Journal of Obstetric Anaesthesia and Critical Care

REVIEW ARTICLE
Year
: 2022  |  Volume : 12  |  Issue : 1  |  Page : 5--16

Anaesthesia for assisted reproductive technology (ART): A narrative review


Ranjana Khetarpal1, Veena Chatrath1, Puneetpal Kaur1, Anjan Trikha2,  
1 Department of Anaesthesia, Government Medical College, Amritsar, Punjab, India
2 Department of Anaesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. Ranjana Khetarpal
Department of Anaesthesia, Government Medical College, Amritsar - 143 001, Punjab
India

Abstract

Assisted reproductive technology (ART) is used primarily to address the treatment of infertility which includes medical procedures such as in vitro fertilisation (IVF), intra-cytoplasmic sperm injection (ICSI), gamete intra-fallopian transfer (GIFT) or zygote intra-fallopian transfer (ZIFT). IVF has revolutionised infertility treatment and is nowadays widely accepted all over the world. The IVF is carried out as a daycare procedure and many anaesthetic regimens have been studied, tried and tested so far. An anaesthesiologist's role mainly comes into play during trans- vaginal oocyte retrieval and embryo transfer (ET) process of IVF. Various techniques of anaesthesia are practised which include general or regional anaesthesia, conscious sedation or monitored anaesthesia care, patient-controlled analgesia, acupuncture and transcutaneous electrical nerve stimulation (TENS). The anaesthetic management needs careful consideration of the effect of drugs on the maturation of oocytes or embryonic development, fertilisation and pregnancy rates. In view of the Coronavirus disease-19 (COVID-19) pandemic, ART clinics have been affected and due to the ambiguity of its effects on the reproductive outcome, anaesthesiologists need to be vigilant and cautious with anaesthetic management during pandemic times. This review includes a discussion of various anaesthetic options and agents along with their advantages or disadvantages if any. The literature sources for this review were obtained via PubMed, Medline, Cochrane Library and Google Scholar. The results of 82 out of 110 articles discussing different methods of anaesthesia for ART procedures over 25 years were compiled.



How to cite this article:
Khetarpal R, Chatrath V, Kaur P, Trikha A. Anaesthesia for assisted reproductive technology (ART): A narrative review.J Obstet Anaesth Crit Care 2022;12:5-16


How to cite this URL:
Khetarpal R, Chatrath V, Kaur P, Trikha A. Anaesthesia for assisted reproductive technology (ART): A narrative review. J Obstet Anaesth Crit Care [serial online] 2022 [cited 2022 Dec 8 ];12:5-16
Available from: https://www.joacc.com/text.asp?2022/12/1/5/339545


Full Text



 Introduction



Fertility medicine is a progressive and dynamic field of medicine with the evolution of new techniques and developments due to ongoing research work. Women now prefer to have few children and that too at a later stage of life, leading to an increase in maternal age which adversely affects fertility. Various assisted reproductive techniques are used worldwide for the treatment of infertility. Some of the indications for the use of these techniques include an inadequate number or quality of oocytes, irreparability of the uterus or absent uterus, deficiency or defect in sperm quality in men or genetic abnormalities in couples. Also, egg freezing is nowadays done in cancer patients before chemotherapy/radiotherapy, for in vitro fertilisation (IVF) to be done later when required. The IVF process involves a series of steps [Table 1] and [Table 2] for fertilisation of male and female gametes outside the female body, i.e. in the laboratory and transfer of embryos into the uterus.[1]{Table 1}{Table 2}

 Methodology



This narrative review was compiled by a comprehensive literature search on the Cochrane Library, PubMed, Medline, EMBASE and Google Scholar using keywords such as anaesthesia for IVF, conscious sedation, acupuncture, transvaginal oocyte retrieval (TVOR). The articles included were those discussing the various anaesthetic considerations, novel techniques and drugs in anaesthesia for ART procedures. After the elimination of duplicates and non-relevant content of the papers, this review was assembled using a mix of case series, retrospective and prospective studies, original research articles, systematic reviews and meta-analysis done all over the world from 1985 to 2021. Our focus was mainly on the ongoing latest anaesthetic techniques like conscious sedation and total intravenous anaesthesia (TIVA) for IVF and newer anaesthetic drugs like dexmedetomidine for better outcomes for the patients. Out of the 110 articles selected, 82 were used for data extraction and analysis and the reference list of the retrieved articles was used for our review.

