1 Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Adelaide, South Australia, 2 Instituto Valenciano de Infertilidad, Madrid and 3 Instituto Valenciano de Infertilidad, Murcia, Spain
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: IVF/intercourse/pregnancy/semen
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To date, no trial has investigated whether vaginal intercourse around the time of embryo transfer has any influence on the chance of conception during IVF treatment. Hypothetically, intercourse may impair implantation by two principal mechanisms: the introduction of infection and the initiation of uterine contractions. Intercourse has been linked with ascending uterine infection during late pregnancy (Naeye, 1979) and sub-clinical infection of the upper reproductive tract is associated with poor IVF-embryo transfer outcome (Franchin et al., 1998a
). During an IVF cycle the uterine cavity is especially vulnerable to intercourse-related infection since the cervical mucous barrier to ascending infection is disrupted by passage of the embryo transfer catheter. Furthermore, uterine myometrial activity is increased during intercourse, especially in the event of female orgasm (Fox et al., 1970
). These contractions may interfere with implantation of the early embryo, since high levels of spontaneous uterine activity are associated with poor IVFembryo transfer outcome (Franchin et al., 1998b
).
On the positive side, intercourse may act to assist implantation. Animal studies reveal that exposure to seminal plasma, the fluid component of the ejaculate, is particularly important for achieving normal embryo development and implantation. Animals that become pregnant through artificial insemination or embryo transfer without being exposed to seminal plasma have substantially lower rates of implantation than those exposed to seminal plasma (Pang et al., 1979; Queen et al., 1981
; O et al., 1988
; Flowers and Esbenshade, 1993
), while rodents inseminated with spermatozoa prior to blastocyst transfer also have a higher rate of implantation compared with those not exposed to spermatozoa (Carp et al., 1984
).
Previous studies investigating the role of semen exposure in assisted human reproduction (IVF, gamete intra-Fallopian transfer, intrauterine insemination) have produced conflicting results, with some reporting a beneficial effect (Bellinge et al., 1986; Marconi et al., 1989
), whereas others have shown no effect (Fishel et al., 1989
; Qasim et al., 1996
). Unfortunately all of these studies were small and inadequately randomized, raising the possibility of random error and bias. In addition, the IVF studies used artificial insemination to deliver semen and therefore cannot be relied upon to determine the safety of intercourse around the time of embryo transfer.
The purpose of this study was to investigate whether exposure to semen through vaginal intercourse around the time of embryo transfer has any influence on pregnancy rates in IVF assisted pregnancy.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Power calculations a priori estimated that 1430 embryos would need to be transferred to achieve the statistical power required to detect a 50% improvement in viable pregnancy rates, as seen in the original report (Bellinge et al., 1986) (
= 0.05, ß = 0.20, historical pregnancy rate 11% of transferred embryos, 10% cycle cancellation rate).
Clinical IVF protocol
The techniques used to generate oocytes, achieve fertilization and culture embryos have previously been reported for the Australian (Warnes et al., 1997) and Spanish (Pellicer et al., 1996
) centres. Briefly, at the Spanish centres a long protocol was used for pituitary desensitization with administration of leuprolide acetate (1 mg/day s.c.; Procrin, Abbott S.A., Madrid, Spain), starting in the luteal phase of the previous cycle. At day 1 and 2 of ovarian stimulation two ampoules of human menopausal gonadotrophin (HMG) were administered (Pergonal; Serono, Madrid, Spain) together with two ampoules of FSH (Fertinorm; Serono). At days 3, 4 and 5 of ovarian stimulation each patient received three ampoules of HMG, with further doses of HMG being tailored on an individual basis according to serum oestradiol concentrations and transvaginal ultrasound scan results. Once an adequate ovarian response had been confirmed (presence of at least two follicles >19 mm in size and a serum oestradiol >2.94 nmol/l), leuprolide and HMG were discontinued and 10 000 IU human chorionic gonadotrophin (HCG, Profasi; Serono) was administered. Transvaginal oocyte retrieval was scheduled 3638 h after HCG administration, followed by standard IVF or intracytoplasmic sperm injection (ICSI) procedures to achieve oocyte fertilization. All embryos were cultured under standard conditions for 48 h until they had reached the 24-cell stage, when they were transferred back to the mother. Intravaginal micronized progesterone (400 mg/day) was routinely used as luteal support in these fresh embryo transfer cycles.
