Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial

ARTICLE IN PRESS Reproductive BioMedicine Online (2015) ■■, ■■–■■

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ARTICLE

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Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial

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Evangelia Goutziomitrou a, Christos A Venetis b, Efstratios M Kolibianakis a,*, Julia K Bosdou a, Aggeliki Parlapani a, Gregoris Grimbizis a, Basil C Tarlatzis a

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Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Greece; b Women’s and Children’s Health, St George Hospital, University of New South Wales, NSW, Australia

Q1 * Corresponding author. E-mail address: [email protected] (EM Kolibianakis). Goutziomitrou Evangelia, MD, is a coordinator of the Anesthesiology Department at Papageorgiou Hospital and a PhD candidate at the Unit for Human Reproduction, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece. She obtained her medical degree from the Aristotle University of Thessaloniki, Greece and her scientific interest is focused on anaesthesia during assisted reproduction.

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Clinical outcomes of IVF cycles using propofol or thiopental sodium as anaesthetic agents for oocyte retrieval were compared. The primary outcome measure was fertilization rate per patient. One hundred and eighty patients undergoing ovarian stimulation with gonadotrophins and gonadotrophin-releasing hormone antagonists for IVF were randomized to receive either propofol (n = 90) or thiopental sodium (n = 90). No significant differences in baseline characteristics were present between the two groups. Overall fertilization rates were similar between propofol and thiopental sodium groups, respectively: median (IQR): 54.8 (29.2) versus 54.6 (29.7); fertilization rates for intracytoplasmic sperm injection only: median (IQR): 70 (50) versus 75 (50), respectively. For secondary outcome measures, time under anaesthesia was significantly increased in the thiopental sodium group: median (IQR): 12 (5) versus 10 (4.5) min, P = 0.019 compared with the propofol group. Number of cumulus oocyte complexes retrieved (median IQR: 7.1 [6.3] versus 6.5 [5.6] did not differ significantly between the two groups. A non-significant difference in live birth rates per randomized patient of +4.4% (95% CI: −5.7 to +14.6) in favour of propofol was observed. Use of propofol compared with thiopental sodium for general anaesthesia during oocyte retrieval results in similar fertilization rates and IVF outcomes. Abstract

© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.

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KEYWORDS: fertilization rate, IVF, oocyte retrieval, propofol, thiopental sodium

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http://dx.doi.org/10.1016/j.rbmo.2015.08.013 1472-6483/© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

ARTICLE IN PRESS 2 1

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E Goutziomitrou et al.

Introduction

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One of the key steps during IVF is the collection of oocytes, which includes paracentesis of follicles through the vaginal wall and aspiration of follicular fluid containing the cumulus oocyte complexes (COC) under ultrasound guidance. Pain during this stage of IVF can be significant and, for this reason, some sort of anaesthetic management is usually required to ensure that discomfort of the patient is minimized. Several approaches are being used for the anaesthetic management of oocyte retrieval, which include local anaesthesia, regional anaesthesia, conscious sedation and general anaesthesia (Vlahos et al., 2009). General anaesthesia, although more invasive and requires the presence of specialized personnel, represents an option with distinct advantages and is being used in a number of IVF clinics (Bokhari and Pollard, 1999). Several drugs have been used as anaesthetic agents for oocyte retrieval, with propofol being preferred in many cases owing to its short induction and recovery time (Boysen et al., 1989, 1990). Nevertheless, experimental evidence has suggested that propofol may be negatively affecting the oocytes (Depypere et al., 1991). More specifically, it has been demonstrated that, in mice, exposure to propofol has a toxic effect on the ability of the oocytes to be fertilized (Depypere et al., 1991; Tatone et al., 1998). Furthermore, in humans, it has been shown that, during oocyte retrieval for IVF, propofol can be identified in the follicular fluid (Christiaens et al., 1999; Coetsier et al., 1992), although this still remains controversial (Alsalili et al., 1997; Ben-Shlomo et al., 2000). Considering the above, reasonable concerns have been expressed about the suitability of propofol as an anaesthetic agent for oocyte retrieval (Hein and Putman, 1997). As an alternative to propofol, thiopental sodium, a barbiturate, has been used for short-term general anaesthesia procedures. The use of thiopental sodium, however, is known to be associated with prolonged recovery time and other complications, such as nausea and vomiting. Whether propofol use is associated with an inferior clinical outcome after assisted reproduction technology, compared with thiopental sodium, has so far been explored in the context of retrospective studies. In these studies, no significant differences were found in fertilization or pregnancy rates (Huang et al., 2000; Pierce et al., 1992). It is well known, however, that retrospective studies are prone to various sources of bias; therefore, evidence of higher quality is required to properly address such an important research question. The aim of this study was to compare the clinical outcome of propofol with thiopental sodium when used as anaesthetic agents for oocyte retrieval during IVF.