 Discussion



An anaesthesiologist is likely to be required for the step of oocyte retrieval which is considered as a fundamental step in the IVF process and the most painful procedure for women. The oocyte retrieval was earlier done using the pelvic laparoscopic technique for direct visualisation of ovarian follicles[2] with the use of insufflation of the carbon dioxide gas to create a pneumoperitoneum, which further added to the pain and distress of the patient and was moreover an invasive approach and anaesthesia were required. Also, carbon dioxide pneumoperitoneum was found to be associated with a decrease in the follicular fluid with alteration of its pH and decreased fertilisation rates, thus, this technique is not done now.[3] The anaesthetic drugs have also been detected in the follicular fluid leading to a detrimental effect on the fertilisation and development of the embryo which results in lower rates of pregnancy.[3] Nowadays, less invasive and less painful ultrasound-guided TVOR is practised and laparoscopic procedures for the retrieval of oocytes are used only for tubal transfers, i.e. gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT) procedures.[4]

Women are usually anxious during the oocyte retrieval due to emotional, psychological and personal factors involved in the whole process of IVF and infertility treatment. Furthermore, pain during the retrieval process adds to it. The pain is due to a puncture of the vaginal tissue and ovarian capsule with the use of a needle for the aspiration of the oocytes and manipulation of ovaries during the entire procedure.[4] Multiple attempts are usually needed according to the condition of the ovary and follicles. For the elimination of the possibility of piercing any major vessel during the process, complete immobilisation and relaxation of the patient are needed. The TVOR though less invasive is more painful too.[5] The anaesthetic technique should be chosen to ensure anxiolysis and optimal analgesia without any detrimental effect on the favourable outcome of pregnancy.

 Ideal Anaesthetic Method



The potential association between the anaesthetic agents and techniques to be used and the outcomes of ART should be kept in mind. The assessment of specific anaesthetic drugs should also be considered in the context of their method of administration, dosage and combination with other drugs, the timing of administration and duration of exposure along with drug interactions.[6] There is no consensus regarding the best or the least harmful anaesthetic technique used for oocyte retrieval although the ideal features of the anaesthetic method are listed in [Table 3].{Table 3}

 Anaesthetic Implications



Drug Interactions: Controlled ovarian stimulation for IVF includes three defined protocols—Gonadotropin releasing hormones (GnRh) agonist long protocol, GnRH antagonist protocol and minimal stimulation protocol. GnRH agonist offers a longer treatment duration while the antagonist protocol offers a shorter duration along with a lesser risk of ovarian hyperstimulation syndrome but associated with low follicular production. The minimal stimulation protocol includes clomiphene citrate and gonadotropins, has lower cost and is used in poor oocyte reserve patients. The use of gonadotropin-releasing hormone agonist/antagonist is done for pituitary down-regulation, improvement of folliculogenesis and oocyte maturation by reducing the endogenous leutenising hormone (LH) surge, thereby, leading to the retrieval of maximum oocytes.[6],[8] These hormonal manipulations result in oestrogen levels varying from zero at the baseline to supraphysiologic concentrations at the time of oocyte pick-up in the patients.[9] The albumin and alpha-1 acid glycoprotein synthesis are affected by the oestrogen which reduces the drug binding and leads to an increase in the free fraction of the highly protein-bound drugs in the circulation. So, the selection of the drugs and their appropriate dosage is extremely important.Coexisting illness: The patients under treatment for IVF usually have coexisting illnesses such as pelvic inflammatory disease due to infections like chlamydia and pre-existing thyroid disorder.Pregnancy is a hypercoagulable state and this gets further aggravated due to the use of gonadotropin injections and the patients might be taking anticoagulants such as heparin or aspirin. Aspirin should be stopped at least 3 days before the oocyte pick-up and monitoring of the activated prothrombin time in the case of unfractionated heparin is essential.[4]Anxiety is usually seen in patients due to the psychological and social stigma attached to IVF. Advanced maternal age and a greater degree of family pressure for bearing the child leads to depression or psychosis. These patients may be on selective serotonin reuptake inhibitors (SSRI).[10] These drugs are involved in cytochrome P450 inhibition, serotonin syndrome and have a synergistic effect with the anticoagulants. There is an increased risk of bleeding due to the anti-platelet effect when used with non-steroidal anti-inflammatory drugs, warfarin and other anticoagulants. Drugs such as fentanyl and other phenyl-piperidine opioids (pethidine, tramadol, remifentanil) are also weak SSRI and one must use them cautiously along with SSRIs which can enhance serotonin release and lead to serotonin syndrome. Thus, the adjustment of the dosage of the anaesthetic agents especially opioids during the procedure is advisable.Many older women come for ART and maternal age is the dominant factor in predicting the success of the IVF outcome as the number of oocytes decrease with the advancing age thus reducing the chances of conception and increasing the chances of miscarriage.[6] For the anaesthesiologist, an older woman is likely to have more comorbid conditions than those in the younger age group.Fertility preservation is an issue in the patients undergoing chemotherapy or radiotherapy along with anaesthetic implications of the basic malignancy. These therapies reduce the response to ovulation induction and increase the risk of organ dysfunction which might complicate the anaesthetic management. So, IVF with cryopreservation of the embryos has to be done before starting chemotherapy or radiotherapy.A large number of women reporting for ART are obese and the body mass index (BMI) of the patients is also an important factor for the dosage of anaesthetic agents to be used during the oocyte retrieval. A BMI greater than 27 leads to a 33% decrease in the live birth rate after one cycle of IVF.[1] The patients may be morbidly obese, with liver, renal dysfunction, cardiac or pulmonary pathology and difficult airway. A study conducted for the analysis of intravenous anaesthesia in the IVF for obese patients and normal BMI patients concluded that visualisation of ovaries during the procedure becomes difficult due to the high-fat content, thus, leading to a longer duration of the procedure along with the risk of damaging the adjacent structures. Thus, an additional dosage of the anaesthetic agents was needed resulting in higher drug consumption and even frequent use of muscle relaxants (e.g. succinylcholine) was observed.[11]

