concentration of the anaesthetic agents plays a major role in the oocyte quality, fertilisation and implantation rates. Prolonged exposure to certain agents can result in significantly lower pregnancy and live birth rates.[3] Although there have been studies on performing TVOR without analgesia, present day clinicians would prefer administering analgesia and/or anaesthesia, especially when there are drugs which are currently considered quite safe and effective.[4]

Methods

Medline, Embase, PubMed and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. We included relevant articles published between the years 1987 and 2022. We have excluded animal studies and studies on anaesthesia for laparoscopic oocyte retrieval from this review.

Conscious sedation

Conscious sedation and analgesia (CSA) or procedural sedation is the most common route of anaesthesia administered for women undergoing TVOR.[5] This is the preferred mode of anaesthesia in 95% and 84% of IVF centres in the USA and UK, respectively.[2,6,7] Physician and patient satisfaction are better with CSA as most of the drugs used are also potent anxiolytics and depression in the level of consciousness is much lesser when compared to GA, thereby not necessitating assisted airway support throughout the surgical procedure.[8,9] The American College of Emergency Physicians mentions CSA as a ’technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. CSA is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently.’[10] With meticulous administration, these drugs have the least short-term and long-term side effects, are well-tolerated and the ease of delivery is also better when compared to other modes of anaesthesia [Table 1].[6,11] A patient on CSA should be monitored as per the American Society of Anesthesiology monitoring system.

Table 1.

Monitored anaesthesia care, conscious sedation and analgesia, total intravenous anaesthesia

Author	Study population and design	Outcome
Bein and Klapproth 1989[12]	NA	Midazolam (0.1 mg/kg) and fentanyl (2 µg/kg) provided better anterograde amnesia along with analgesic and anxiolytic effects
Ben-Shlomo et al., 1999[13]	Randomised prospective study in 50 patients	Arousability was better in patients sedated with midazolam and ketamine when compared to GA with propofol, fentanyl and isoflurane, whereas oocyte retrieval rate, embryo transfers and pregnancy rates were similar in both groups
Wilhelm et al., 2002[14]	Retrospective data analysis of 251 patients	Pregnancy rates were better in patients who received MAC with remifentanil (30.6%) when compared to GA with alfentanil, propofol and nitrous oxide induction with isoflurane-propofol maintenance (17.9%)
Lok et al., 2002[15]	Prospective randomised trial in 106 patients. Patient-controlled sedation (n=51), Physician-administered sedation (n=55)	Level of sedation and co-operation was similar in both group PCS using propofol and alfentanil and PAS using diazepam and pethidine. Pain score was higher during and two h post-procedure (53±23 vs. 35±24; P <0.01 and 29±27 vs. 17±22; P <0.05, respectively) in the PCS group. Although patient satisfaction was similar in both groups, physician satisfaction was better with PAS
Fiebai et al., 2008[16]	Cross-sectional survey	With conscious sedation, mean pain score was low, and the pain intensity did not alter with the duration of the procedure
Murthy et al., 2008[17]	Retrospective analysis of records of 1496 patients	GA provided through FM with isoflurane or ETT with isoflurane, LMA with isoflurane or TIVA with propofol/fentanyl/pethidine/morphine. Induction agents were propofol, thiopentone, ketamine or midazolam. Hemodynamic parameters were similar in all groups. Patient satisfaction was better in the TIVA group due to lesser post-operative adverse effects
Saleh et al., 2012[18]	Prospective randomised observer-blinded study of 60 patients	Patients who received TIVA with remifentanil and propofol had a shorter recovery time, shorter PACU and hospital stay, lesser propofol requirement and better patient satisfaction when compared to the group that received fentanyl and propofol. There was no difference in the intraoperative hemodynamic parameters, post-operative pain and adverse effects. The chemical pregnancy rate was similar 43.33% (P=1.000) in both groups
Matsota et al., 2012[19]	Randomised controlled trial including 58 women, among whom 29 patients received analgesia with remifentanil and 29 patients received anaesthesia with propofol and alfentanil	There was no significant difference in anaesthetic outcome and ART outcome in terms of number of oocytes retrieved, fertilization and cleavage rate, embryo quality, implantation rates and pregnancy rates between both groups
Tewari et al., 2016[20]	Prospective, randomised study involving 100 women who underwent TVOR under IV propofol. Randomised to compare drugs titrated as per entropy values: state entropy and response entropy (Group EM) and drugs titrated as per standard clinical monitoring (Group CM)	Propofol and fentanyl consumption was 6.7% lesser (P=0.01) and 10.9% more (P=0.007) in the EM group, respectively. The on-table recovery was earlier (P=0.009), and requirement of supplemental analgesia was also lesser (10% vs. 28.3%, P=0.01) in the EM group
Singhal et al., 2017[21]	Prospective cross-sectional study of 100 women who underwent TVOR under CSA	Post-procedure pain score increased with the duration of surgery. Otherwise, there was no correlation between number of oocytes retrieved or the transmyometrial passage of needle and the pain score. Patient satisfaction was good

TIVA=Total intravenous anaesthesia, MAC=Monitored anaesthesia care, CSA=Conscious sedation and analgesia, TVOR=Transvaginal oocyte retrieval, GA=General anaesthesia, PCS=Patient-controlled sedation, PAS=Physician-administered sedation, FM=Face mask, ETT=Endotracheal tube, LMA=Laryngeal mask airway, PACU=Post-anaesthesia care unit, ART=Assisted reproductive techniques

