1 Departments of Obstetrics and Gynaecology and Physiology, Göteborg University, Gothenburg, 2 IVF Centre Falun, Falun, 3 Fertility Centre Scandinavia, Gothenburg, 4 IVF-Kliniken Öresund, Medeon-Malmö, Malmo and 5 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm/Department of Rehabilitation Medicine, Karolinska Hospital, Stockholm, Sweden
6 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital,SE-413 45 Göteborg, Sweden. e-mail: elsv{at}fhs.gu.se
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Abstract |
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Key words: alfentanil/analgesia/electro-acupuncture/neuropeptide Y/oocyte aspiration
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Introduction |
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Conventional analgesic methods during oocyte aspiration commonly consist of a local analgesic administered as a paracervical block (PCB) (Ng et al., 1999) in combination with intravenous (i.v.) opiates administered during the aspiration procedure itself. In addition, a sedative premedication is sometimes administered. These conventional analgesic methods are not uncommonly associated with side-effects such as tiredness, nausea and confusion. Furthermore, many of these agents have been detected in follicular fluid (FF), but evidence from human studies which indicates any negative effect on pregnancy rates is sparse (Wikland et al., 1990
; Soussis et al., 1995
). However, one of these groups (Soussis et al., 1995
) recommended that the time taken to collect the oocytes should be kept to a minimum in order to avoid any harmful effects of the drugs reaching the FF. Neuropeptide Y (NPY) is a peptide which exerts different effects in the central and peripheral nervous systems. NPY has, for example, been shown to have a modulatory role on the hypothalamicpituitaryovarian axis (Barreca et al., 1998
). NPY reaches the ovary via the plexus ovarian nerve, and high concentrations have been found in FF. NPY has been hypothesized to play a physiological role in the regulation of ovarian functions, follicular growth and ovulation (McNeill and Burden 1987
; Jörgensen et al., 1989
; 1990).
Acupuncture is a pain-relieving method that activates endogenous pain-inhibiting systems such as the spinal/segmental gate mechanism and the endogenous opioid systems (Andersson and Lundeberg, 1995). It should be stressed that any acupuncture effect rests on physiological and/or psychological mechanisms (Stener-Victorin et al., 2002
). Despite both experimental and clinical evidence of the effects claimed for electro-acupuncture (EA), its role in conventional medicine has been questioned (Renckens, 2002
). The effect of EA as a pain-relieving method during surgical procedures has been evaluated in different situations, one of which is in connection with oocyte aspiration during IVF treatment. In this procedure, EA was reported to be as effective as conventional analgesics without any observed negative side-effects (Stener-Victorin et al., 1999
). Another interesting observation in the same study, which evaluated the effect of EA as an analgesic during oocyte aspiration, was the significantly higher pregnancy rate in the group of women who underwent EA compared with a group that used conventional analgesics (45.9 versus 28.3%). Even though these observations were interesting, the number of studied patients was small, and hence the power of the findings too low for the results to be considered reliable. A study with a larger number of patients was thus needed to clarify this point. In a recent study (Paulus et al., 2002
), acupuncture during embryo transfer in IVF cycles resulted in significantly higher pregnancy rates compared with the group that did not undergo acupuncture (42.4 versus 26.3%). The results in that study cannot be directly compared with those of a previous investigation (Stener-Victorin et al., 1999
) as the study design and acupuncture protocol were different.
The present study was designed to test the hypotheses that EA in combination with PCB as analgesics during oocyte aspiration would result in: (i) a better IVF pregnancy rate than alfentanil in combination with PCB; (ii) peroperative analgesia that was as good as that produced by alfentanil in combination with PCB; (iii) less postoperative abdominal pain, nausea and stress; and (iv) a reduction in the use of additional analgesics. In addition, an investigation was made as to whether NPY concentrations in the FF differed between the two analgesic groups, and whether there was any correlation between pregnancy rate and NPY concentration.
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Materials and methods |
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Participants
Women who were aged ≤38 years, with a body mass index (BMI) ≤28 kg/m2, who had four or more follicles of an expected size ≥18 mm at the time of hCG injection, and who had undergone no more than three IVF treatments previously, were accepted for the study. Each woman contributed data from one cycle only. The women were informed about the study 3 days before oocyte aspiration, which was performed using transvaginal ultrasound guidance (Wikland et al., 1987
).
Randomization and progress through trial
Participants were randomly allocated within blocks to the EA or alfentanil groups (Figure 1). A total of 286 women was recruited, all of whom were willing to use EA if randomized to that group. Each centre randomized its patients using sealed, unlabelled envelopes, each of which contained a unique study number. The envelopes were distributed into groups of 20 (10 from the EA group and 10 from the alfentanil group) in order to avoid extended treatment periods of EA-only or alfentanil-only.