 Anaesthetic Techniques for Oocyte Retrieval



TVOR is usually performed as a daycare procedure of short duration.[12] Various anaesthetic approaches are being utilised for oocyte retrieval with each one having its own merits and demerits [Table 4] and [Table 5].{Table 4}{Table 5}

General anaesthesia

General anaesthesia makes aspiration of the fluid easier for the surgeon by relaxing the uterus and preventing the movement of the patient during the process, thus, increasing the comfort level of both the patient and the surgeon and improves the success rate of oocyte pick-up. With proper relaxation of the walls, the aspiration of even smaller ovarian follicles becomes simpler. The key is to use the safest drug in the minimal possible dosage for the minimal possible time duration. All patients are instructed to follow the standard fasting guidelines and informed consent, as usual, is to be taken from the patient before the procedure for any type of anaesthesia.

Propofol

Its pharmacokinetic profile makes it a first-choice drug for anaesthesia. Propofol accumulates in the follicular fluid which shows a rise in the concentration only with an increased duration of exposure,[13] suggesting its cautious use. A cohort study of 130 women was done to assess the effect of exposure to increasing concentrations of propofol on IVF, cleavage and embryo development. Oocyte retrieval was done using propofol and fentanyl. The follicular fluid concentrations of propofol were measured and there was no difference in the ratio of mature to immature oocytes although there was an increase from the first to the last follicle but there were no differences in fertilisation and cleavage.[14] In a survey of anaesthesia for conception in which a standard questionnaire was used to enquire about the ART procedure, the anaesthetic technique and drugs used, it was observed that there was no detrimental effect of propofol on the quality of oocytes and fertilisation rates.[15]

Thiopentone sodium

This is considered a safe choice as an induction agent with no toxic effects.[16] A randomised controlled trial was done for the comparison of thiopentone and propofol as induction agents for oocyte retrieval.[17] A total of 180 patients were included and they were given either propofol or thiopentone for induction as well as maintenance of general anaesthesia along with fentanyl. No baseline characteristic differences were noted and the overall fertilisation rates were comparable between the two groups. General anaesthesia showed similar fertilisation rates, oocyte retrieval number and IVF outcome. Propofol anaesthesia had a more favourable complication profile intraoperatively, after emergence and during recovery, along with a shortened recovery phase. The thiopentone group had more time under anaesthesia, prolonged recovery time and was associated with nausea, an extended period of somnolence along with agitation during emergence from anaesthesia. It can be, thus, concluded that thiopentone is a safe option if propofol is not available.

Ketamine

Both ketamine and ketamine-propofol mixture have been used as anaesthetic agents for ART. A study compared propofol and ketamine separately and in combination for the oocyte pick-up process.[18] The fertilisation rate was reduced with ketamine as compared to propofol (P = 0.013) and the combination group of propofol with ketamine (P = 0.008). It was concluded that the use of ketamine alone for oocyte pick-up reduced the fertilisation rates while implantation, pregnancy rates and oocyte retrieval parameters (number of total retrieved oocytes and embryo quality) did not differ between the groups. An increased anaesthesia duration (more than 30 min) was found to be associated with low implantation and pregnancy rate.

In a study comparing midazolam-ketamine sedative combination and propofol-fentanyl anaesthesia, it was concluded that ketamine (0.75 mg/kg), when given with midazolam (0.06 mg/kg) is an acceptable method of sedation for oocyte retrieval, although patient satisfaction rates and pregnancy rates were similar in both the groups.[19]

Therefore, ketamine alone is not one of the good choices for ART, though there are reports of satisfactory outcomes when it is mixed with propofol or midazolam.

Etomidate

It is an ultra-short-acting non-barbiturate hypnotic with minimal cardiovascular and respiratory effects. A prospective comparative study was done by Heytens et al.[20] to study the effect of etomidate and thiopentone anaesthetic induction on ovarian hormones during laparoscopic oocyte retrieval. A decreased plasma concentration of 17 beta-oestradiol, progesterone and testosterone was observed after 10 min of induction with etomidate (0.25 mg/kg) which later returned to baseline levels while no such changes were observed with thiopentone. It was concluded that etomidate might also affect the endocrine function of the ovary along with adrenocortical suppression. Therefore, it is not the preferred drug for ART procedures.

