Cublex – Problemstellung 1 Drehe die acht miteinander beweglich verbundenen Würfelchen so, dass eine „Stange" entsteht, wie das untere Bild zeigt. Cublex – Problemstellung 2 Drehe die acht miteinander beweglich verbundenen Würfelchen so, dass das weisse Band im Würfel verschwindet. Cublex – Problemstellung 3 Drehe die acht miteinander beweglich verbundenen Würfelchen so, dass ein weisses Band durchgehend über den Würfel führt.
Ivf-saar.deImmobilisation versus immediate mobilisation afterintrauterine insemination: randomised controlled trial Inge M Custers, PhD student and registrar,1 Paul A Flierman, fertility doctor,2 Pettie Maas, fertility doctor,3Tessa Cox, fertility doctor,4 Thierry J H M Van Dessel, gynaecologist,5 Mariette H Gerards, fertility doctor,6Monique H Mochtar, gynaecologist,1 Catharina A H Janssen, gynaecologist,7 Fulco van der Veen, professor ofgynaecology and fertility specialist,1 Ben Willem J Mol, professor of gynaecology1,3 1Centre for Reproductive Medicine, Several studies have investigated sperm migration Department of Obstetrics and Objective To evaluate the effectiveness of 15 minutes of and survival in the female genital tract. Spermatozoa Gynaecology, Academic Medical immobilisation versus immediate mobilisation after may reach the fallopian tube Centre, Meibergdreef 9, 1105 —the site of fertilisation— AZ Amsterdam, Netherlands within two to 10 minutes.1-4 These data suggest that 2Department of Obstetrics and Design Randomised controlled trial.
sperm migration to the site of fertilisation is indepen- Gynaecology, Onze Lieve Vrouwe Setting One academic teaching hospital and six non- dent of the position of the woman directly after intra- Gasthuis, Amsterdam3 academic teaching hospitals.
Department of Obstetrics and Participants Women having intrauterine insemination for In 2000, however, Saleh et al reported that if a Centre, Veldhoven, Netherlands unexplained, cervical factor, or male subfertility.
woman remained in a supine position for 10 minutes 4Department of Obstetrics and Interventions 15 minutes of immobilisation or immediate after intrauterine insemination, the pregnancy rates Gynaecology, Antonius mobilisation after insemination.
increased significantly compared with immediate Main outcome measure Ongoing pregnancy per couple.
mobilisation (13% v 4% per cycle).5 Unfortunately, 5Department of Obstetrics and Results 391 couples were randomised; 199 couples were this randomised controlled trial was rather small and Gynaecology, TweeSteden allocated to 15 minutes of immobilisation after unbalanced, as 40 couples were compared with 55 cou- Ziekenhuis, Tilburg, Netherlands intrauterine insemination, and 192 couples were ples. Also, the outcome of pregnancy was not defined.
Department of Obstetrics and allocated to immediate mobilisation (control). The As the subject has not been studied since then, we Gynaecology, Martini Ziekenhuis,Groningen, Netherlands ongoing pregnancy rate per couple was significantly assessed the effectiveness of immobilisation after intra- 7Department of Obstetrics and higher in the immobilisation group than in the control uterine insemination in a large multicentre rando- Gynaecology, Groene Hart group: 27% (n=54) versus 18% (34); relative risk 1.5, mised clinical trial.
Ziekenhuis, Gouda, Netherlands 95% confidence interval 1.1 to 2.2 (crude difference in Correspondence to: I [email protected] ongoing pregnancy rates: 9.4%, 1.2% to 17%). Live birth rates were 27% (53) in the immobilisation group and 17% Subfertile women between 18 and 43 years of age with Cite this as: BMJ 2009;339:b4080 (32) in the control group: relative risk 1.6, 1.1 to 2.4 an indication for treatment with intrauterine insemina- (crude difference for live birth rates: 10%, 1.8% to 18%).
tion were eligible for the trial. Couples using donor In the immobilisation group, the ongoing pregnancy rates semen (fresh or cryopreserved) could also be included in the first, second, and third treatment cycles were 10%, in the trial. We made no restrictions with regard to the 10%, and 7%. The corresponding rates in the use and type of controlled ovarian hyperstimulation mobilisation group were 7%, 5%, and 5%.
during treatment cycles.
Conclusion In treatment with intrauterine insemination, All couples had been investigated for infertility 15 minutes' immobilisation after insemination is an according to the guidelines of the Dutch Society of effective modification. Immobilisation for 15 minutes Obstetrics and Gynaecology.6 This included a medical should be offered to all women treated with intrauterine history, cycle monitoring, semen analysis, postcoital test, and assessment of tubal patency. The woman's Trial registration Current Controlled Trials age, duration of subfertility, and whether subfertility was primary or secondary were documented. Wedefined duration of subfertility as the time from when the couple started actively trying to conceive to the Intrauterine insemination with or without ovarian time of start of treatment. If the couple had a previous hyperstimulation is probably the most frequently pregnancy that had not resulted in a live birth, we applied fertility treatment in the world. One of the defined duration of subfertility as the time from the questions that has remained unresolved is whether first day of the pregnancy to the time of start of treat- pregnancy rates are positively influenced by immobi- ment. We defined primary subfertility as the absence of lisation after insemination.
pregnancy in the current relationship.