General anaesthesia

GA was the technique of choice during the earlier days of ART. The anaesthetic agents used are either intravenous; such as propofol, ketamine, opioids or benzodiazepines; or inhalational agents such as nitrous oxide (N₂O) and vapours of isoflurane, desflurane and sevoflurane [Table 2]. Isoflurane is the most commonly used drug due to its low blood gas solubility when compared to halothane and thereby has lesser central nervous system effects.[17] Patients may be kept on either spontaneous ventilation through face mask or laryngeal mask airway or mechanically ventilated through laryngeal mask airway or endotracheal tube. Apart from the less favourable effects such as prolonged recovery and post-operative nausea and vomiting, studies have also shown adverse ART outcomes such as reduced fertilisation and pregnancy rates when halogenated fluorocarbons with nitrous oxide were used.[3] The use of N₂O for GA during oocyte retrieval is controversial as many studies have shown a detrimental effect on embryos.[22] There was a recent case report on violent cough following GA with propofol and pentazocine, which resulted in ovarian haemorrhage and severe haemoperitoneum.[23] GA may be the preferred mode of anaesthesia in selected situations such as,[24]

Table 2.

General anaesthesia

Author	Study population and design	Outcome
Ben-Shlomo et al., 1999[13]	Randomised prospective study in 50 patients	Arousability was better in patients sedated with midazolam and ketamine when compared to GA with propofol, fentanyl and isoflurane, whereas oocyte retrieval rate, embryo transfers and pregnancy rates were similar in both groups
Hammadeh ME et al., 1999[26]	Prospective comparative study in 202 women among whom 96 women opted for sedation with midazolam and diazepam/propofol and 106 opted for GA with remifentanil and propofol/isoflurane	Number of oocytes retrieved were significantly higher with GA than with sedation, whereas there was no difference in fertilization, cleavage and pregnancy rates. Authors suggested that the favourable outcome could be due to the avoidance of nitrous oxide
Wilhelm et al., 2002[14]	Retrospective data analysis of 251 patients	Pregnancy rates were better in patients who received MAC with remifentanil (30.6%) when compared to GA with alfentanil, propofol and nitrous oxide induction with isoflurane-propofol maintenance (17.9%)
Murthy et al., 2008[17]	Retrospective analysis of records of 1496 patients	GA provided through FM with isoflurane or ETT with isoflurane, LMA with isoflurane or TIVA with propofol/fentanyl/pethidine/morphine. Induction agents were propofol, thiopentone, ketamine or midazolam. Hemodynamic parameters were similar in all groups. Patient satisfaction was better in the TIVA group due to lesser post-operative adverse effects

TIVA: Total intravenous anaesthesia, GA=General anaesthesia, LMA=Laryngeal mask airway, ETT=Endotracheal tube, FM=Face mask, MAC=Monitored anaesthesia care

• Anxiety or other psychological issues

• When longer procedure time or more manipulation due to the difficult procedure is expected in cases such as endometriosis/endometrioma, pelvic adhesions or difficult-to-access ovaries

• Adverse effects during conscious sedation/regional anaesthesia in previous attempts.

Literature from the earlier days of ART suggested the significant negative impact of GA on fertilisation, cleavage rates and embryo quality. There is a fair chance that the CO2 pneumoperitoneum which was created for laparoscopic oocyte retrieval could have also contributed to these findings significantly.[3,25]

Patient controlled analgesia

Although conventionally anaesthesia administration is performed by physicians, patient-controlled analgesia (PCA) offers patients control over the drug administration as per their requirements. PCA has been considered an effective alternative to physician-administered anaesthesia, especially in low-resource settings and also for patients with low ovarian reserve undergoing TVOR where the duration of the procedure may be very less [Table 3].

Table 3.

Patient-controlled analgesia

Author	Study population and design	Outcome
Zelcer et al., 1992[27]	Prospective study in 80 women comparing physician-administered and patient- controlled alfentanil administration	The average drug requirement (1.49±0.50 and 1.46±0.55 µg/kg/min) and post-operative complications were similar in both groups. Patient comfort and satisfaction were better with PCA
Cook et al., 1993[28]	Prospective randomised study where 25 patients received propofol and 22 patient received midazolam	PCA with midazolam and propofol were compared. Alfentanil was administered on demand. Onset of sedation took 70.6 s (SD 22.4) in the propofol group and 106.3 s (SD 50.7) in the midazolam group. Procedure was completed successfully and none of the patients required additional sedation
Bhattacharya et al., 1997[29]	Prospective randomised study with 39 women in the PCA group and 42 women in the PAS group	Pain score was less and patient satisfaction was better in the PCA group when compared to the PAS group, whereas fentanyl utilization was significantly more in the PCA group
Thompson et al., 2000[30]	Randomised controlled trial where 57 women received PCA with isodesox (1% desflurane, 0.25% isoflurane and 60% oxygen in nitrogen) and 55 women received IV fentanyl	The mean pain score was significantly lesser in the TIVA group (P=0.02), whereas a fall in oxygen saturation of less than 94% was seen in around 29% of women who received TIVA when compared to 1.7% in the PCA group
Lok et al., 2002[15]	Prospective randomised trial in 106 patients. Patient-controlled sedation (n=51), Physician-administered sedation (n=55)	Level of sedation and co-operation was similar in both group PCS using propofol and alfentanil and PAS using diazepam and pethidine. Pain score was higher during and two h post-procedure (53±23 vs. 35±24, P<0.01 and 29±27 vs. 17±22, P <0.05, respectively) in the PCS group. Although patient satisfaction was similar in both groups, physician satisfaction was better with PAS
Lier et al., 2015[31]	Randomised control trial involving 76 women Forty women received pethidine and midazolam-induced conscious sedation and 36 women received PCA with remifentanil and diclofenac	Pain score during the procedure was comparable for remifentanil and pethidine groups (4 [3-7] vs. 6 [4-8], P=0.13), whereas pain score was significantly lower in the CSA group (1 [0–3] vs. 2 [1–5], P=0.016). Reproductive and safety outcomes were similar, though patient satisfaction was better in the PCA group

PCA=Patient controlled analgesia, PAS=Physician-administered sedation, PCS=Patient-controlled sedation, TIVA=Total intravenous anaesthesia, SD=Standard deviation

Regional anaesthesia

In women undergoing ART, regional anaesthesia has the advantage of minimal systemic absorption of the local anaesthetic agent and thereby very minimal follicular fluid concentration. Studies comparing regional anaesthesia with sedation and GA have not shown gross differences in anaesthetic parameters or ART outcomes [Table 4].