Opioids

Various opioids are used as components of balanced general anaesthesia or monitored anaesthesia care. Pethidine is most commonly used as a pre-medication for such cases. All synthetic opioids have been studied regarding their effect on the fertilisation rates, penetration in the follicular fluid and toxic effect on oocyte structure. Most of them have been found to be safe without any toxic effects. Fentanyl and alfentanil have the least penetration in the follicular fluid, i.e., 10:1 ratio in the serum and follicular fluid.[21]Alfentanil, remifentanil, fentanyl and pethidine have not been found to be associated with any effect on, pregnancy rates or embryo development.[22],[23] In comparison, the remifentanil-based monitored anaesthesia care (MAC) technique has been shown to have higher chances of successful pregnancy as compared to fentanyl. Another study done by MH Jarahzadeh et al.[16] has suggested remifentanil as superior to fentanyl leading to higher pregnancy rates.

Benzodiazepine

Midazolam is one of the most commonly used benzodiazepines for oocyte retrieval. Though a minimal amount of this drug is found in the follicular fluid, it neither has any detrimental effects nor is it teratogenic.[24] Various studies have proposed the safe use of a combination of midazolam, fentanyl and remifentanil for the oocyte pick-up process.[25]

Bromocriptine and non-steroidal anti-inflammatory drugs

Bromocriptine, a potent dopamine agonist, can be given before anaesthesia which leads to the suppression of anaesthesia-induced hyperprolactinemia and has a positive effect on the development of the embryos.[26] In a retrospective study by Mialon et al.,[27] comparing paracetamol/alprazolam with ketoprofen/nefopam combination as an analgesic in the IVF process, it was concluded that both groups provided a similar level of patient satisfaction and IVF outcome.

 Inhalational Agents



Nitrous oxide

The use of nitrous oxide as a component of balanced general anaesthesia for the oocyte retrieval process is still under research. It reduces methionine synthetase activity, DNA synthesis, non-methylated folate derivatives, impairs the function of mitotic spindles in the cell culture. Gonen et al.[28] concluded that nitrous oxide has deleterious effects on the IVF outcome as it decreases the amount of thymidine while Rosen et al.[29] observed increased rates of successful IVF outcome due to the reduction of the concentration of other toxic and less diffusible agents by the use of nitrous oxide. Its role is considered controversial till further trials are carried out.

Volatile halogenated agents

These agents are usually avoided due to the adverse effects of halogenated fluorocarbons with nitrous oxide on the oocyte cleavage and increased rate of abortions.[30] Matt et al.[31] studied the effect of nitrous oxide and isoflurane on the IVF pregnancy rates which adversely affected oocyte maturation. Isoflurane is known to adversely affect embryo development in vitro[32] and an increase in prolactin levels is noted with volatile halogenated agents leading to a decrease in oocyte development and receptivity of the uterus. Fishel et al.[33] concluded that halothane anaesthesia led to lower pregnancy and delivery rates compared to enflurane. Compound A, a breakdown product formed due to the reaction of sevoflurane with carbon dioxide absorbent in the closed circuit, is associated with genotoxic ovarian cell effects. Sevoflurane induces a reduction in the number of good-quality embryos so caution is to be exercised with sevoflurane/desflurane. Although these data suggest that volatile agents can affect ART outcomes, the mechanisms remain incompletely evaluated and the safety profile is not clear. So, only guarded use is recommended in laparoscopic ART procedures.

General anaesthesia with spontaneous/assisted mask ventilation is usually preferred in the form of TIVA with propofol and midazolam or fentanyl. Raftery and Sherry in a study done on 80 women concluded that TIVA with propofol and alfentanil is superior to inhalational anaesthesia with nitrous oxide and enflurane in the context of nausea and vomiting and has lesser need of anti-emetics along with faster recovery time in a daycare IVF procedure.[34] A study was conducted on the comparison of different anaesthetic methods for sedation during IVF procedures.[35] The effect on the physiology of the patient and oocyte competence was studied. Four analgesic techniques, i.e., the use of the eutectic mixture of lidocaine and prilocaine, propofol, thiopentone and sevoflurane were compared separately for oocyte retrieval. The eutectic mixture was applied on the vaginal fornices 1 hour before the operation and a vaginal tampon was inserted. The eutectic mixture of lidocaine and prilocaine and sevoflurane group showed similar fertilisation rates which were significantly higher than the propofol and thiopentone group. So, the study suggested local anaesthetic cream like Eutectic mixture of Local Anaesthetics (EMLA) as an admissible choice for oocyte retrieval when compared to other used techniques in terms of no effect on oocyte maturation and fertilisation rates.

Antiemetic agents

Antiemetic agents such as droperidol and metoclopramide rapidly induce hyperprolactinemia which can impair the maturation of ovarian follicles and function of the corpus luteum.[36] Forman et al.[37] observed that lower plasma prolactin concentration during ART procedures was associated with an increased incidence of pregnancy. While ondansetron does not affect prolactin levels, it has not yet been studied for ART. The search for an ideal antiemetic agent which can be safely used for ART procedures is still on while ondansetron can be considered a safe choice.