The Australian centres protocol for ovulation induction and fertilization is similar to that used in the Spanish centres and has been previously published (Warnes et al., 1997). Thawed 2-8-cell embryos were transferred to naturally cycling women 3 days following their LH surge. Luteal support was not routinely used in thawed embryo transfer cycles.
Study protocol
Consenting patients attending the Australian centre were randomized either to have intercourse on at least one occasion in a 4 day period encompassing the 2 days before and after embryo transfer, or to abstain during this same period. Patients attending the Spanish centres were randomized to abstain for the entire IVF cycle (as was routine practice at these centres) or to have intercourse on at least two occasions, once in the 12 h before oocyte collection and once 12 h following embryo transfer. The two centres had different protocols for timing of intercourse because it was judged unreasonable to ask couples undergoing fresh embryo transfer to have intercourse shortly following transvaginal oocyte collection. All couples were asked whether they had adhered to their trial allocation.
Study assignment and masking
Randomization was performed using a computer-generated balanced block (n = 4) sequence to generate study allocations, which in turn were sealed in opaque envelopes. The randomization process was stratified according to maternal age (35 years, >36 years) and treatment centre. Study allocations for both the Australian and Spanish centres were performed by personnel based in Australia who were not directly involved in patient care.
Participant follow-up
A pregnancy test was performed on day 16 following embryo transfer in all women who had not commenced their menstrual period. Implantation was defined as the presence of a positive urine ßHCG or a serum quantitative ßHCG >20 mU/ml. All women with a positive pregnancy test had a pelvic ultrasound 46 weeks after embryo transfer. All pregnancies at the Australian centre were followed to birth. Outcome data beyond 68 weeks gestation were not available for the Spanish participants since the majority of these patients received antenatal care outside the IVF treatment centres.
Analysis
Couples were excluded from the final analysis if they did not reach embryo transfer; however, all couples who reached embryo transfer had their outcome data analysed on an `intention to treat' basis, even if they did not comply with their study allocation. Two-sample t-tests (two-tailed) were used to test for equality of the means of continuous variables. 2 and confidence interval (CI) calculations were used to test the equality of categorical variables. Statistical analysis was performed using SPSS (Version 6.1, SPSS, Chicago, IL, USA) and EpiInfo (Version 6.04b, CDC, Atlanta, GA, USA) software.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
At the Australian centre 15.7% of treatment cycles resulted in pregnancy, with no significant difference existing between the intercourse and abstain groups [15.4 and 16.1% respectively, odds ratio (OR) 0.95, 95% CI 0.42.3] (Table II). At the Spanish centre 26.3% of cycles resulted in pregnancy, but again no significant difference existed between the intercourse and abstain groups [28.5 and 24.2% respectively, OR 1.25, 95% CI 0.722.16]. Furthermore, the proportion of biochemical pregnancies that progressed to viable pregnancies did not differ between the intercourse and abstain groups at either the Spanish (88.4% intercourse versus 86.1% abstain, OR 1.23, 95% CI 0.35.5) or Australian centres (64.3% intercourse versus 57.1% abstain, OR 1.35, 95% CI 0.238.1). When the data from the two treatment centres were pooled (Table III
), thereby reducing the chance of a type II statistical error, a significant improvement in the proportion of transferred embryos viable at 68 weeks gestation was seen in the intercourse group compared with the abstain group (11.01 versus 7.69 viable embryos per 100 transferred, P = 0.036, OR 1.48, 95% CI 1.012.19).