or younger, were considered eligible for this trial. Women with a known hypersensitivity to the active substance of the investigating drugs or any of their excipients were excluded from this trial. Each woman was allowed to participate only once. The study was approved by the Ethics Committee Review Board of Papageorgiou General Hospital on 23 November 2009 (approval number: A6869). Once informed consent was obtained, women were randomized to general anaesthesia either with the use of propofol or thiopental sodium. The random allocation of women was made by the anaesthesiologist based on a table of random numbers using a 1:1 allocation ratio on the day of oocyte retrieval. The patient, the physician performing the oocyte retrieval and the embryologists were not aware of the group that each patient was allocated to.

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Ovarian stimulation and oocyte retrieval

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Patients were stimulated for IVF using gonadotrophins either recombinant FSH (Gonal-F, Merck Serono Europe Ltd, London, UK; Puregon, NV Organon, Oss, the Netherlands), urinary FSH (Altermon, IBSA Institut Biochimique S.A. Switzerland) or longacting FSH (Elonva, NV Organon, Oss, the Netherlands). Prevention of premature LH surge was carried out (when necessary) using gonadotrophin-releasing hormone (GnRH) agonists (Arvekap, Ipsen Ltd, France) or antagonists (Orgalutran, NV Organon, Oss, the Netherlands). Recombinent (Ovitrelle, Merck Serono Europe Ltd, London, UK) or human (Pregnyl, NV Organon, Oss, the Netherlands) HCG, or a combination of both, was used to trigger final oocyte maturation. If the treating physician deemed that the patient was at a high risk for ovarian hyperstimulation syndrome, GnRH agonist (Arvekap, Ipsen Ltd, France) was used in GnRH antagonist cycles. An experi- Q4 enced physician retrieved oocytes 36–38 h later using a transvaginal probe with a needle guide. All follicles 11 mm in diameter or wider from each ovary were aspirated using a 17G needle. Oocytes were handed to the embryologist and fertilization was carried out either by conventional insemination, intracytoplasmic sperm injection (ICSI), or both conventional IVF and ICSI. Sequential media was used to culture the embryo (COOK Medical, Ireland, Ltd.), up until day 5 depending on the quality and the number of the resulting embryos. Up to four embryos were transferred according to Greek laws on reproduction. Vaginal micronized progesterone (600 mg daily) was used for luteal support (Utrogestan, Basins Iscovesco, Paris, France, vaginal tablets, 200 mg three times a day).

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General anaesthesia protocol

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Materials and methods

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Patient population and randomization procedure

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This randomized controlled trial (RCT) was carried out at the Unit for Human Reproduction of the 1st Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki from November 2009 to March 2013. Women undergoing oocyte retrieval for IVF under general anaesthesia, and aged 45 years

On arrival to the operating theatre, patients were connected to the monitoring equipment, and a Venturi mask was placed for the delivery of oxygen. A peripheral 18-gauge catheter was placed in the cephalic or basilic vein for the administration of crystalloid fluids and anaesthetic medications. For the induction and maintenance of general anaesthesia, patients received either propofol 2.5 mg/kg and 0.1 mg of fentanyl, with additional doses of 0.5 mg/kg of propofol if required or thiopental 5 mg/kg and 0.1 mg of fentanyl, with additional doses of 1.0 mg/kg of thiopental if required.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