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Treatment protocols
Electro-acupuncture
Well-trained and experienced nurses, two at each IVF unit, administered the acupuncture. Before the start of the study, all nurses were instructed and coordinated in the technique. The acupuncture stimulation began at least 30 min before oocyte aspiration; this was found to be the optimum time needed for a thorough onset of analgesia and relaxation prior to operation. The acupuncture stimulation was terminated directly after oocyte aspiration. Acupuncture points were selected in somatic segments according to the innervation of the ovaries and uterus; the type of stimulation was the same in all women (Figure 2). The stainless steel needles (Hegu: Hegu AB, Landsbro, Sweden; size 0.32 x 30 or 50 mm) were inserted intramuscularly to a depth of 1535 mm. Points ST36 and GV20 were stimulated manually. The needles were rotated by hand every 10th minute to evoke the needle sensation, which reflects activation of muscle-nerve afferents (of A-delta and possibly C fibres) (Haker and Lundeberg, 1990). The remaining needles (inserted in points ST29, TE5 and LI4) were stimulated electrically. These were attached to an electrical stimulator (CEFAR ACU II; Cefar, Lund, Sweden) that emitted continuous square-wave pulses of alternating polarity with a high frequency of 80 Hz with a pulse duration of 180 µs to the points in the stomach, and a low burst frequency of 2 Hz (each pulse has a duration of 180 µs, a burst length of 0.1 s and a burst frequency of 80 Hz) to the points in the hand. The stimulation intensity for both the high and low frequencies was optimized for each woman. The high-frequency stimulation induced non-painful paraesthesia and was intended to influence the pain inhibitory systems involving the gate control mechanism at the spinal/segmental level. The low-frequency stimulation was sufficient to cause non-painful local muscle contractions in an attempt to activate the central descending pain inhibitory systems, including central
-endorphinergic systems.
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PCB and heating pad
Both groups received a PCB comprising 10 ml lidocaine (5 mg/ml). Lidocaine was injected into the right and left lateral regions of the upper fornix; that is, where the aspiration needle was intended to penetrate the vaginal wall. In addition, both groups were given an electric heating pad to place on the abdomen during oocyte aspiration. No premedication was administered in any group. If EA or the initial dose of alfentanil did not result in sufficient pain relief, additional alfentanil (0.25 or 0.5 mg) was administered.
Outcome measures
IVF variables
The IVF outcome variables that were recorded and analysed included the number of oocytes retrieved, fertilization rate, number of embryo transfer procedures undergone, number of embryos transferred, number of pregnancies, number of gestational sacs, and number of miscarriages before the 16th week. The following figures were calculated: pregnancy rate (number of pregnancies per embryo transfer), implantation rate (number of gestational sacs per number of transferred oocytes) and on-going pregnancies (number of pregnancies per embryo transfer after the 16th week of gestation).
Radioimmunoassay (RIA)
Clear FF was collected, when possible, from the largest follicle of the second ovary for testing for NPY-like immunoreactivity (NPY-LI). The FF was stored at 80°C until taken for analysis. Samples were extracted using a reverse-phase C18 cartridge (Sep Pak, Waters) and analysed with a competitive RIA. NPY-LI was analysed using antiserum N1, which cross-reacts 1.0% with avian pancreatic polypeptide, but not with other peptides. Intra- and inter-assay coefficients of variation were 7 and 14% respectively. The detection limit of NPY-LI with this RIA was 1.5 ng/ml.
Rating of subjective experience
Nine visual analogue scales (VAS) (McCormack et al., 1988) were used to evaluate pain and subjective experience before, during and after oocyte aspiration. Each VAS consisted of a 100 mm line oriented vertically on a paper with nine different dimensions. The nine variables had the following endpoints: abdominal pain no pain and unbearable pain; pain directly related to oocyte aspiration no pain and unbearable pain; pain during placement of PCB no pain and unbearable pain; other pain no pain and unbearable pain; time of discomfort never and all the time; adequacy of analgesia enough and would have needed much more; stress not at all stressed and very stressed; calm very calm and not at all calm; nausea no nausea and unbearable nausea. The measurements were assessed approximately 30 min before, directly after, and 2 h after oocyte aspiration.
Additional analgesic
Amounts of additional analgesic were recorded, and differences between the groups were calculated.
Statistical analyses
Based on the results of a previous study (Stener-Victorin et al., 1999), a power calculation indicated that 150 patients in each group would be necessary to detect a 10% increase in pregnancy rate with a power of at least 80% at a 5% level of significance. The study was ended pre-term based on the results of an interim analysis. The interim analysis revealed no difference in pregnancy rate between the two study groups. In addition, hypothetical calculations of different outcomes were also made, and when all possibilities were taken into account it was found that there would be no differences in pregnancy rate between the two study groups. All data were analysed using the software package Statistica 4.1 for Macintosh. The
2-test was used to compare differences between the groups concerning need for additional analgesic and IVF variables; pregnancy per embryo transfer, implantation rate, miscarriage before the 16th week of gestation, and take-home baby rate. Students t-test for unpaired data was used to compare differences between the groups with regard to NPY concentrations in the FF. The significance of the correlation between NPY concentrations and pregnancy was tested with Spearmans rank order correlation test. The MannWhitney U-test was used to compare differences between the groups concerning VAS ratings, the number of oocytes retrieved, and the fertilization rate (Altman, 1996
). A P-value <0.05 was considered statistically significant. The median and range or mean and SEM were calculated when possible.