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It could be suggested that natural conception may explain the improvement in pregnancy outcome seen in the intercourse group. This is unlikely to be the case for three reasons. First, the average duration of infertility in our study cohort was 4.7 years. The spontaneous fecundity rate for couples experiencing infertility of >4 years duration is reported to be <1% per menstrual cycle (Collins et al., 1983). This observation, combined with the facts that oocyte retrieval harvests the majority of pre-ovulatory follicles in the fresh embryo transfer cycles and that intercourse occurred in the post-ovulation non-fertile period in the thawed embryo transfer cycles, would ensure that natural conception is unlikely to occur.
The observation that semen exposure had a stronger effect on pregnancy outcome in the Spanish compared to the Australian trial may be explained by several factors. First, couples enrolled in the Spanish trial were asked to have intercourse on two occasions, whereas the Australian group was only required to have intercourse on at least one occasion. The stronger benefit of semen exposure in the Spanish trial may simply reflect a dose-response effect. Second, couples randomized to the abstain arm at the Spanish centre were precluded from having intercourse for the entire treatment cycle, where Australian couples were only asked to abstain for 2 days before and after embryo transfer. If the beneficial effect of semen exposure persists for more than 2 days, couples in the abstain group at the Australian centre may have benefited from recent intercourse outside the study abstinence period. Finally, the smaller number of pregnancies in the Australian trial, a reflection of the inferior pregnancy rate inherent in thawed embryo transfers, and the lower number of transferred embryos, makes it more difficult for any positive trend in pregnancy outcome to become statistically significant. It is also possible that physiological differences between stimulated (fresh embryo) and unstimulated (thawed embryo) IVF cycles may alter the responsiveness of the female reproductive tract to semen. Alternatively, fresh and thawed embryo metabolism may be different, resulting in altered responsiveness of the embryos to semen-initiated changes in the female reproductive tract.
The mechanism by which semen might benefit early embryo development is presently unknown. In rodents, a lack of exposure to seminal plasma results in a decrease in the rate of preimplantation embryo cleavage (O et al., 1988) and a reduction in the proportion of transferred embryos that successfully implant (Vickery et al., 1969
). In humans, seminal plasma pessaries have been successfully used to enhance implantation rates in women experiencing recurrent miscarriage of unknown origin (Coulam and Stern, 1995
). Hence it is possible that semen mediates its positive effect on pregnancy outcome through a combination of preimplantation and early implantation events. Couples undergoing assisted reproduction treatment have a higher rate of early pregnancy loss than fertile couples, with 70% of embryos being lost within 16 days of embryo transfer (Simon et al., 1999
). In this study, no significant difference in the rate of clinical miscarriage was observed between the intercourse and abstain groups, thereby indicating that improvements in early embryo survival must be responsible for the increase in viable embryos observed in the intercourse group. Since abstinence is common during IVF treatment cycles, a lack of exposure to semen may play a significant role in the high rate of early embryo attrition observed during IVF treatment.
We have previously postulated that immune-active compounds such as transforming growth factor beta (TGFß) and prostaglandin E, both present in high concentrations in human semen, may be responsible for the beneficial effect (Robertson et al., 1997). In mice, exposure of the uterine epithelium to seminal TGFß induces synthesis of pro-inflammatory cytokines including granulocyte-macrophage colony-stimulating factor (Tremellen et al., 1998
), which is reported to accelerate preimplantation embryo cleavage and hatching in both mice and humans (Robertson and Seamark, 1992
; Robertson et al., 1999
; Sjoblom et al., 1999
).