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ARTICLE IN PRESS Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval 1

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Embryo quality assessment

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The morphology of embryos on days 2 and 3 was assessed according to the Ziebe criteria (Ziebe et al., 1997). Each embryo received a score, which was calculated by multiplying the number of cells on that day and its morphological score (1.0 or 2.0: 4, 2.1: 3, 2.2: 2 and 3.1 or 3.2: 1). For example, a day-3 embryo with eight cells and a morphological score of 2.1 would have a total score of 8 × 3 = 24. The mean embryo quality score was calculated per patient for the specific day of embryo culture by adding up the scores of all embryos and dividing this figure by the total number of embryos on that day (Ziebe et al., 1997).

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Outcome measures

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On the basis of published evidence on the potentially toxic effect of propofol on fertilization rates, the primary outcome measure for this study was fertilization rate per patient. Given that both IVF and or ICSI cycles were included in this RCT, Q5 the fertilization rate was defined as the number of two pronuclear zygote (2PN) oocytes divided by the number of cumulus oocyte complexes retrieved per patient. Fertilization rate was also calculated for ICSI cycles only by dividing the number of 2PN oocytes to the number of second metaphase (MII) oocytes inseminated per patient, as well as for IVF cycles only by dividing the number of 2PN oocytes to the number of cumulus oocyte complexes retrieved per patient. Secondary outcomes included number of oocytes retrieved, mean embryological score per patient on day 2 or day 3 of embryo culture, duration of anaesthesia, the mean arterial pressure (MAP) and the heart rate, the complications during anaesthesia and during emergence as well as the complications occurring during the first 2 h after anaesthesia, the total time of recovery after anaesthesia, biochemical pregnancy rate (defined as a positive pregnancy test), clinical pregnancy rate (defined as the presence of an intrauterine gestational sac and live birth rate (defined as the pregnancy of a living infant after 24 completed weeks of gestation).

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Sample size analysis

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A sample size of 86 patients in each group was necessary to detect a difference in fertilization rates of 15% (from 65% to 50%) with a standard deviation of 30% for both groups using a two-sided Fisher’s exact test at an alpha level of 0.05. Assuming potential drop out rates of 5%, it was decided that 90 patients would be recruited in each group.

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Statistical analysis

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Continuous variables are presented as means and SD or medians and interquartile ranges (IQR) depending on the normality of the distribution, which examining visually the disQ6 tribution assessed plots and by using the Shapiro Wilk test. Comparisons between groups were made using the Student’s t-test or the Mann– Whitney U test depending on whether or not the distributions of the variables were normal.

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Categorical variables are presented as percentages and comparisons between groups were made by using Fisher’s exact test. All statistical tests were two-sided and statistical significance was set at P = 0.05. The main analysis in this report was made according to the principle of intention to treat.

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Results Population characteristics One hundred and eighty patients were randomized between a propofol group (n = 90) and thiopental sodium (n = 90) group. Patient participation in the study is shown in the Figure 1. Baseline demographics of the two groups compared are presented in Table 1. Most patients were stimulated using recombinant FSH (n = 131 [72.8%]) and GnRH antagonists (n = 161 [89.4%]) for prevention of premature surge. Final oocyte maturation was triggered in the majority of cases with recombinent HCG (n = 148 [82.2%]). None of the stimulation parameters differed significantly between women who received propofol and those who received thiopental sodium for general anaesthesia during oocyte retrieval (Table 2).

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Primary outcome Fertilization rates per COC retrieved were comparable between the propofol and thiopental sodium groups (Table 3).

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Table 1

Baseline demographics.