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Results |
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Additional analgesic
A total of 19 (14%) women in the EA group and 54 women (38.6%) in the alfentanil group were given additional i.v. alfentanil (Table VI). In total, the alfentanil group received significantly more additional alfentanil compared with the EA group (P < 0.0001). Differences in the doses of alfentanil between the groups were also significant (Table VI).
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Discussion |
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The present study included a larger number of patients and thus had the statistical power to clarify whether EA had a positive influence on implantation and pregnancy rates in IVF cycles. The present results do not support the hypothesis of a higher IVF pregnancy rate in the EA group compared with the alfentanil group.
As NPY concentrations in the FF were significantly higher in the EA group, it might be concluded that these were elevated by EA. This is an important finding as NPY has been shown to play a role in human steroidogenesis (Barreca et al., 1998). On the other hand, alfentanil may well have reduced the NPY concentrations in the FF, which infers that NPY concentrations in the EA group may have been near-normal. EA involves biological activation of the endogenous pain-inhibiting systems (Andersson and Lundeberg, 1995
), and it is unlikely that EA influences the FF or the oocyte in any negative manner. In addition, a previous study found that repeated EA treatment decreases the pulsatility index in the uterine arteries (Stener-Victorin et al., 1996
)an effect which may improve endometrial receptivity (Steer et al., 1992
; 1995). Interestingly, acupuncture was shown recently to inhibit uterine motility in pregnant rats (Kim et al., 2000
), and it may be speculated that acupuncture could be used to regulate complicated preterm labour.
Results of the present study demonstrate the major advantages of using acupuncture in the clinical management of IVF patients. EAwhen used in combination with a PCBhas, in two repeated trials, been found to be as good as alfentanil in inducing adequate peroperative analgesia during oocyte aspiration. The finding that EA induces adequate analgesia during minor surgery is not new, and has been substantiated in different clinical areas (Kho et al., 1991; Wang et al., 1997b
). In addition, the results of the present study show that women given EA require significantly less quantities of additional opiates than those given alfentanil group. This is in line with previous findings where the consumption of analgesics was reduced by 50% when EA was used in combination with conventional analgesics (Wang et al., 1997a
). A reduction in the use of pharmacological medication during oocyte aspiration may be desirable, as alfentanil has been found in the FF (Soussis et al., 1995
). The disadvantage of the EA procedure used in the present study was that the time taken to induce analgesia was more time-consuming than when conventional analgesics only were used. It would be of interest to investigate whether analgesia could be induced by EA in a <30 min procedure performed prior to oocyte aspiration.
Many couples undergoing IVF suffer great stress and anxiety and may need to undergo repeated attempts before treatment is successful. It is therefore important that patients are not left with unpleasant memories of the oocyte aspiration procedure. An interesting observation in the present study was that the EA group had less postoperative abdominal pain, nausea and stress compared with the alfentanil group. Stress may affect the implantation rate (Csemiczky et al., 2000), and for that reason this finding may be of great value.
Although in the past scepticism has been voiced over the effects claimed for acupuncture, in recent years the effect of acupuncture on different conditions (pain and diseases) has been studied from a Western scientific perspective, and the results have demonstrated that acupuncture has both physiological and psychological impacts (Andersson and Lundeberg, 1995). Needle insertion into the skin and deeper tissues, in addition to subsequent stimulation of the needles, results in a particular pattern of afferent activity in peripheral nerves, mainly the A-delta and possibly also the C fibres. Acupuncture stimulation has been demonstrated to activate inhibitory systems in the spinal cord, which results in segmental inhibition of the sympathetic outflow (Sato et al., 1997
) and pain pathways, as predicted by the gate control theory (Melzack and Wall, 1965
). EA releases endogenous opioids and oxytocin, which seem to be essential in the induction of functional changes in different organ systems (Andersson and Lundeberg, 1995
). In this respect, particular interest has been dedicated to
-endorphinan endogenous opioid with a high affinity for the µ receptor (Basbaum and Fields, 1984
). Indeed, evidence suggests that this hypothalamic
-endorphin system plays a central role in mediating the pain-relieving effect of acupuncture (Wang et al., 1990a
;b). Furthermore, it has been shown that intense stimulation results in the activation of supraspinal pain inhibitory centres, and this mechanism is denoted diffuse noxious inhibitory controls (DNIC) or counter-irritation (Bing et al., 1990
).
In conclusion, in the present clinical situation EA does not improve pregnancy rates. In the present study, NPY concentrations in FF were higher in the EA group, which may be important for human ovarian steroidogenesis. In addition, the findings of the present study support the view that EA might be a valuable alternative to conventional analgesics during oocyte aspiration in assisted reproduction. For those women who are willing to try EA, it may be a better analgesic method as the pain relief achieved peroperatively is as effective as that induced by conventional analgesics. The women experience less abdominal pain, less nausea and less stress at 2 h after oocyte aspiration, and also use less opiate analgesics than when conventional analgesics alone are used.
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Acknowledgements |
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References |
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Submitted on December 20, 2002; resubmitted on February 12, 2003; accepted on March 17, 2003.