There is also evidence to suggest that semen may contribute to the induction of immunological tolerance towards paternal transplantation antigens, thereby favouring the survival of the semi-allogeneic conceptus (Robertson et al., 1997). Adverse immune responses towards trophoblast antigens have been linked with recurrent miscarriage, a late form of implantation failure, while tolerant maternal immune responses are associated with pregnancy success (Hill et al., 1995
; Piccinni et al., 1998
). Semen contains paternal transplantation antigens and prostaglandin E and TGFß, with the latter two compounds reported to have immune-deviating activity capable of initiating tolerance towards foreign antigens (Wilbanks and Streilein, 1992
; Kelly et al., 1997
). There is evidence in rodents to suggest that semen exposure can initiate paternal antigen-specific immune tolerance (Lengerova and Vojtiskova, 1963
; Robertson et al., 1997
), and in humans observations surrounding the aetiology of pre-eclampsia also support this proposal. The incidence of pre-eclampsia, a disorder believed to be caused by an overly aggressive maternal immune response towards paternal trophoblast antigens (Dekker and Sibai, 1999
), is diminished in women following prolonged exposure to a partner's semen, with this protection being partner-specific (Marti and Herrmann, 1977
; Klonoff et al., 1989
; Robillard et al., 1994
). Acute exposure to semen around the time of embryo transfer may boost immunological memory in leukocytes reactive against paternal antigens, thereby strengthening immunological tolerance which, at least in animal studies, is known to have limited longevity (Tafuri et al., 1995
).
This study is the first to indicate that intercourse during the peri-transfer period of an IVF cycle is beneficial to pregnancy outcome. This is important information to convey to infertile couples since abstinence is commonly practised during infertility treatment and often recommended by the treating physician. Encouraging couples to engage in intercourse during IVF treatment might also have additional psychological advantages in terms of normalizing the `conception' process by allowing couples to participate actively in their reproductive outcome.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Carp, H.J.A., Serr, D.M., Mashiach, S. et al. (1984) Influence of insemination on the implantation of transfered rat blastocysts. Gynecol. Obstet. Invest., 18, 194198.[ISI][Medline]
Collins, J.A., Wrixon, W., Janes, L.B. et al. (1983) Treatment-independent pregnancy among infertile couples. N. Engl. J. Med., 309, 12011206.[Abstract]
Coulam, C.B. and Stern, J.J. (1995) Effect of seminal plasma on implantation rates. Early Pregnancy, 1, 3336.[Medline]
Dekker, G.A. and Sibai, B.M. (1999) The immunology of preeclampsia. Semin. Perinatol., 23, 2433.[ISI][Medline]
Fishel, S., Webster, J., Jackson, P. and Faratian, B. (1989) Evaluation of high vaginal insemination at oocyte recovery in patients undergoing in vitro fertilization. Fertil. Steril., 51, 135138.[ISI][Medline]
Flowers, W.L. and Esbenshade, K.L. (1993) Optimizing management of natural and artificial matings in swine. J. Reprod. Fertil., 48 (Suppl.), 217228.
Fox, C.A., Wolff, H.S. and Baker, J.A. (1970) Measurement of intra-vaginal and intra-uterine pressures during human coitus by radio-telemetry. J. Reprod. Fertil., 22, 243251.[Medline]
Franchin, R., Harmas, A., Benaoudia, F. et al. (1998a) Microbial flora of the cervix assessed at the time of embryo transfer adversely affects in vitro fertilization outcome. Fertil. Steril., 70, 866870.[ISI][Medline]
Franchin, R., Righini, C., Olivennes, F. et al. (1998b) Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization. Hum. Reprod., 13, 19681974.[Abstract]
Gervaize, P.A. (1993) The psychosexual impact of infertility and its treatment. Can. J. Hum. Sex., 2,141147.
Hill, J.A., Polgar, K. and Anderson, D.J. (1995) T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. J. Am. Med. Assoc., 273, 19331936.[Abstract]
Kelly, R.W., Carr, G.G. and Critchley, H.O. (1997) A cytokine switch induced by human seminal plasma: an immune modulation with implications for sexually transmitted disease. Hum. Reprod., 12, 677681.[Abstract]
Klonoff, C.H, Savitz, D.A., Cefalo, R.C. et al. (1989) An epidemiologic study of contraception and preeclampsia. J. Am. Med. Assoc., 262, 31433147.[Abstract]
Lamont, J.A. and Anderson, L. (1993) The interactions between sexuality and infertility. Can. J. Hum. Sex., 2, 107112.