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Variablea

Propofol (n = 90)

Thiopental sodium (n = 90)

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Woman’s age (years) Weight (kg) Body mass index (kg/m2) Median (IQR) Previous assisted reproduction technique cycles Median (IQR) Duration of Infertility (years) Median (IQR) Origin of subfertility Female factor Male factor Combined Unexplained Smoking (yes/no) Alcohol (yes/no) Baseline hormonal levels FSH (mIU/mL) LH (mIU/mL) Oestradiol (pg/mL) P (ng/mL)

36.2 (4.3) 66.6 (15.4) 24.0 (6.9)

36.3 (5.5) 66.1 (13.9) 23.4 (5.3)

0 (2)

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5 (5)

5 (4)

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n (%) 13 (14.4) 26 (28.9) 46 (51.1) 5 (5.6) 33 (36.7) 3 (3.3) Median (IQR) 7.6 (2.0) 4.8 (2.5) 40 (26) 0.4 (0.2)

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(17.8) (28.9) (50.0) (3.3) (47.8) (2.2)

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8.6 5.0 37 0.3

(2.4) (2.4) (25) (0.2)

a Continuous variables are presented as mean (SD) or median (interquartile range). Categorical factors are presented as n (%). No statistically significant differences were present between the two groups. IQR, interquartile range.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

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ARTICLE IN PRESS 4

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Enrolment

Assessed for eligibility (n = 195)

Excluded (n = 15) Not meeting inclusion criteria • (n = 15) • Other reasons (n = 0)

Randomized (n = 180)

Allocation •

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Allocated to the propofol group (n = 90) Received allocated intervention (n = 90) Did not receive allocated intervention

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Allocated to the thiopental sodium group (n = 90) Received allocated intervention (n = 90) Did not receive allocated intervention (n = 0)

Follow-Up Follow-up (n = 90)

Follow-up (n = 90)

Cycles cancelled owing to ovulation before oocyte retrieval (n = 0)

Cycles cancelled owing to ovulation before oocyte retrieval (n = 0)

Analysis •

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Figure 1

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Analysed (n = 90) Excluded from analysis (n = 0)

Analysed (n = 90) Excluded from analysis (n = 0)

Patient participation in the study.

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Table 2

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Ovarian stimulation characteristics and oocyte retrieval parameters.

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Variablea

Propofol (n = 90)

Thiopental sodium (n = 90)

Antagonist: 79 (87.8) Agonist: 11 (12.2) Recombinent FSH: 64 (71.1) Urinary FSH: 21 (23.3) Long-acting FSH: 5 (5.6) 275 (250) 9 (3) 2550 (2450) Urinary HCG: 5 (5.6) Recombinent HCG: 70 (77.8) GnRH agonist: 15 (16.7)

Antagonist: 82 (91.1) Agonist: 8 (8.9) Recombinnat FSH: 67 (74.4) Urinary FSH: 19 (21.1) Long-acting FSH: 4 (4.4) 300 (250) 9 (3) 2300 (2350) Urinary HCG: 2 (2.2) Recombinent HCG: 78 (86.7) GnRH agonist: 10 (11.1)

7.1 (6.3) 88 (97.8)

6.5 (5.6) 87 (96.7)

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Type of GnRH analogue

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Type of gonadotrophins

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Starting dose of FSH (IU) Duration of FSH stimulation (days) Total dose of FSH (IU) Type of triggering

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Oocyte retrieval COCs retrieved Patients with at least one COC retrieved

Continuous variables are presented as median (interquartile range). Categorical factors are presented as n (%).No statistically significant differences were present between the two groups. COC, cumulative oocyte complexes; GnRH, gonadotrophin-releasing hormone.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

ARTICLE IN PRESS Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval Table 3

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Primary outcome measure: fertilization rate.

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Variable

Propofol (n = 90)

Fertilization rates (%) Fertilization rate (IVF, ICSI, IVF versus ICSI) (2PNs/COCs) ICSI fertilization rate (2PN/MII)

Median (IQR) 54.8 (29.2) 54.6 (29.7) 70 (50) 75 (50)

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Thiopental sodium (n = 90)

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No statistically significant differences were present between the two groups. COC, cumulative oocyte complexes; ICSI, intracytoplasmic sperm injection; MII, second metaphase; 2PN, two-pronuclear zygote.

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For cases in which ICSI was used, the fertilization rates per MII oocytes were also comparable between the propofol and thiopental sodium groups (Table 3).

were comparable between women who underwent general anaesthesia with the use of propofol compared with those who received thiopental sodium (Table 4).