Regional anaesthesia

Regional anaesthesia in the form of central neuraxial blockade or peripheral nerve blockade has been advocated for TVOR.

Sub-arachnoid and epidural block

Spinal anaesthesia is an effective method in which low-dose local anaesthetic along with opioids can be employed. Martin et al.[38] used a solution of 1.5% lidocaine mixed with low dose of 10 mcg fentanyl in one group of patients and lidocaine alone in another group of patients for spinal anaesthesia administred for oocyte retrieval and observed more patient satisfaction in the fentanyl with lidocaine group. LC Tsen et al.[39] compared low-dose (3.75 mg) bupivacaine (0.75%) and 25 mcg fentanyl versus low-dose (30 mg) lidocaine (1.5%) and 25 mcg fentanyl for spinal anaesthesia in the IVF procedure and found no significant difference in their analgesic and anaesthetic effects. In another study, Aghaamoo et al.[40] tried to observe the advantages of spinal anaesthesia, if any, over general anaesthesia for IVF. Both techniques were compared for oocyte retrieval in terms of success in infertility treatment. These authors concluded and recommended that spinal anaesthesia was better for the retrieval of oocytes as compared to General anaesthesia (GA) in terms of cost-effectiveness, higher pregnancy rates (two times more when compared with GA), duration of hospitalisation and respiratory complications.

In another study done by Azmude et al.,[41] it was observed that spinal anaesthesia led to enhanced fertilisation rates (27%) than general anaesthesia. Intrathecal fentanyl l0 mcg added to lidocaine (45 mg) has been documented to improve postoperative analgesia with no increase in time to ambulation, urination and discharge.[42] However, due to concerns about transient neurological symptoms (TNS) reported after hyperbaric xylocaine, low-dose spinal bupivacaine, though associated with a relatively long time to urination and discharge, is preferred.

A study was done to compare spinal mepivacaine–fentanyl combination versus spinal bupivacaine–fentanyl combination for anaesthesia in ultrasound-guided TVOR. Patients in one group received intrathecal 37.5mg of isobaric mepivacaine 1.5% with 10μg fentanyl while patients in another group received intrathecal 12.5mg of hyperbaric bupivacaine 0.5% with 10μg fentanyl. The mepivacaine–fentanyl combination was found superior to the bupivacaine–fentanyl combination because of a faster resolution of sensory and motor block, earlier ambulation and hospital discharge with acceptable surgical anaesthesia.[43]

Epidural anaesthesia can be an option but has no added advantage over intravenous sedation or any other methods.[44] The sub-arachnoid block is preferred over epidural due to lower failure rates, faster recovery rates along with decreased follicular concentration of the anaesthetic agents. In conclusion, spinal anaesthesia is a safe option and the preferred local anaesthetic as per evidence is either bupivacaine or mepivacaine mixed with fentanyl.

However, as IVF is done on an ambulatory basis and sensory and motor function recovery is a prerequisite for discharge, spinal anaesthesia is not much acceptable to the patient and is not routinely practised.

Paracervical block and pre-ovarian block

Paracervical block (PCB) using different doses of lidocaine along with sedation has been used for oocyte retrieval.[45] PCB with bupivacaine for oocyte retrieval was studied by Corson et al.[46] In PCB, the local anaesthetic is injected at 2–6 sites at a depth of 3–7 mm along the vaginal fornices and along the cervix. It does not cover the ovarian walls and the sensations from vaginal and ovarian pain fibres are incompletely blocked, thus, needs to be supplemented with sedation. The pre-ovarian block is a newer technique in which the local anaesthetic is injected in the vaginal area between the vaginal walls and peritoneal surface near the ovary under the transvaginal ultrasound guidance.[47]

Various sedation regimes involving medications like midazolam, alfentanil can be used with PCB to ensure the proper analgesic effect. A study was conducted for the use of PCB for TVOR in a public health facility in Nigeria[48] in which a total of 66 patients who underwent IVF-ET (embryo transfer) were assessed. The patients were given PCB with a needle using 100 mg (10 mL) of 1% lidocaine into the lateral fornices. This study showed that PCB has no deleterious effect on fertilisation and development of the embryo, although the pain relief effect was restricted suggesting the use of multimodal analgesia approach with the block for effective analgesia. The concentration of lidocaine in the follicles was minimal with the use of 50 mg lidocaine when the oocytes were washed after retrieval. PCB along with electroacupuncture and alfentanil analgesia has also been tried to enhance pain relief.[49]

A study was done to compare PCB and general anaesthesia. Its effect on live birth rate, pain and patient satisfaction.[50] It concluded that the type of anaesthesia has no impact on the live birth rate. General anaesthesia offered better analgesia and patient satisfaction. The number of oocytes retrieved and the number of mature oocytes that were picked up was more in the patients who had received general anaesthesia.