Table 4.

Regional anaesthesia-spinal anaesthesia, epidural anaesthesia

Author	Study population and design	Outcome
Manica et al., 1993[32]	Randomized study of 56 women, comparing SA with 1.5% and 5% hyperbaric lidocaine in combination with 10 µg of fentanyl	The sensory level, maximum motor block, requirement for additional IV sedation, time to two-segment regression and time to full sensory recovery were similar in both groups. Recovery time in terms of time to ambulation (141±21 min vs. 162±29 min; P<0.05), time to void (147±21 min vs. 174±28 min; P<0.05), time to achieve full motor recovery (86±21 min vs. 111±22 min, P<0.0001), and discharge time (170±38 min vs. 201±41 min, P<0.05) was significantly shorter in women who received 1.5% lidocaine
Botta et al., 1995[33]	Study comparing 50 oocyte retrievals done under EA and 112 retrievals done under IV propofol with nitrous oxide mask ventilation	Fertilisation, cleavage and pregnancy rates were similar in both groups (67.2%, 92% and 20% in the EA group and 69.3%, 93% and 19.6% in the IV sedation group. Post-operative nausea and vomiting were significantly higher in the IV sedation group
Viscomi et al., 1997[34]	Retrospective pilot study involving 95 women who underwent TVOR under TIVA (n=44) or SA (n=51)	ART outcome was similar in both groups. The time to discharge (P=0.03), and post-operative side effects such as vomiting (46% vs. 6%, P<0.01) was significantly higher in the TIVA group
Guasch et al., 2005[35]	Ninety women were randomized into 4 groups to receive either GA, SA, CSA with alfentanil + midazolam+PCB or CSA with remifentanil+PCB	Plasma levels of prolactin and cortisol were compared in all four groups. Prolactin levels were highest in patients receiving GA. There was complete attenuation of increase in prolactin level in women who received SA
Piroli et al., 2012[36]	Retrospective analysis comparing local anaesthetic agent EMLA cream (lidocaine 2.5% and prilocaine 2.5%), propofol, sevoflurane and thiopental sodium	Analgesia and hemodynamic parameters were similar in all groups. Both EMLA and sevoflurane groups resulted in higher yield of MII oocytes and better fertiliation rate when compared to the propofol and thiopental sodium groups (P<0.001)
Azmude et al., 2013[37]	Randomized clinical trial involving 200 women, randomly allocated to receive either GA (n=100) or SA (n=100)	Pregnancy rates were significantly higher in the SA group (27%) when compared to the GA group (15%), P<0.001
Aghaamoo et al., 2014[38]	Retrospective analysis of case records comparing GA and SA for TVOR in terms of achieving a chemical pregnancy	The chance of achieving chemical pregnancy (positive pregnancy test) was significantly higher in women who received SA (adjusted OR=2.07, 95% CI: 1.02,4.20, P=0.043)
Heo et al., 2020[39]	Retrospective analysis of records of 95 patients who underwent TVOR under SA (n=77) or MAC (n=18)	The pregnancy rates were similar in both groups (32.5% in the SA group and 33.3% in the MAC group, P - 0.575). Time taken for the procedure was significantly longer in the MAC group (P<0.001).

TVOR=Transvaginal oocyte retrieval, TIVA=Total intravenous anaesthesia, MAC=Monitored anaesthesia care, GA=General anaesthesia, PCB=Paracervical, CSA=Conscious sedation and analgesia, ART=Assisted reproductive techniques, CI=Confidence interval, OR=Odds ratio, EA=Epidural anaesthesia, SA=Spinal anaesthesia, EMLA=Eutectic mixture of local anaesthetics, MII oocyte=Metaphase II oocyte

Paracervical and pre-ovarian block

Paracervical (PCB) and pre-ovarian block (POB) involve injecting a local anaesthetic agent adjacent to the respective neural plexus. The paracervical block is performed under sterile conditions, with the patient in the lithotomy position. The local anaesthetic agent is injected through the cervicovaginal fornix and deposited around the cervix at four locations, usually at the 1,5,7 and 11 o’clock positions. The pre-ovarian block is performed under ultrasound guidance, by infiltrating the local anaesthetic agent in the vaginal wall and peritoneal surface adjacent to the ovary [Table 5].

Table 5.