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Anaesthesia-specific outcomes Embryological data A median of 7.1 (IQR 6.3) oocytes was retrieved in the propofol group whereas a median of 6.5 (IQR 6.3) oocytes was retrieved in the thiopental sodium group (Table 2). The number and quality of the available embryos on days 2 and 3 of development were not significantly different between the two groups compared (Table 4). Furthermore, the number of embryos transferred to the uterus and those cryopreserved

The median dose (IQR) of propofol used per patient was 200 mg (50) whereas that of thiopental sodium was 450 mg (180). The duration of anaesthesia was significantly increased in the thiopental sodium group compared with the propofol group (P = 0.019) (Table 5). In both groups, the MAP and heart rate decreased after the induction of anaesthesia; however, the difference in MAP and the heart rate between the assessment

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Table 4

Embryological parameters.

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Variablea

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Propofol (n = 90)

Thiopental sodium (n = 90)

IVF: 7 (7.8) ICSI: 79 (87.8) IVF and ICSI: 4 (4.4) 4 (5)

IVF: 7 (7.8) ICSI: 78 (86.7) IVF and ICSI: 5 (5.6) 4 (5)

83.3 (42.8) 3 (5)

83.3 (44.4) 3 (5)

3 (4) 3 (4) 12.4 (4.8)

3 (4) 3 (4) 12.3 (4.4)

4 (4) 3 (4) 20.9 (7.2) 65 (72.2) 2: 39 (60.0) 3: 24 (36.9) 5: 2 (3.1) 2 (2) 0.8 (2.2) Freeze-all because of OHSS risk: 12 (48.0) No embryos available: 13 (52.0)

3 (4) 2.5 (4) 18.9 (9.7) 68 (75.6) 2: 39 (57.4) 3: 28 (41.2) 5: 1 (1.5) 2 (1) 0.7 (2.6) Freeze-all because of OHSS risk: 6 (27.3) Breast cancer: 2 (9.1) No embryos available: 14 (63.6)

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Method of fertilization

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MII oocytes (ICSI alone or IVF versus ICSI cycles) Median (IQR) Maturation rate (%) Median (IQR) in ICSI cycles only 2PN oocytes Median (IQR) Day 2 (patients with assessment of embryos scores on day 2 of in-vitro culture) Median (IQR) Number of available embryos Number of transferrable embryos Quality of available embryos-score Day 3 (patients with assessment of embryos scores on day 3 of in-vitro culture) Median (IQR) Number of available embryos Number of transferrable embryos Quality of available embryos, score Embryo transfer, n (%) Day of embryo transfer

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Number of embryos transferred Number of cryopreserved embryos Reason for embryo transfer cancellation

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Secondary outcomes

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64 65 66

Continuous variables are presented as median (interquartile range). Categorical factors are presented as n (%). No statistically significant differences were present between the two groups. ICSI, intracytoplasmic sperm injection; IQR, interquartile range; MII, second metaphase; OHSS, ovarian hyperstimulation syndrome; 2PN, two-pronuclear zygote.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

68 69 70 71 72 73 74 75 76

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ARTICLE IN PRESS 6

E Goutziomitrou et al. Table 5

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Anesthesia specific parameters.

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Variablea

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Propofol (n = 90)

Thiopental sodium (n = 90)

10 (4.5)

12 (5)

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99.0 (0)

P

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Duration of anesthesia (min) Median (IQR) SpO2 % Median (IQR) MAP differencec HR differencec Complications during anaesthesia or during emergence

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Complications during the first 2 h after recovery

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Duration of recovery (h) MAP at discharge

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23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61

−15 (8) −10 (5) 2 (2.2) (Hiccups: 2)

−10 (6) −6 (15) 12 (13.3) (Hiccups: 11 Mild bronchospasm: 1) 2 (2.2) 22 (24.4) (Dizziness: 1, (Nausea: 12 Abdominal pain: 1) Dizziness: 6 Abdominal pain: 2 Vomit: 2) 1.5 (0) 2 (0) 80 (6.7) 83.3 (12.5)

0.019b <0.001b <0.001b <0.001b 0.010d

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a Continuous variables are presented as mean (SD) or median (interquartile range). Categorical factors are presented as n (%). b Mann–Whitney U test. c The difference between the value 5 min after the induction of anesthesia and the baseline value before induction of anaesthesia. d Fisher’s exact test. NS, not statistically significant.