Another local anaesthetic that has been used for oocyte retrieval is tetracaine. As a local anaesthetic, it acts on the peripheral nerves to block nerve impulse transmission providing stable and safe analgesia.[12] The tetracaine gel preparation used also possesses a lubricating effect like paraffin oil. It has been shown to also relax the sphincter, which is helpful for vaginal oocyte retrieval under ultrasound guidance. It has been shown to decrease the total dose of propofol required when both of them are used together—propofol for sedation and tetracaine as a local anaesthetic.[51],[52]

Regarding the anaesthesia technique for TVOR—both general and regional anaesthesia have been found to be satisfactory but there are inherent concerns regarding the interactions between maternal hormones and drugs used for general anaesthesia.

 Conscious Sedation and Monitored Anaesthesia Care



In these patients, though there is a dearth of data available about the various combination of drugs used for conscious sedation, it is a widely accepted anaesthetic method for TVOR.[53] It involves minimal depression of the consciousness level and the patient can maintain her airway and can respond to physical and verbal stimulation, thus, verbal contact is maintained with the patient during the procedure. Conscious sedation is reported to be safer, economical and well-tolerated with the clinical pregnancy rate reported to be 47.9% and a higher patient satisfaction rate.[53] There have been reports in the literature where different medications have been used for conscious sedation with satisfactory results.

In the recent Cochrane review, there were four studies which compared different drug regimens used for conscious sedation and found no significant difference in the analgesia between midazolam and fentanyl versus propofol and fentanyl, though the midazolam and fentanyl combination was associated with lesser nausea and vomiting.[54] It was observed that the use of more than one technique of anaesthesia simultaneously offered better analgesia than using a single modality.

In a study carried out on 71 patients undergoing TVOR, a combination of pethidine and midazolam was used for sedation as a bolus and then followed by top-up doses depending on the patient's responses. The authors found it to be a satisfactory combination for the procedure.[55]

An earlier randomised study compared conscious sedation using midazolam and ketamine with general anaesthesia using propofol and found similar patient satisfaction and pregnancy rates in both groups.[19] A randomised trial on IVF outcome using remifentanil versus propofol-alfentanil for TVOR was conducted.[56] Both regimens showed a similar anaesthetic profile in terms of efficacy, safety and satisfaction scores of patients and also similar effect on the cleavage and pregnancy rates. In another study for sedation in TVOR, the pregnancy rates were found to be significantly higher after remifentanil infusion than fentanyl.[16]

Another drug, dexmedetomidine is a centrally acting alpha-2 receptor agonist, having both analgesic and sedative effects and devoid of respiratory depression.[57] It can be used as an effective sedative in the oocyte retrieval process, providing better satisfaction and reducing opioid need.[58] Dexmedetomidine offered a favourable analgesic effect for TVOR along with a shorter hospital stay without any side effects.[59] Two sedation protocols were compared during TVOR in a cohort study.[60] One group was given dexmedetomidine at 1 mcg/kg/min with fentanyl and the second group was given remifentanil at 0.2 mcg/kg with midazolam 1 mg IV. In case of non-compliance, propofol was used as a rescue drug in both groups. The use of dexmedetomidine was found to be associated with higher propofol consumption but it did not impair the fertilisation rates and was associated with good quality of embryos but needed monitoring for hypotension or bradycardia. Candiotti et al.[58] concluded that dexmedetomidine is effective, safe and a well-tolerated sedative alternative to other Benzodiazepines (BZD)/opioid combinations and showed a lower incidence of respiratory depression in addition to higher compliance rates.

A retrospective study compared the chemical pregnancy rates (elevation in beta-Human Chorionic Gonadotropin (HCG) levels 15 days after implantation) according to the anaesthetic methods used during TVOR in IVF.[61] Similar rates of pregnancy were seen in the MAC and spinal anaesthesia group. Conscious sedation methods were preferable to using fentanyl, remifentanil and alfentanil. The inferior outcomes of IVF were noticed under general anaesthesia rather than under spinal or MAC and the procedural time was significantly short in the spinal group.

Conscious sedation using a combination of benzodiazepines, opioids like fentanyl/remifentanil and newer drugs like dexmedetomidine is a safe and efficacious option for oocyte pick-up and is related to improved outcomes. It provides analgesia with a minimal level of sedation which allows verbal communication with the patient. The level of sedation may need to be increased to prevent movement during the procedure.

Patient-Controlled Analgesia

It is an alternative analgesic technique which offers a great degree of patient satisfaction by allowing the patient to exercise control over the drug administration. Patient-controlled analgesia (PCA) with fentanyl has been found to enhance patient comfort and satisfaction. A study done by Lok et al.[62] compared PCA using propofol along with alfentanil versus diazepam and pethidine (given by the physician) and concluded that PCA was better acceptable to the patients, although providing lesser analgesia. PCA with remifentanil has shown acceptable analgesic effect during oocyte retrieval when compared with the use of pethidine with midazolam for the same and is associated with lesser sedation and better patient comfort than pethidine.[63] PCA is an acceptable method for TVOR by enhancing patient cooperation and satisfaction.