Paracervical and pre-ovarian block

Author	Study population and design	Outcome
Wikland et al., 1990[40]	Comparative study of 46 women who received PCB with lidocaine 50 mg and 46 women who did not	The mean follicular fluid concentration of lidocaine was 0.36±1.1 μg/mL. The fertilisation rate did not vary in oocytes retrieved from follicles containing lidocaine in their fluid. The fertilisation, cleavage and pregnancy rates were similar in both groups
Corson et al., 1994[41]	Prospective, randomized, double-blinded, placebo-controlled study involving 101 women who received IV sedation, randomly allocated to either receive PCB or not	Patient and physician-assessed pain scores were lesser in the group that received the PCB along with the IV sedation
Christiaens et al., 1998[42]	Prospective study comparing GA with propofol and PCB in 202 women	The fertilisation, cleavage, implantation and ongoing pregnancy rates were similar in both groups
Ng et al., 1999[43]	Prospective, double-blinded, placebo-controlled study on 135 women, randomly allocated to receive 10 ml of 1.5% lignocaine (group A) or normal saline (group B) in the PCB and no local injection (group C)	The procedure duration, number of follicles punctured and pregnancy rates were similar in all groups. Though vaginal puncture pain score was similar in all groups, abdomen pain was significantly lesser by 40%–50% in group A when compared to the other groups
Ng et al., 2000[44]	Prospective, double-blinded study on 150 women, randomised to receive either 200 mg or 150 mg lignocaine in the PCB	The fertilisation, implantation and pregnancy rates were similar in both groups. The median pain levels during vaginal punctures and abdominal pain were similar in both groups. Therefore, 150 mg of lignocaine seemed to be satisfactory for the procedure
Ng et al., 2001[45]	Prospective double-blinded study of 150 women, randomised to receive either PCB alone or PCB with conscious sedation	Level of vaginal and abdominal pain was 2.5 times higher in women who received only PCB
Ramzy et al., 2001[46]	Prospective, randomised study to evaluate post-operative pain relief by administration of sub-ovarian capsule and vaginal puncture site local anaesthetic. Seventy-two women underwent TVOR under IV sedation, randomised to receive lignocaine (Group A, n=24), normal saline (Group B, n=24), or no intervention (Group C, n=24) after TVOR	Post-operative analgesic requirement was similar in all groups, (Group A-41.7%, Group B-41.7%, in Group C-29.2%). Subcapsular local anaesthetic administration did not prove useful
Ng et al., 2003[47]	Prospective, double-blinded study on 153 women under IV sedation, randomised to receive three different doses of either 50, 100 and 150 mg lignocaine in the PCB	Vaginal and abdominal pain levels during and 4 h after the procedure were not significantly different among the three groups. Therefore, authors recommend the use of 50 mg of lignocaine for PCB
Tummon et al., 2004[48]	Randomised trial comparing use of use of lidocaine gel or PCB with lidocaine in adjunct to IV sedation	Pain experience was more in the group on lidocaine vaginal gel when compared with lidocaine PCB
Öztürk et al., 2006[49]	Prospective comparative study of two groups (n=100) receiving either TIVA with remifentanil infusion alone or in combination with PCB	Haemodynamic and respiratory parameters were similar in both groups. Pain score, remifentanil requirement and post-operative nausea and vomiting was significantly higher in the group that received remifentanil alone (P<0.05)
Atashkhoii 2006[50]	Prospective randomised double-blinded study. Sixty-women were randomised to receive either CSA alone (Fentanyl + Midazolam + Propofol) or CSA with PCB	Vaginal and abdominal pain were significantly lesser in the CSA + PCB group. Propofol requirement was also significantly lesser in the PCB group (8.67±2.42 mg) when compared to CSA alone (25.60±5.29 mg), P<0.0005. Incidence of intraoperative and post-operative adverse effects were significantly lesser in the CSA + PCB group
Cerne et al., 2006[51]	Prospective, multicentre study, where 183 women were randomised to receive POB (n=96) or PCB (n=87)	The pain score, level of anxiety, alfentanil requirement, fertilisation rate, number of good-quality embryos and clinical pregnancy rates were similar in both groups
Gunaydin et al., 2007[52]	Randomised controlled trial involving 40 women, randomly allocated to receive either remifentanil infusion alone (n=20) or with PCB (n=20)	Plasma remifentanil concentration and pulmonary function was compared in both groups. Haemodynamic and respiratory parameters were similar in both groups. Remifentanil requirement and therefore plasma remifentanil concentration was significantly higher when adjuvant PCB was not given (P<0.05)
Milanini et al., 2008[53]	Retrospective study comparing local anaesthesia with continuous IV remifentanil	Number of oocytes retrieved were more and the procedure was more comfortable in the IV remifentanil group
Bumen et al., 2011[54]	Prospective randomised study comparing TIVA with remifentanil + propofol with PCB	Fertilisation rate was similar in both groups. Though the number of retrieved and mature oocytes, embryo numbers and pregnancy rate were higher in the TIVA group, only the increased number of embryos was statistically significant (P=0.045)
Oliveira et al., 2016[55]	Randomised double-blinded clinical trial involving 61 women who were randomly allocated to receive 1mcg/kg of fentanyl with 1.5 mg/kg of propofol (n=32), or 0.075mg/kg of midazolam with 0.25mcg/kg/min of remifentanil, and paracervical block with 3 mL of 2% lidocaine (n=29)	Haemodynamic and anaesthetic parameters were similar in both groups. Though pregnancy rate was higher in the fentanyl/propofol group (44% vs. 22%), it was not statistically significant
Rolland et al., 2017[56]	Non-randomised prospective cohort study, where 234 women received PCB and 247 women received GA	Post-operative vaginal and abdominal pain was significantly more in the PCB group when compared to the GA group (2.26±0.159 vs. 1.66±0.123, respectively, P=0.005, and 3.80±0.165 vs. 3.00±0.148, respectively, P<0.001). Therefore, patient satisfaction was also significantly more in the GA group, (P<0.001). Whereas, the live birth rates were similar in both groups (19.8% in the GA group vs. 20.9% in the PCB group, P=0.764)