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point (5 min after the induction of anaesthesia) and the baseline value (before the induction of anaesthesia) was significantly larger in the propofol group than the thiopental sodium (P < 0.001) (Table 5). Complications during anaesthesia and during emergence, as well as the complications occurring during the first 2 h after anaesthesia were significantly more in the thiopental sodium group than in the propofol group (P = 0.010 and P < 0.001, respectively). Moreover, the total time of recovery after anaesthesia was significantly prolonged in the group of women that received thiopental sodium compared with women who received propofol (P < 0.001) (Table 5).

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Pregnancy outcome

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Although biochemical pregnancy rate per randomized patient was increased in the propofol group compared with the thiopental sodium group, this difference was not statistically significant (rate difference: +12.2, 95% CI −0.3 to 24.3). A statistically significant increase in biochemical pregnancy rate per embryo transfer (P = 0.041) and the implantation rates (P = 0.05) were observed in the propofol group. Clinical pregnancy rates (+8.8, 95% CI −2.9 to +20.4 in favour of propofol) and live birth rates per randomized patient (+4.4%, 95% CI −5.7 to +14.6 in favour of propofol) were not significantly different between the two groups compared (Table 6).

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Discussion

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This RCT suggests that the use of propofol for induction of general anaesthesia during oocyte retrieval for IVF is not

associated with lower fertilization rates compared with the use of thiopental sodium. This finding was stable when assessing IVF cycles only fertilization rates (defined as the number of 2PN oocytes per COC), ICSI cycles only fertilization rates (defined as the number of 2PN oocytes per MII oocyte) and the combined fertilization rates. Previously published data have suggested a dose-dependent and time-dependent toxic effect of propofol on fertilization rates of oocytes in mice (Depypere et al., 1991; Tatone et al., 1998), although this was not confirmed in further studies (Alsalili et al., 1997). Other experimental evidence in the mouse IVF model supported that exposure of unfertilized oocytes to propofol for 30 min was associated with significantly more frequent parthenogenetic activation of these oocytes (Janssenswillen et al., 1997). In humans, an observational study assessed whether a time or dose-dependent effect of propofol (when used during oocyte retrieval) on the fertilization rates after IVF takes place. The time spent under anaesthesia as well as the total dose of propofol administered, however, were not associated with fertilization and embryo quality (Ben-Shlomo et al., 2000). To date, one retrospective study has compared fertilization rates after assisted reproductive technology cycles, where oocyte retrieval was carried out with the use of propofol or thiopental sodium. In that study, 72 propofol cycles were compared with 20 thiopental sodium cycles and similar fertilization rates were reported (Huang et al., 2000). Data from the present RCT confirm that the use of propofol instead of thiopental sodium for general anaesthesia induction during oocyte retrieval does not lead to lower fertilization rates after IVF. In the present study, no differences were observed between patients who received propofol and those who received thiopental sodium in embryo quality. This finding is in agreement

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

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Table 6

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Outcome of IVF cycle.

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Variablea

Propofol (n = 90)

Thiopental sodium (n = 90)

Biochemical Pregnancy (%) per OR

27 30.0

16 17.8

41.5

23.5

19.0 (31.7) 22 24.4

9.1 (22.2) 14 15.6

33.8

20.6

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Difference (95% CI)

P

12.2 (−0.3 to +24.3) 18.0 (2.1 to 32.8)

NSb

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(%) per embryo transfer

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Implantation rate Clinical Pregnancy (%) per OR

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(%) per embryo transfer

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Clinical spontaneous abortion

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8 (36.4)

4 (28.6)

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Live birth (%) per OR

14 15.6

10 11.1

21.5

14.7

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(%) per embryo transfer

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0.041b 0.050c

8.8 (−2.9 to +20.4) 13.2 (−1.9 to +27.7) 7.8 (−23.1 to +34.5)