Alternative Newer Approaches—Acupuncture and Transcutaneous Electrical Nerve Stimulation

Acupuncture, electroacupuncture and TENS have all been used either alone or along with various techniques like regional anaesthesia and conscious sedation for ARTS. Acupuncture is a traditional Chinese technique, non-toxic and acceptable therapy with additional beneficial effects such as sympatho-inhibitory effect, raises beta-endorphin levels and anti-depressant effect.[13] Various medications along with acupuncture have been studied to ensure proper analgesia for the oocyte pick-up process.[7] The electroacupuncture technique can be used along with paracervical block for TVOR analgesia which utilises the mechanism of neuropeptide release produced by electrical stimulation of different frequencies.[64]

Analgesia during oocyte retrieval was studied using transcutaneous electrical acupoint stimulation (TEAS) in a randomised control trial.[65] It is a user-friendly technique without the use of manual needles and electroacupuncture, to reduce the invasiveness. It was administered 30 min before the procedure till the end of the procedure. The study concluded that the pain relief during oocyte pick-up was lesser. So, it could be utilised for oocyte pick-up procedures for reducing pain and discomfort.

Paulus et al.[66] showed acupuncture as an effective choice for improved pregnancy rates after ART procedures. But, the mechanism of action of acupuncture is not well-understood yet and its application time and placebo effects are not known.[13]

Nowadays, some women prefer to have an option to undergo oocyte retrieval without sedation or analgesia. A recent prospective study, including 100 healthy women who underwent IVF, was conducted to study why women prefer to choose no anaesthesia or analgesia for oocyte retrieval.[67] It was observed that women who underwent oocyte retrieval without any analgesia/sedation reported more fear of anaesthesia, and also, had a lesser number of oocyte aspirations and more pain but still chose to undergo any subsequent oocyte retrieval without sedation/analgesia. It was observed in another study that such women had concerns regarding anaesthetic drugs and wanted to have a natural course of IVF.[13] In another study, it was observed that women experienced lesser pain, even when choosing no sedation/analgesia during the oocyte pick-up process[68],[69] which was attributed to the use of the newly designed thin-tipped needles for aspiration.

 Anaesthesia for Embryo Transfer



Transcervical ET procedures are generally painless and done without anaesthesia or analgesia, though sedation may be required in some cases. For procedures like zygote intra-fallopian transfer (ZIFT) and gamete intra-fallopian transfer (GIFT), the general anaesthesia technique is preferred as both of these procedures involve trans-abdominal or transvaginal collection of oocytes using the laparoscopic technique and these are performed with the patient in the Trendelenburg position.[6]

The induction of general anaesthesia is delayed till the skin incision to minimise the exposure to both carbon dioxide pneumoperitoneum and anaesthetic drugs to the oocytes in the GIFT procedure in which retrieval and transfer are done laparoscopically by trans-abdominal approach in the same sitting. General anaesthesia with tracheal intubation is preferred using induction agents, opioids, muscle relaxants and volatile halogenated agents. While in the ZIFT procedure, oocyte retrieval can be done trans-vaginally and the ET is done using the laparoscopic method later which avoids the prolonged exposure to pneumoperitoneum and drugs to oocytes. The intra- and postoperative complications associated with the laparoscopic technique are rare but can occur such as gastric or intestinal perforation, haemorrhage, pneumothorax, gas embolism and even cardiac arrest.[70]

The spinal or epidural anaesthesia can also be employed for GIFT as suggested by a study.[71] Healthy, non-obese patients have been reported to undergo laparoscopic surgeries under spinal or epidural block while limiting the intra-peritoneal pressure to less than 10 mmHg.[72] Local anaesthesia combined with intravenous sedation analgesia has also been tried and tested for laparoscopic ART procedures.[73]

The technical improvements in the ultrasound procedures and fibreoptic techniques in the form of mini-laparoscopic procedures for oocyte retrieval and fallopian tube cannulation can make the laparoscopic approaches less invasive for GIFT. Such developments can lead to alterations in the options of anaesthetic techniques.

The evidence is that simple balanced anaesthesia using propofol and alfentanil/remifentanil with midazolam as pre-medication provides optimal conditions for oocyte pick-up. In a daycare procedure done on an ambulatory basis as for IVF, the recovery of sensory and motor functions is needed for timely hospital discharge. So, spinal anaesthesia is not usually preferred though there are studies reporting the use of spinal mepivacaine–fentanyl combination with satisfactory results. Regional anaesthesia using a paracervical block with conscious sedation is an acceptable alternative. General anaesthesia is used restrictively because the laparoscopic methods of oocyte retrieval have been replaced by less invasive TVOR. However, a multimodal approach to anaesthesia and analgesia is advised to enhance patient comfort and better IVF results.