GA=GA=General anaesthesia, PCB=Paracervical, TIVA=Total intravenous anaesthesia, POB=Pre-ovarian block, CSA=Conscious sedation and analgesia, TVOR=Transvaginal oocyte retrieval

Drugs

Drugs used for anaesthesia and their dosage plays a major role in the anaesthetic management as well as the ART outcome [Table 6]. For providing sedation, most anaesthesiologists prefer midazolam and/or propofol with fentanyl. Choosing the right drug is extremely important as it not only involves patient safety, but the outcome may also be affected if the drug accumulates in the follicular fluid. Midazolam is the most preferred benzodiazepine due to its potent sedative and anxiolytic properties. When combined with opioids, the synergistic action is known to provide better analgesic effect.[8] The combined action also necessitates lesser dose requirement for both drugs. A randomized trial published in 2008 concluded that side effects were lesser with midazolam and fentanyl combination when compared to propofol and fentanyl.[57] While considering opioid administration, remifentanil has proved to be better than fentanyl in terms of faster recovery.[58]

Table 6.

Drugs

Author	Study population and design	Outcome
CSA/TIVA/MAC
Endler et al., 1987[61]	Prospective study comparing follicular fluid level of thiopental (n=15) and thiamylal (n=9)	The mean plasma concentration of thiamylal was 7.99±3.97 µg/mL and thiopental was 4.13±0.90 mcg/ml. Though the mean follicular fluid concentration of the drugs were similar (thiopental 1.62±0.61 µg/mL; thiamylal 1.67±0.83µg/mL), the mean FF/plasma concentration ratio was greater in the thiopental group (0.41±0.19) when compared with the thiamylal group (0.22±0.14)
Shapira et al., 1991[62]	Prospective double-blinded study of 36 women, where 19 women received alfentanil up to 0.025 mg/kg and 17 received fentanyl up to 0.0025 mg/kg	Duration of procedure, analgesic effect and pregnancy rates were similar in both groups. When compared to fentanyl (3.4±2.2 min), induction was significantly shorter with alfentanil (1.3±0.7 min). Post-procedure drowsiness was also less with alfentanil
De Amici et al., 1992[63]	Studied safety of continuous IV infusion of propofol for TVOR	Authors observed that the haemodynamic and respiratory parameters were stable, there were no adverse effects and regaining psychomotor functions were rapid
Coetsier et al., 1992[59]	Studied follicular fluid concentration of propofol in 9 patients	Follicular fluid propofol levels showed a steady increase and it was time dependent
Soussis et al., 1995[64]	Clinical trial in 28 women, 15 of whom received midazolam and fentanyl and 13 received midazolam and alfentanil	Both plasma and follicular fluid levels of the agents administered were monitored. Follicular fluid levels increased significantly up to 25 minutes after administration of the agents. Fertilisation and pregnancy rates were similar in all groups, but patient numbers were small
Shapira et al., 1996[62]	Observational study conducted on 14 women to determine serum and follicular fluid alfentanil concentration	Follicular fluid level of alfentanil (8.9±0.8 ng/mL at 15 min) was significantly lesser than the serum level (92±20 ng/mL at 5 min)
Casati et al., 1999[65]	Randomised clinical trial of 60 women, randomly allocated to receive either propofol and fentanyl or midazolam and remifentanil	Need for manual ventilation was more frequent in the propofol/fentanyl group when compared to the midazolam/remifentanil group (50% vs. 30%, P<0.05) and the time to achieve an Aldrete’s score of 10 was also shorter in the midazolam and remifentanil group
Ben-Shlomo et al., 2000[66]	Prospective cohort study of 130 women who had TIVA with propofol and fentanyl	Even though there was an increase in the follicular fluid concentration of propofol with time, there was no difference in the oocyte maturity, quality, fertilisation, cleavage rates or embryo numbers for the first and last retrieved oocytes as per elapsed procedure time
Huang et al., 2000[67]	Retrospective comparative study of GA with propofol (n=72) and thiopental sodium (n=20)	The fertilisation and cleavage rates were similar in propofol and thiopentone groups (68.9 vs. 66.7% and 96.5 vs. 94.8%, respectively). Embryo quality, pregnancy, implantation and miscarriage rates were also similar in both groups
Ma et al., 2008[57]	Randomised control trial in 80 patients receiving conscious sedation who were randomly assigned to receive either midazolam with fentanyl or propofol with fentanyl	Analgesic effect and haemodynamic parameters were similar in both groups, but midazolam when combined with fentanyl was found to better in terms of lesser incidence of respiratory depression (5% vs. 25%), post-operative vomiting (10% vs. 27.5%) and better amnesia (25% vs. 7.5%)
Coskun et al., 2011[68]	Randomised control trial involving 69 women who received remifentanil at varying doses. They were randomly allocated into three groups consisting of 23 patients who received either 1.5, 2.0 or 2.5 ng/mL of remifentanil	Haemodynamic parameters, level of sedation and pain scores were similar in all three groups, whereas recovery was earlier in the groups which received 1.5 or 2.0 ng/mL
Sarikaya et al., 2011[69]	A double-blinded prospective randomised controlled trial involving 86 women. Group 1 received remifentanil dose of 0.1 µg/kg/min while Group 2 received 0.15 µg/kg/min infusion	Haemodynamic parameters and patient satisfaction was similar in both groups. Anaesthesiologist satisfaction was better in group 1 (P=0.009) whereas surgeon satisfaction was better in group 2 (P=0.01). There was no difference in fertilisation, cleavage or pregnancy rates
Jarahzadeh et al., 2011[58]	Double-blinded randomised clinical trial of 145 women, comparing monitored anaesthesia care with remifentanil and fentanyl, preceded by induction with thiopental	Recovery from anaesthesia and pregnancy rates were better in the remifentanil group when compared to the fentanyl group
Liang et al., 2011[70]	Randomised controlled trial of 81 women to assess the efficacy of subclinical doses of 0.4 mg/kg of pentazocine with 1.5 mg/kg propofol and 0.5 mg/kg pentazocine with 1.5 mg/kg propofol	The analgesic effect, propofol requirement, adverse effects, unconsciousness time, awake time and hospital stay were similar in both groups. Intraoperative consciousness and need for increasing propofol dose was more in the group which received the subclinical dose
Goutziomitrou et al. 2015[71]	Randomised controlled trial comparing IV sedation with propofol (n=90) and thiopental sodium (n=90)	Number of oocytes retrieved, overall fertilisation rates and fertilisation rates for ICSI were similar in both groups. Though live birth rate was higher in the propofol group, there was no statistical significance. The time under anaesthesia was significantly more in the thiopental sodium group when compared to the propofol group: median (IQR): 12 (5) versus 10 (4.5) min, P=0.019
Elnabtity and Selim 2017[72]	Prospective randomised double-blinded trial involving 52 patients who were equally allotted to receive either dexmedetomidine or midazolam for conscious sedation. All received an initial loading dose of fentanyl and a paracervical block	Pain score was significantly lesser in the dexmedetomidine group when compared to the midazolam group both intra-operatively and at 20 min during PACU time. Although there was significant bradycardia in the dexmedetomidine group, the need for rescue sedation and PACU stay time was also significantly lesser in this group