Lengerova, A. and Vojtiskova, M. (1963) Prolonged survival of syngenic male skin grafts in parous C57 B1 mice. Folia Biol. (Praha), 9, 7274.[ISI][Medline]
Marconi, G., Auge, L., Oses, R. et al. (1989) Does sexual intercourse improve pregnancy rates in gamete intrafallopian transfer? Fertil. Steril., 51, 357359.[ISI][Medline]
Marti, J.J. and Herrmann, U. (1977) Immunogestosis: a new etiologic concept of `essential' EPH gestosis, with special consideration of the primigravid patient; preliminary report of a clinical study. Am. J. Obstet. Gynecol., 128, 489493.[ISI][Medline]
Naeye, R.L. (1979) Coitus and associated amniotic-fluid infections. N. Engl. J. Med., 301, 11981200.[Abstract]
O, W.S., Chen, H.Q. and Chow, P.H. (1988) Effects of male accessory sex gland secretions on early embryonic development in the golden hamster. J. Reprod. Fertil., 84, 341344.[Abstract]
Pang, S.F., Chow, P.H. and Wong, T.M. (1979) The role of the seminal vesicles, coagulating glands and prostate glands on the fertility and fecundity of mice. J. Reprod. Fertil., 56, 129132.[Abstract]
Pellicer, A., Valbuena, D., Cano, F. et al. (1996) Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period. Fertil. Steril., 65, 11901195.[ISI][Medline]
Piccinni, M.P., Beloni, L., Livi, C. et al. (1998) Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual cells in unexplained recurrent abortions. Nat. Med., 10, 14861491
Qasim, S.M., Trias, A., Karacan, M. et al. (1996) Does the absence or presence of seminal fluid matter in patients undergoing ovulation induction with intrauterine insemination? Hum. Reprod., 11, 10081010.[Abstract]
Queen, K., Dhabuwala, C.B. and Pierrepoint, C.G. (1981) The effect of the removal of the various accessory sex glands on the fertility of male rats. J. Reprod. Fertil., 62, 423426.[Abstract]
Robertson, S.A. and Seamark, R.F. (1992) Granulocyte-macrophage colony stimulating factor (GM-CSF): one of a family of epithelial cell-derived cytokines in the preimplantation uterus. Reprod. Fertil. Dev., 4, 435448.[ISI][Medline]
Robertson, S.A., Mau, V.J. and Tremellen, K.P. (1997) Cytokine-leukocyte networks and the establishment of pregnancy. Am. J. Reprod. Immunol., 37, 438442.[ISI][Medline]
Robertson, S.A., Roberts, C.T., Farr, K.L. et al. (1999) Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol. Reprod., 60, 252261.
Robillard, P.Y., Hulsey, T.C., Perianin, J. et al. (1994) Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet, 344, 973975.[ISI][Medline]
Simon, C., Landeras, J., Zuzuarregui, J.L. et al. (1999) Early pregnancy losses in in vitro fertilization and oocyte donation. Fertil. Steril., 72, 10611065.[ISI][Medline]
Sjoblom, C., Wikland, M.F. and Robertson, S.A. (1999) Granulocyte-macrophage colony-stimulating factor promotes human blastocyst development in vitro. Hum. Reprod., 14, 30693076.
Tafuri, A., Alferink, J., Moller, P. et al. (1995) T cell awareness of paternal alloantigens during pregnancy. Science., 270, 630633.[Abstract]
Tremellen, K.P., Seamark, R.F. and Robertson, S.A. (1998) Seminal transforming growth factor beta1 stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus. Biol. Reprod., 58, 12171225.[Abstract]
Vickery, B.H., Erickson, G.I. and Bennett, J.P. (1969) Non-surgical transfer of eggs through the cervix in rats. Endocrinology, 85, 12021203.[ISI][Medline]
Warnes, G.M., Payne, D., Jeffrey, R. et al. (1997) Reduced pregnancy rates following the transfer of human embryos frozen or thawed in culture media supplemented with normal serum albumin. Hum. Reprod., 12, 15251530.[Abstract]
Wilbanks, G.A. and Streilein, J.W. (1992) Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-beta. Eur. J. Immunol., 22, 10311036.[ISI][Medline]
Submitted on May 2, 2000; accepted on September 15, 2000.