NSb

4.4 (−5.7 to +14.6) 6.8 (−6.4 to +20.0)

NSb

NSb NS

NSb

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with previously published retrospective studies (Huang et al., 2000; Rosenblatt et al., 1997). In addition, in-vitro studies have failed to identify an adverse effect of propofol on the quality of resulting embryos (Ben-Shlomo et al., 2000; Tatone et al., 1998). Notably, even in the original publication (Depypere et al., 1991), which showed impaired fertilization rates, the developmental competence of resulting mouse embryos did not appear to be compromised. Not unexpectedly, the biochemical pregnancy rates per oocyte retrieval were also similar between the two groups compared. Implantation rates, however, were significantly lower in the thiopental sodium group compared with the propofol group, although this was not reflected in pregnancy rates or live birth rates when an intention-to-treat analysis was conducted. A non-significant difference in live birth rates per randomized patient in favour of propofol was observed in the present RCT. . Although it is likely that this difference represents a chance finding, a type II error cannot be ruled out especially considering that this study was not powered to detect differences in the probability of pregnancy. Another important aspect of this study that should be discussed is the complication profile of each medication. In this RCT, propofol use was associated with a more favourable complication profile than thiopental sodium. During anaesthesia but also after emergence and during recovery, propofol was associated with fewer cases of complicated recovery as well as a shorter recovery phase. This is compatible with the pharmacokinetics and the adverse effects profile of the two medications. Propofol is known for its ultra rapid induction phase, its fast recovery and its inherent anti-emetic properties (Boysen et al., 1989, 1990). On the other hand, thiopental sodium is a barbiturate, with a rapid induction of anaesthesia but with, often, prolonged recovery and with known

adverse effects, such as nausea, prolonged somnolence and agitated emergence (Sung et al., 1991). Ultimately, these Q7 differences might determine the preferable protocol for induction of anaesthesia for oocyte retrieval, especially considering that these two protocols do not seem to be associated with a different IVF outcome. It should be noted that the results of this study do not necessarily exclude an adverse effect of both propofol and thiopental sodium on the ability of the oocyte to be fertilized. It has been suggested that the use of both thiopental sodium and propofol might be associated with lower fertilization rates compared with other methods of anaesthesia, such as EMLA (lidocaine 2.5% and prilocaine 2.5%) cream or sevoflurane Q8 (Piroli et al., 2012). To properly evaluate such a hypothesis, however, proper well-designed RCTs need to be conducted. Another important issue, which is significant for the interpretation of the results of the present RCT, is that during induction of general anaesthesia, other medication besides propofol and thiopental sodium were administered to these patients. Per protocol, these co-interventions were identical between the two groups compared so that the actual effect of propofol or thiopental sodium could be isolated. A specific pharmacologic interaction of either propofol or thiopental sodium with fentanyl, however, cannot be excluded and this should be taken into consideration when interpreting the results of this RCT. Similarly, whether the effects would be different if different doses of either propofol or thiopental sodium were used is unclear. In conclusion, the use of propofol for induction of general anaesthesia during oocyte retrieval results in similar fertilization rates and IVF outcome with the use of thiopental sodium. Considering the favourable adverse effects profile, it seems that propofol is a more appropriate agent than

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

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thiopental sodium for induction of general anaesthesia during oocyte retrieval for IVF.

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Acknowledgement

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Trial registration number: NCT02377778.