Morue et al., 2018[73]	Randomised controlled, prospective, double-blinded study of 132 women out of which 121 completed the study. One group received a ketamine infusion (40 µg kg min over 5 min followed by 2.5 µg kg min) and the other, a 0.9% saline infusion in addition to the variable remifentanil TCI	There was no episode of respiratory depression in both groups and no patient required ventilatory support. Pain score and remifentanil concentrations were reduced significantly in the ketamine group, but the latter remained above 2 ng ml. The incidence of post-operative nausea was lesser in the ketamine group, but it did not influence length of stay nor patient satisfaction
Tola 2019[74]	Retrospective analysis of records of 333 women. They were evaluated under three groups depending on whether they received propofol (n=217), or ketamine (n=60), or propofol and ketamine (n=56)	Fertilisation rates were lesser in the ketamine group, whereas implantation, clinical pregnancy and live birth rates were similar in all groups. An extended duration of anaesthesia of more than 30 min was associated with lower implantation and clinical pregnancy rates
Farzi et al., 2019[75]	Double-blinded clinical trial. Three hundred and forty patients were randomly allocated to receive alfentanil (A; 15 µg/kg), fentanyl (F; 1.5 µg/kg) or remifentanil (R; 1.5 µg/kg). One hundred and five women were lost to follow up	Time to respond to verbal command was significantly more in the fentanyl group (A: 1.99±1.64, F: 2.56±1.72, R: 1.78±1.34, P=0.014). Intensity of post-operative pain and patient satisfaction were similar in all groups. Although the implantation, biochemical and chemical pregnancy rates were similar in the groups, the fertilisation rate was significantly lesser in the alfentanil group when compared to the others (A: 51.6%, F: 54.4%, R: 62.2%, P=0.018)
Matsota et al., 2021[76]	Prospective cohort study of 72 cycles/patients where group 1 received dexmedetomidine and fentanyl and the group 2 received remifentanil and midazolam	Propofol consumption was significantly higher in group 1 when compared to group 2 (77.0±10.6 mg vs. 12.1±6.1; P<0.001). Post-anaesthesia discharge score was better in group 2 (15.0 vs. 5.0 min, P=0.028). Fertilisation rates were similar in both groups whereas quality of embryos on day 3 was better in group 1
Orak et al., 2021[77]	A prospective, randomised and controlled trial with 60 patients. Patients were randomly allocated into two groups of 30 patients each. Group 1 received remifentanil and propofol and Group 2 received remifentanil and sevoflurane	Neuroendocrine stress response was evaluated with the help of certain blood parameters. In group 1 ACTH, glucagon, and PGE2 increased post-operatively, while cortisol decreased. In group 2 aldosterone and CRH increased post-operatively. Post-operative levels of Glucagon and PG E2 were higher in group 1 when compared to group 2
Saravanaperumal and Udhayakumar 2021[78]	Prospective randomised control study of 66 patients. They were randomised into two equal groups who received TIVA with either dexmedetomidine and propofol or fentanyl and propofol	Dexmedetomidine and propofol combination provided statistically better quality of recovery, lesser requirement of rescue analgesia and lesser incidence of post-operative nausea and vomiting
General anaesthesia
Handa-Tsutsui and Kodaka 2007[79]	Randomised prospective study of 47 women to determine the target concentration of propofol needed to prevent movement in 50% (Cp50) and 95% (Cp95) of women and whether nitrous oxide supplementation had an influence on the same	Addition on 50% nitrous oxide significantly reduced the Cp50 value for target controlled infusion of propofol by a factor of 1.24 (95% CI: 1.07–1.44)
Spinal anaesthesia
Martin et al., 1999[80]	Randomised clinical trial where 78 women were randomly allocated to receive spinal anaesthesia with 45 mg of hyperbaric 1.5% lidocaine with or without additional 10 mcg of fentanyl	Intraoperative (P<0.05) and post-operative (P<0.0005) VAS pain scores, and post-operative narcotic requirement (P<0.005) were significantly lower in the fentanyl group. The other variables such as time to ambulation, urination and discharge were similar in both groups
Tsen et al., 2001[81]	Prospective double-blinded clinical trial of 40 women, randomised to receive either intrathecal hyperbaric bupivacaine 3.75 mg (0.5 mL of 0.75%) with fentanyl 25 µg or hyperbaric lidocaine 30 mg (2.0 mL of 1.5%) with fentanyl 25 µg	Though time to onset and recovery of sensory and motor function was similar in both groups, time taken to void and hospital stay were significantly longer in the bupivacaine group. Some patients required intravenous analgesic supplementation in both groups
Paracervical block
Godoy et al., 1993[82]	Randomised clinical trial comparing paracervical block with mepivacaine 1% (n=46) and prilocaine 1% (n=54)	When combined with standard pre-medication, both the local anaesthetic agents were equally effective in reducing pain during TVOR, but Mepivacaine was preferred over prilocaine due to the risk of methaemoglobinaemia
Local anaesthetic
Shao et al., 2020[83]	Prospective study of patients who underwent TVOR, comparing addition of vaginal topical tetracaine to intravenous propofol (n=53) and propofol alone (n=48)]	Tetracaine when combined with propofol anaesthesia effectively reduced the propofol requirement, post-operative pain and better surgeon and patient satisfaction
Pre-medication
Ng et al., 2002[84]	Randomised double-blinded controlled trial. Hundred women were randomised to either receive the pre-medication (50 mg pethidine and 25 mg promethazine) or placebo (normal saline intramuscularly) 30 min prior to TVOR	There was no difference in procedure duration, number of follicles punctured and clinical outcome. Pre-operative anxiety level, level of vaginal and abdominal pain during TVOR and 4 h after the procedure was significantly higher in the placebo group. Patients who received pre-medication complained of persistent drowsiness post-procedure
Post-operative pain relief
Sacha et al., 2022[85]	Randomised double-blinded, placebo controlled trial comparing post-operative pain scores in women who were randomly allocated to receive Group A - 1000 mg of IV acetaminophen + PO placebo, Group B-IV placebo + 1000 mg PO acetaminophen, Group C-IV and PO placebo	Mean pain score and ART outcome was similar in all three groups. Post-operative opioid requirement was lesser in Group A when compared to Groups B and C (0.24 vs. 0.59 vs. 0.58 mg IV morphine equivalents, respectively)
Analgesics
Seidler et al., 2021[86]	Retrospective cohort study of women receiving a single 30 mg of intravenous ketorolac intraoperatively (n=1780) compared to women who did not receive the drug (n=826)	Need for post-operative narcotics was significantly lesser in the ketorolac group when compared to the non-ketorolac group (12% vs. 25%). There was no significant difference in the clinical pregnancy rate