BMJ ONLINE FIRST bmj.com If cryopreserved donor sperm was used, we defined study. We defined male subfertility as total motile subfertility as at least 12 cycles of unsuccessful intra- sperm count less than 10×106 spermatozoa/ml and cervical insemination before intrauterine insemina- unexplained subfertility as total motile sperm count tion. Ovulation was confirmed by basal body more than 10×106 spermatozoa/ml and exclusion of a temperature curve, midluteal serum progesterone, or cervical factor.
sonographic monitoring of the cycle. We included Controlled ovarian hyperstimulation, semen pre- anovulatory women in the trial only after ovulation paration, and insemination regimens were done had been induced for at least six to 12 months without according to hospital specific protocols. Controlled conception or if a male factor was also present, as in ovarian hyperstimulation was done with clomiphene these instances an indication for intrauterine insemina- citrate 50-150 mg on days five to nine of the cycle or tion existed.
subcutaneous injections of recombinant or urinary fol- At least one well timed postcoital test was done licle stimulating hormone daily (Gonal F, Serono Ben- (except in couples using cryopreserved donor sperm) elux, The Hague, Netherlands; Puregon, Organon, during the basic assessment of fertility. The test was Oss, Netherlands; or Menopur, Ferring, Hoofddorp, planned according to the basal body temperature Netherlands). Controlled ovarian hyperstimulation curve or findings of ultrasonography. A cervical factor was primarily done with recombinant follicle stimulat- was diagnosed if no progressive spermatozoa were ing hormone in all clinics but one, where clomiphene seen in five high power fields at 400 times magnifica- citrate was used as a first line treatment. Ovulation was tion and the total motile sperm count was less than induced with 5000 IU or 10 000 IU of human chorionic 10×106 spermatozoa/ml. Tubal pathology was gonadotrophin (Pregnyl, Organon), and women were assessed by a chlamydia antibody test, a hysterosalpin- inseminated 36-40 hours later. If more than three gogram, or laparoscopy. In the case of a positive chla- dominant follicles (>16 mm) were present, the treat- mydia antibody test, the tubal status was subsequently ment cycle was cancelled. Semen samples were pro- evaluated with a hysterosalpingogram or laparoscopy; cessed within one hour of ejaculation by density in women with a negative chlamydia antibody test, gradient centrifugation followed by washing with cul- tubal pathology was considered to be absent. Patients ture medium. The volume of semen that was insemi- had to have at least one patent tube to be eligible for the nated varied between 0.2 ml and 1.0 ml.
Patients were asked to participate before start of the first intrauterine insemination cycle. After giving writ-ten informed consent, the couples were randomly Couples randomly assigned to treatment (n=391) assigned to have three cycles of intrauterine insemina-tion followed by 15 minutes of immobilisation (inter-vention group) or three cycles of intrauterine Assigned to 15 minutes of immobilisation Assigned to immediate in supine position after IUI (N=199) mobilisation after IUI (n=192) insemination with immediate mobilisation (controlgroup). We randomised the couples before the first Ongoing pregnancies after IUI (n=49) Ongoing pregnancies after IUI (n=29) insemination, by using a web based computer program Twin pregnancies (n=3) Twin pregnancies (n=1) with a stratification procedure for age (18-34 years and Spontaneous ongoing pregnancies between Spontaneous ongoing pregnancies between 35-43 years) and centre. Women were inseminated in the lithotomy position in a Trendelenburg tilt.
Depending on their allocation, women remained in Ongoing pregnancy after converted cycle (to IVF) Miscarriages (n=17) the supine position for 15 minutes (timed by an alarm Ongoing pregnancy not achieved (n=158 couples) clock) or were mobilised immediately.
Miscarriages (n=14)Ectopic pregnancy (n=1) The primary outcome measure was the occurrence Biochemical pregnancy (n=1) of an ongoing, viable intrauterine pregnancy (within Ongoing pregnancy not achieved (n=145 couples) four months after randomisation), defined as fetalheart beat seen by transvaginal ultrasonography at Completed intervention (n=174) Completed intervention (n=166) 12 weeks' gestation. Secondary outcomes includedlive birth, biochemical pregnancy, ectopic pregnancy, One cycle within study without achieving One cycle within study without achieving and miscarriage. Pregnancy was determined by a qua- pregnancy (n=7 couples) pregnancy (n=6 couples) Two cycles within study without achieving Two cycles within study without achieving litative urine test for β human chorionic gonadotrophin pregnancy (n=18 couples) pregnancy (n=20 couples) if no menstruation occurred 14 days after insemina-tion.