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References

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Alsalili, M., Thornton, S., Fleming, S., 1997. The effect of the anaesthetic, Propofol, on in-vitro oocyte maturation, fertilization and cleavage in mice. Hum. Reprod. 12, 1271–1274. Ben-Shlomo, I., Moskovich, R., Golan, J., Eyali, V., Tabak, A., Shalev, E., 2000. The effect of propofol anaesthesia on oocyte fertilization and early embryo quality. Hum. Reprod. 15, 2197–2199. Bokhari, A., Pollard, B.J., 1999. Anaesthesia for assisted conception: a survey of UK practice. Eur. J. Anaesthesiol. 16, 225–230. Boysen, K., Sanchez, R., Krintel, J.J., Hansen, M., Haar, P.M., Dyrberg, V., 1989. Induction and recovery characteristics of propofol, thiopental and etomidate. Acta Anaesthesiol. Scand. 33, 689– 692. Boysen, K., Sanchez, R., Ravn, J., Pedersen, E., Krintel, J.J., Dyrberg, V., 1990. Comparison of induction with and first hour of recovery from brief propofol and methohexital anesthesia. Acta Anaesthesiol. Scand. 34, 212–215. Christiaens, F., Janssenswillen, C., Verborgh, C., Moerman, I., Devroey, P., Van Steirteghem, A., Camu, F., 1999. Propofol concentrations in follicular fluid during general anaesthesia for transvaginal oocyte retrieval. Hum. Reprod. 14, 345–348. Coetsier, T., Dhont, M., De Sutter, P., Merchiers, E., Versiehelen, L., Rosseel, M.T., 1992. Propofol anaesthesia for ultrasound guided oocyte retrieval: accumulation of the anaesthetic agent in follicular fluid. Hum. Reprod. 7, 1422–1424. Depypere, H.T., Dhont, M., De Sutter, P., Vanderkerckhove, D., 1991. The influence of propofol on in vitro fertilization in mice. Hum. Reprod. 127, 151. Hein, H.A., Putman, J.M., 1997. Is propofol a proper proposition for reproductive procedures? J. Clin. Anesth. 9, 611–613.

Huang, H.W., Huang, F.J., Kung, F.T., Tsai, M.Y., Lin, H., Chang, S.Y., Hsu, Y.H., Chang, H.W., 2000. Effects of induction anesthetic agents on outcome of assisted reproductive technology: a comparison of propofol and thiopental sodium. Chang Gung Med. J. 23, 513–519. Janssenswillen, C., Christiaens, F., Camu, F., Van Steirteghem, A., 1997. The effect of propofol on parthenogenetic activation, in vitro fertilization and early development of mouse oocytes. Fertil. Steril. 67, 769–774. Pierce, E.T., Smalky, M., Alper, M.M., Hunter, J.A., Amrhein, R.L., Pierce, E.C., Jr., 1992. Comparison of pregnancy rates following gamete intrafallopian transfer (GIFT) under general anesthesia with thiopental sodium or propofol. J. Clin. Anesth. 4, 394–398. Piroli, A., Marci, R., Marinangeli, F., Paladini, A., Di Emidio, G., Giovanni Artini, P., Caserta, D., Tatone, C., 2012. Comparison of different anaesthetic methodologies for sedation during in vitro fertilization procedures: effects on patient physiology and oocyte competence. Gynecol. Endocrinol. 28, 796–799. Rosenblatt, M.A., Bradford, C.N., Bodian, C.A., Grunfeld, L., 1997. The effect of a propofol-based sedation technique on cumulative embryo scores, clinical pregnancy rates, and implantation rates in patients undergoing embryo transfers with donor oocytes. J. Clin. Anesth. 9, 614–617. Tatone, C., Francione, A., Marinangeli, F., Lottan, M., Varrassi, G., Colonna, R., 1998. An evaluation of propofol toxicity on mouse oocytes and preimplantation embryos. Hum. Reprod. 13, 430– 435. Vlahos, N.F., Giannakikou, I., Vlachos, A., Vitoratos, N., 2009. Analgesia and anesthesia for assisted reproductive technologies. Int. J. Gynecol. Obstet. 105, 201–205. Ziebe, S., Petersen, K., Lindenberg, S., Andersen, A.G., Gabrielsen, A., Andersen, A.N., 1997. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum. Reprod. 12, 1545–1549.

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Declaration: The authors report no financial or commercial conflicts of interest.

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Received 9 May 2015; refereed 13 August 2015; accepted 20 August 2015.

Please cite this article in press as: Evangelia Goutziomitrou, et al., Propofol versus thiopental sodium as anaesthetic agents for oocyte retrieval: a randomized controlled trial, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2015.08.013

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