TVOR=Transvaginal oocyte retrieval, ART=Assisted reproductive techniques, CI=Confidence interval, PACU=Post-anaesthesia care unit, IQR: Interquartile range, PG=Prostaglandin, CRH=Corticotropin releasing hormone, ACTH=Adrenocorticotropic hormone

Propofol is used both for conscious sedation as well as GA. It has both sedative and analgesic properties and the advantage of faster onset, short elimination time and lesser incidence of post-operative nausea and vomiting.[17] Daycare procedures such as TVOR require drugs with a shorter half-life which aids in rapid weaning from anaesthesia. Both patient and physician satisfaction are better when there is early awakening and orientation to time with quick return of normal psychomotor performance. The rapid metabolisation of propofol in the liver aids in accelerated clearance from the system and thereby faster recovery when compared to other intravenous anaesthetic agents.[17] There is a dose-dependent incidence of respiratory and myocardial depression with propofol, which can be overcome by combined administration of an opioid such as fentanyl. The follicular fluid concentration of propofol was also found to be dose-dependent.[59] There was no difference in ART outcome in terms of fertilisation, cleavage, implantation or abortion rates when compared with thiopental. Propofol requirement was found to more in patients who were highly anxious before the procedure.[60]

Ketamine belongs to the phencyclidine family of drugs and causes dissociative anaesthesia through a central neurological action. Due to its additional properties such as analgesic effect, loss of consciousness and anterograde amnesia without cardiorespiratory depression, it was once considered an ideal anaesthetic agent, both for GA and conscious sedation. Yet, the drug lost its popularity due to its undesirable post-operative effects such as vivid dreaming, illusions and feelings of fear or excitement which persist for considerable several hours.

Other interventions

Various other modalities such as electroacupuncture and acupressure have also been suggested for pain management during oocyte retrieval.[87,88] Although these techniques have provided better pain relief when combined with intravenous sedation, they have not been quite helpful as a stand-alone treatment for intra-or post-operative pain relief.[89] Simple and inexpensive interventions such as music therapy can also reduce pain scores and patient anxiety and improve patient satisfaction.[90] A booklet for coping intervention for oocyte retrieval was developed by a psychologist. The booklet has information about the oocyte retrieval procedure in detail, including pain and possible outcomes and coping strategies such as muscle relaxation, distraction techniques, deep breathing and positive reappraisal. These coping strategies may also improve patient satisfaction and recovery.[91]

SPECIAL CONSIDERATIONS

Comorbidities

Patients should be evaluated for co-existing medical conditions before the administration of anaesthesia. With increasing age at conception and fertility treatment, it is crucial to evaluate women for possible associated medical conditions such as diabetes, hypertension and heart disease. Moreover, subfertile women may also have associated hypothyroidism, obesity, diabetes or hypertension or a history of tuberculosis or severe acute respiratory syndrome (SARS) COVID-19 in the past. They may be on drugs not only for the above-mentioned conditions but may also be on anticoagulants or psychiatric medications. All of these should be taken into consideration before deciding on the drug, the route of administration and the intra-operative and post-operative monitoring protocol. Special care should be taken for cancer patients who have presented for fertility preservation. Lately, ART is being done solely for the purpose of pre-implantation genetic testing for monogenic disorders. Patients undergoing the procedure may have conditions such as myotonic dystrophy, Marfan's syndrome or neurofibromatosis, which can influence the anaesthetic management and post-operative recovery.[92]