Live births (n=53) Live births (n=32) Assuming an ongoing pregnancy rate of 10% per Lost to follow-up (n=0) Lost to follow-up (n=0) cycle in the mobilisation group, we believed that anincrease in the ongoing pregnancy rate from 10% to Excluded from analysis (n=0) Excluded from analysis (n=0) 14% per cycle would be relevant. This corresponds toa 12% difference after three cycles. As expecting that15 minutes of immobilisation would perform worse Fig 1 Trial profile. Couples who completed the intervention were those who had three cyclesof intrauterine insemination (IUI) within four months or achieved pregnancy. IVF=in vitro than immediate mobilisation would not be logical, we used one sided statistical tests. Using an α error of 0.05 BMJ ONLINE FIRST bmj.com and a β error of 0.20, and assuming a dropout rate of 10%, we needed 185 couples in each arm.
We calculated the rates of ongoing pregnancy per couple in each group and the corresponding relative risk with 95% confidence intervals. We used a two tailed Fisher's exact test to test for significance. Wedid stratified analyses for different subgroups and used Kaplan-Meier analysis to calculate time to preg- nancy. We initially analysed data according to theintention to treat principle and followed this with a Couples with ongoing pregnancy (%) per protocol analysis.
No of couples not yet pregnant 15 minutes' immobilisation Between September 2005 and October 2007, we ran- domly assigned 391 couples to immobilisation in a supine position for 15 minutes (199 couples; inter- vention group) or immediate mobilisation (192 cou- Fig 2 Kaplan-Meier curve of time to ongoing pregnancy ples; control group). Figure 1 shows the trial profile.
The baseline characteristics were comparable in thetwo groups; very small differences existed only in dis- One treatment cycle in the immobilisation group was tribution of diagnoses and use of controlled ovarian converted to in vitro fertilisation because of ovarian hyper-response, and this cycle resulted in an ongoing The ongoing pregnancy rate per couple was signifi- cantly higher in the immobilisation group than in the In the per protocol analysis, we excluded these 10 control group: 27% (54/199) versus 18% (34/192); ongoing pregnancies that did not result from intra- relative risk 1.5, 95% confidence interval 1.1 to 2.2; uterine insemination. Again, the ongoing pregnancy P=0.03. The crude difference in ongoing pregnancy rate in the immobilisation group was significantly rates was 9.4% (95% confidence interval 1.2% to higher: 25% (49/199) versus 15% (29/192); relative 17%). Live birth rates were 27% (53/199) in the immo- risk 1.6, 1.1 to 2.5; P=0.01.
bilisation group and 17% (32/192) in the mobilisation One patient was randomised twice in the study: the group (relative risk 1.6, 1.1 to 2.4; P=0.02). The crude first time she was allocated to immediate mobilisation.
difference in live birth rates was 10% (1.8% to 18%).
An ongoing pregnancy occurred but was terminated at During the study, nine spontaneous pregnancies 20 weeks' gestation because of multiple congenital occurred between treatment cycles: four in the immo- abnormalities. The second time, the patient was rando- bilisation group (one after the first cycle, three after the mised to immobilisation. Again an ongoing pregnancy second cycle) and five in the mobilisation group (two occurred; this time it resulted in a live birth.
after the first cycle, three after the second cycle) (fig 1).
The Kaplan-Meier curve in figure 2 shows time to ongoing pregnancy. We found a significant differencein time to pregnancy in favour of immobilisation (logrank test, P=0.026). The mean number of cycles per Baseline characteristics. Values are numbers (percentages) unless stated otherwise couple during the study was 2.4 in the immobilisation Immediate mobilisation group and 2.5 in the control group. In the immobilisa- immobilisation (n=199) tion group, ongoing pregnancy rates in the first, sec- Mean (SD) woman's age (years) ond, and third cycles were 10%, 10%, and 7%. The Mean (SD) duration of subfertility (years) corresponding rates in the immediate mobilisation Primary subfertility group were 7%, 5%, and 5%.
Cause of subfertility: In the immobilisation group, 25 (13%) patients did not complete three cycles or achieve pregnancy within the study period compared with 26 (14%) in the mobi- lisation group (fig 1). Reasons for not completing three cycles were delay by the patient between cycles, bur- One sided tubal pathology den of the treatment, or doctor's advice to stop intra- More than one diagnosis uterine insemination treatment.