In view of the current pandemic situation, recent American Society for Reproductive Medicine (ASRM) guidelines have been published for COVID-19 and ART and it is advisable to follow them strictly during ART procedures.[74]

 Obstetric Complications



Hormonal stimulation with gonadotropin agonist/antagonist during ART can lead to increased coagulation and decreased fibrinolysis. The ovarian hyperstimulation syndrome is an iatrogenic complication of ovarian stimulation that occurs during the luteal phase of early pregnancy. Usually, it is seen after the induction of the follicular rupture following administration of human chorionic gonadotropin hormone when follicular growth has been medically induced by medications like clomiphene citrate or gonadotrophins. Earlier in this disease there is an increase in the size of the ovaries and this causes abdominal discomfort. Later this may progress to the formation of cysts in the ovary causing abdominal distension, pain, nausea, vomiting and diarrhoea. This may be followed by ascites, pleural effusion and even pericardial effusion.[75] In severe cases, hypoalbuminaemia, hypovolaemia, oliguria and electrolyte imbalance develop. Liver dysfunction can also occur. Thromboembolism is the most dreaded complication and can be fatal. Oocyte retrieval can be done earlier and ET is delayed in such cases.

The anaesthetic management requires immobility during the procedure to avoid injury to all adjacent structures,[76] so methods are to be individualised according to the clinical status of the patient. Manual ventilation with a face mask or laryngeal mask airway is recommended usually. However, controlled ventilation is required with balanced general anaesthesia with Rapid Sequence Intubation (RSI) and TIVA using propofol and rocuronium as a neuromuscular relaxant when respiratory distress develops secondary to tension ascites. Cis-atracurium may be used in the context of liver or renal dysfunction. Thromboprophylaxis is initiated with low molecular weight heparin in severe cases of Ovarian Hyperstimulation syndrome (OHSS) due to the risk of thromboembolism secondary to haemoconcentration, immobility and thrombocytosis.[77] The patient might have an electrolyte imbalance, thus, fluid therapy for intravascular volume repletion is crucial. Adequate anaesthetic management is also required in case of emergency laparoscopy or laparotomy for cyst rupture or oophorectomy.Multiple gestation pregnancies: The rates of multiple gestation have been found to be higher in the ART procedures after the use of hormonal therapy along with the transfer of multiple oocytes and embryos. The rate of pre-term birth and related complications is higher in twin and triplet births which further pose difficult anaesthetic management.[78] The higher BMI (obese) of the women, specific airway concerns or any contraindications to neuraxial anaesthesia complicate the anaesthetic management. Multiple births lead to a higher chance of pregnancy loss, obstetrical complications and neonatal morbidity or mortality along with an increased rate of caesarean delivery.[1] Intraoperative complications such as maternal hypotension (more aortocaval compression than singleton pregnancy), uterine atony, intra- and post-partum haemorrhage, hysterectomy are associated with such cases. So many countries such as the United States have now imposed a limit to the number of oocytes (not more than three to four) to be transferred during the IVF.[79]Ectopic Pregnancy: It occurs five times more frequently in ART pregnancy than with natural pregnancy (2%) due to the prevalence of tubal disorders as a cause of infertility in women.[80] Other risk factors being endometriosis, ZIFT, large ET, deep fundal transfer, assisted hatching technique, difficult or technical issues of IVF procedure, etc. Usually, it requires termination or surgical removal of the ectopic pregnancy within the first trimester under anaesthesia or it may present as emergency ectopic rupture which will need urgent surgical intervention under anaesthesia. Depending upon the hemodynamic status of the patient, neuraxial blockade or balanced general anaesthesia can be employed.Low birth weight/Pre-term/small for gestational age babies are more commonly observed in ART singleton pregnancies.[81] Birth defects such as septal heart clefts, atresia, cleft palate, etc., have been shown to have an increased incidence in ART pregnancies.[1]

 Conclusion



Assisted reproductive techniques are increasingly being practised worldwide. The anaesthesiologists are faced with the challenge of using the technique that alleviates the patient's anxiety with adequate analgesia and at the same time does not have detrimental effects on the successful outcome of pregnancy. The focus is to target minimal pharmacological exposure of short duration with the least penetration in the follicular fluid and to be able to manage complications associated with various steps. Conscious sedation is a safe, efficacious and sustainable anaesthetic option, but it needs the patient's cooperation. Drugs like dexmedetomidine and midazolam along with a multimodal approach of analgesia seem to be promising options. The impact of anaesthetic agents on gametes need to be continuously revisited. Studies on different techniques of anaesthesia and agents fail to pinpoint the best one. The ideal practice should involve judicious use of anaesthetic drugs.

Special attention should be given to the psychological aspects of the patients and obese patients with various comorbidities. The improvement in ultrasonography and use of fibreoptic methods for oocyte retrieval and cannulation of the fallopian tubes have rendered laparoscopic procedures avoidable. Mini-laparoscopic procedures are already being performed for GIFT therapy, allowing a broader view of anaesthetic options. Alternative medicine techniques like acupuncture and the TENS role has to be clarified in future investigations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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