Anti-coagulant and anti-platelet use

Women with recurrent pregnancy loss due to antiphospholipid antibody syndrome may be on low-molecular-weight heparin injections and aspirin. Aspirin may be continued, whereas the last dose of heparin should be given at least 12 h before the procedure and the post-procedure dose should be administered 24 h later.[93]

Severe acute respiratory syndrome coronavirus 2

Patients were not taken up for ART during the initial days of the COVID-19 pandemic. When services resumed, ART procedures were done while abiding to the COVID-19 protocol. In our personal experience, patients were tested for the SARS coronavirus 2 infection before TVOR, and the procedure was cancelled if the result showed a positive status. In exceptional situations such as ovarian hyperstimulation syndrome (OHSS) or fertility preservation, it was decided to proceed with the TVOR after explaining the benefits and risks to the patient. As far as anaesthesia was concerned, both conscious sedation with analgesia and regional anaesthesia proved to be a safe option in these patients.[94] Cycle cancellation involves both mental and financial strain on the patient, especially in the Indian setting, where patients cannot avail of insurance for ART services.

Ovarian hyperstimulation syndrome

OHSS is one of the most dreaded complications of assisted reproduction. The supraphysiological hormone levels from the hyperstimulated and enlarged ovaries lead to the production of excessive inflammatory mediators including vasoendothelial growth factor. These changes ultimately result in increased capillary permeability and a shift of intravascular fluid to the third space. Although it is quite unusual for these changes to happen before oocyte retrieval, there are reports of the onset of symptoms within 24 h of administration of hCG.[95] Patients may present with complications ranging from varied levels of ascites to hypotension, hydrothorax or even pulmonary oedema and shock. These women require rapid-sequence induction for endotracheal intubation and airway protection. Fluid management must be meticulous and patients may require an arterial or central venous line for both fluid administration and adjustment to maintain perfusion and avoid fluid overload and consequences due to increased capillary permeability. In case of extensive ascites or hydrothorax, paracentesis or thoracocentesis may be planned before the administration of GA to improve the respiratory reserve.[96]

DISCUSSION

This review includes research articles on all modalities of pain relief administered during TVOR. There was no strong evidence to prove that a particular anaesthetic technique was better than the rest. Conscious sedation provided better patient and physician satisfaction due to faster recovery and lesser adverse effects when compared to GA.[13,14] Although the ART outcome was similar in both groups, some studies have shown a negative effect when nitrous oxide was used.[14] Similarly, the administration of opioids along with CSA or GA was found to be beneficial with regard to recovery, adverse effects and ART outcome.[8] Intraoperative pain was significantly higher with PCA when compared to the other modalities, although there was no difference in pregnancy rates.[15,31] Paracervical block alone may not provide adequate pain relief unless it is combined with another modality such as conscious sedation[45] or GA,[56] whereas remifentanil[49] or propofol[50] when combined with PCB provides better pain relief and also reduces the requirement of the anaesthetic drug. Various doses of lignocaine have been tried and 50 mg of lignocaine for PCB has proven to be effective in managing pain.[47]

Post-operative side effects such as nausea and vomiting are common with GA or CSA when compared to regional anaesthesia.[33] A recent Indian study suggested that the incidence of nausea and vomiting was more with the use of opioids and that the use of dexmedetomidine instead of fentanyl improved symptoms.[78] Studies have not compared regional anaesthesia with GA or CSA in terms of ambulation, but the use of 1.5% lidocaine resulted in earlier ambulation when compared to 5% lidocaine,[32] whereas the addition of fentanyl to 1.5% lidocaine did not alter the time to ambulation.[80] In our experience, both physicians and patients prefer CSA or TIVA when compared to EA/SA for earlier ambulation and lesser duration of hospital stay. Although GA may provide the best pain relief, disadvantages such as prolonged recovery, need for assisted ventilation, post-operative side effects and the cost factor makes it less favourable when compared to CSA.

Although the review is a compilation of the available evidence for pain relief, statistical analysis was not done to pool the evidence due to the heterogeneity of the studies, different study designs, comparators, dosage and types of drugs. Moreover, the ART outcome also depends on numerous variables and is not confined to the mode of anaesthesia and the anaesthetic drugs alone.

CONCLUSION

In recent times, both patient and specialist prefer an anaesthetic modality which provides early recovery with the least adverse effects. For TVOR especially, women prefer alternatives to GA for faster recovery, cost-effectiveness or for the fear of anaesthesia.[97,98] No single technique or drug has been identified as the best choice for TVOR. Yet, it is the duty of the physician and the anaesthesiologist to individualise and identify the best suitable modality for every woman, discuss the available techniques and the reason for suggesting a particular modality for her, its advantages and possible adverse effects. According to this review, conscious sedation appears to be the most preferred mode of anaesthesia in women undergoing TVOR owing to its fewer adverse effects, faster recovery, better patient and specialist comfort and the least effect on oocyte quality and embryo development. Combining it with paracervical block resulted in lesser consumption of the anaesthetic drug, which may have a beneficial effect on the oocyte quality. Therefore, a multimodal approach may be able to provide effective pain relief and better recovery with fewer adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.