Use of donor semen Use of controlled ovarian hyperstimulation: Clomiphene citrate In this large randomised controlled trial, we found that 15 minutes of immobilisation after intrauterine insemi- nation significantly increased ongoing pregnancy FSH=follicle stimulation hormone; GnRH=gonadotrophin releasing hormone.
rates. Although the difference in ongoing pregnancy *Total motile sperm count less than 10×106/ml.
rate per couple was somewhat lower than assumed in BMJ ONLINE FIRST bmj.com standard approach before start of the study. In the WHAT IS ALREADY KNOWN ON THIS TOPIC immobilisation group, prolongation of the period of Intrauterine insemination with or without ovarian immobilisation at the initiative of the patient may hyperstimulation is the most frequently applied fertility have occurred in some cases.
treatment in the world Spermatozoa may reach the fallopian tube—the site of fertilisation—as soon as two minutes after insemination We found a clinically relevant and statistically signifi-cant improvement in ongoing pregnancy rates after WHAT THIS STUDY ADDS 15 minutes of immobilisation, confirming the results Fifteen minutes of immobilisation after intrauterine of a previous study.5 As immobilisation is easily done insemination significantly improves ongoing pregnancy and carries very little cost, we suggest incorporating rates compared with immediate mobilisation immobilisation as a standard procedure in intrauterineinsemination treatment.
the power analysis (9.5% observed versus 12% This work was presented as an oral presentation at the 24th Annual expected), we consider this difference to be clinically Meeting of the European Society of Human Reproduction and relevant, especially as 15 minutes of immobilisation is Embryology 2008, in Barcelona, Spain.
Contributors: BWJM and FvdV designed the study. IMC promoted it, a simple intervention with low additional costs.
coordinated this randomised controlled trial, collected the data, and Although immobilisation takes more time and occu- sought ethical approval. PAF, PM, TC, HJHMVD, MHG, MHM, and CAHJ pies more space in busy rooms, the intervention will included couples and collected data. IMC did the analysis, under the be economic in the long run, as pregnant patients will supervision of BWJM. All authors helped to prepare the final report. IMC,BWJM, and PvdV are the guarantors.
not return in subsequent cycles.
The mechanism of the effect of immobilisation after Competing interests: None declared.
insemination is unclear. After coitus, spermatozoa Ethical approval: The institutional review board of the Academic Medical enter the cervix through the cervical mucus into the Centre, Amsterdam, approved study protocol. Local permission wasobtained in each of the seven participating hospitals. All participants gave uterus, leaving the seminal plasma behind in the written informed consent.
vagina. In intrauterine insemination, spermatozoa areinseminated in a small volume of fluid directly into the Hafez ES. In vivo and in vitro sperm penetration in cervical mucus.
uterus. As a consequence, immediate mobilisation Acta Eur Fertil 1979;10(2):41-9.
might cause leakage of this volume together with sper- Settlage DS, Motoshima M, Tredway DR. Sperm transport from theexternal cervical os to the fallopian tubes in women: a time and matozoa out of the uterus; alternatively, movement of quantitation study. Fertil Steril 1973;24:655-61.
processed sperm to and up the fallopian tubes may take Kissler S, Siebzehnruebl E, Kohl J, Mueller A, Hamscho N, Gaetje R, longer than after intercourse.7 et al. Uterine contractility and directed sperm transport assessed byhysterosalpingoscintigraphy (HSSG) and intrauterine pressure (IUP) Small differences in treatment protocols among par- measurement. Acta Obstet Gynecol Scand 2004;83:369-74.
ticipating centres existed in this multicentre study, such Kunz G, Beil D, Deininger H, Wildt L, LeyendeckerG. The dynamics of as inseminated volume of semen and type of hyper- rapid sperm transport through the female genital tract: evidence from stimulation. However, randomisation generated an vaginal sonography of uterine peristalsis andhysterosalpingoscintigraphy. Hum Reprod 1996;11:627-32.
equal distribution of the couples over the two treat- Saleh A, Tan SL, Biljan MM, Tulandi T. A randomized study of the ment groups. Also, as heterogeneity in treatment pro- effect of 10 minutes of bed rest after intrauterine insemination. Fertil tocols is likely among different fertility clinics, our Dutch Society of Obstetrics and Gynaecology. Guideline—basic findings represent daily practice and are therefore fertility work-up. NVOG-guideline nr 1, 2004 (available at www.nvog.
more generalisable to other populations.
Protocol violation in the control group was unlikely, Suarez SS, Pacey AA. Sperm transport in the female reproductivetract. Hum Reprod Update 2006;12:23-37.
as the woman was immediately mobilised with thephysician in the room. In most centres, this was the Accepted: 31 August 2009 BMJ ONLINE FIRST bmj.com
HISTORY: Reviews of New Books older men and one in his twenties had Of course, acts of revenge do not ex- of convivencia (or perhaps because of been disfigured by a severe beating and plain why bloody violence and murder it), the principal historiographical pre- shot several times, and two of the three were generally seen as the appropriate occupation over the centuries was to