Nitric oxide donors for patients undergoing IVF. A prospective, double-blind, randomized, placebo-controlled trial*

Jeanine Ohl1,6, Catherine Lefèbvre-Maunoury2, Christiane Wittemer1, Gabriel Nisand3, Marie-Christine Laurent4 and Pascale Hoffmann5

1 Département d’AMP de Strasbourg, Service de Gynécologie-Obstétrique, CMCO, 19 rue Louis Pasteur, BP 120, 67303 Schiltigheim, 2 Service d’AMP, Hôpital Jeanne de Flandres, 59037 Lille cedex, 3 Département d’Informatique Médicale, Hospices Civils, 67091 Strasbourg cedex, 4 Service de Gynécologie-Obstétrique B, Hôpital Sud, 16 boulevard de Bulgarie, BP 56129 35056 Rennes cedex 2 and 5 Service de Gynécologie-Obstétrique et Médecine de la Reproduction, CHU Nord, BP 217 38043 Grenoble cedex 9, France


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Nitric oxide (NO) is involved in local control of the uterine cycle and in preparation of the uterus for pregnancy. NO donors, acting as vasodilating agents, may therefore have possible therapeutic uses, for example they may be of benefit to patients with a history of implantation failure. In a prospective, comparative, randomized, placebo-controlled study, we assessed the efficacy of nitroglycerin (NTG) administered to 138 IVF patients with a history of implantation failure. METHODS: Controlled ovarian stimulation was performed with long agonist protocol combined with recombinant FSH. Embryos were transferred on day 2 or 3 after oocyte retrieval. Eligible patients were those who had at least two ‘good quality’ embryos. The NTG patch was administered the day before embryo transfer and continued until either the results of the pregnancy test were known or until menstruation occurred. RESULTS: Ovarian response, implantation rate and pregnancy rate were comparable between both groups. No difference was observed in uterine Doppler findings, particularly the mean pulsatility index. CONCLUSIONS: NTG treatment the day before embryo transfer was no more effective than placebo in improving the implantation or pregnancy rates in a population of IVF patients with a previous history of implantation failures.

Key words: implantation/IVF/nitric oxide donors


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In the light of its well-known beneficial effects in cardiology, nitric oxide (NO) has been the object of recent attention in obstetrics and gynecology (Lees, 1996Go). During pregnancy, NO donors have been suggested to improve fetal prognosis in cases of intrauterine growth retardation (IUGR) (Morris et al., 1995Go; Hata et al., 1998Go). They can also be used as tocolytic agents (Black et al., 1999Go; Lees et al., 1999Go). Progress in reproductive physiology has shown that NO is involved in the fertilization process and is found in the follicle as well as in the sperm (Rosselli et al., 1995Go; O’Bryan et al., 1998Go). It also plays a role in decidualization and implantation (Telfer et al., 1997Go; Chwalisz et al., 1999Go). Nonetheless, there have been very few clinical studies of NO donors for the treatment of infertility.

High resistance to uterine blood flow on the day of either hCG administration or embryo transfer is reported to be correlated with a poor pregnancy rate for patients undergoing IVF (Favre et al., 1993Go; Coulam et al., 1995Go; Cacciatore et al., 1996Go). Aspirin has been used in IVF programmes to improve implantation in patients with repeated failures (Wada et al., 1994Go; Rubinstein et al., 1999Go). These observations, considered together, suggested that uterine vasodilatation might be induced by an NO donor during IVF, thereby improving endometrial receptivity. We therefore performed a randomized evaluation of treatment with nitroglycerin (NTG) before embryo transfer, aiming to assess the impact of this NO donor on the pregnancy rates. As a secondary outcome, we observed eventual changes in uterine arteries, reflected by Doppler measurements.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This prospective, randomized, multicentre study was double-blinded and placebo-controlled. Randomization was performed by the Medical Research Department of Laboratoires Schwarz Pharma (France), who also provided placebo and NO donor patches. Randomization was by randomly permuted four blocks and stratified by centre.

The study was approved by the Ethics Committee.

In a pilot study in 1997 (unpublished data), 5 mg patches of nitroglycerin (NTG), were administered to 15 patients with at least two previous implantation failures despite the transfer of at least two ‘good quality’ embryos each time. Five pregnancies were achieved after treatment and transfer, again, of at least two ‘good quality’ embryos, for a per cycle pregnancy rate of 33%. During the same period, 59 patients with the same history and the same transfer conditions received no specific treatment. There were eight pregnancies in that group, for a per cycle pregnancy rate of 13.6%. These preliminary results in favour of NTG treatment seemed promising and a success rate after treatment of 25% could be expected, which is the general pregnancy rate in an IVF population. Based on those two percentages, a total sample of 288 patients was calculated (144 placebo and 144 NTG) in a unilateral test at the 5% significance level with 80% power. In January 2000, whereas 164 patients out of 288 were enrolled in the study, placebo as well as NTG patches became out of date. New patches were not affordable. A new power calculation led to 53% in a unilateral test at the 5% significance level.

Inclusion criteria were the same as in the preliminary study: all patients had a history of two or more previous implantation failures despite the transfer 48 h after oocyte retrieval of two or more ‘good quality’ embryos as previously defined (Veeck, 1991Go), with blastomeres of equal size and anucleated fragments totalling <10%. Informed written consent was given by all patients.

Exclusion criteria were hypersensitivity to nitric oxide donors, heart failure, severe anaemia, high intracranial blood pressure and high intraocular blood pressure.

Controlled ovarian stimulation was performed using a GnRH agonist long protocol (Decapeptyl®; Ipsen, Paris, France; or Suprefact®; Hoechst, France) given daily and s.c. combined with recombinant FSH (Gonal F®; Serono, France; Puregon®; Organon, France). The GnRH analogue was continued up to the day when 5000 IU hCG (Gonadotrophine chorionique ‘endo’®; Organon, France) was administered. The cycles were monitored with serial transvaginal ultrasonography and serum LH and estradiol assays. Oocytes were retrieved transvaginally under ultrasound guidance. Sperm characteristics determined the choice of ICSI with metaphase II oocytes or conventional IVF.

Embryos were transferred on day 2 or day 3 after oocyte retrieval. We included only patients with transfers of at least two ‘good quality’ embryos. The patients were randomized the day before embryo transfer. They received active treatment or placebo. The active treatment group received 5 mg NTG patches (Schwarz Pharma, Monheim, Germany), and the control group placebo patches (Schwarz Pharma). Patches were applied once daily, beginning the morning of the day before transfer, just after transvaginal ultrasonography and colour Doppler were performed. The patch was removed at bedtime for ~8 h to avoid adverse effects and a new patch placed in the morning (Cowan et al., 1987Go). Patients continued using the patches until either the results of the pregnancy test were available or menstruation occurred. Micronized progesterone 200 mg intravaginally twice daily was used as luteal support (Utrogestan®; Besins-Iscovesco, France). Serum ß-HCG was assayed 3 weeks after transfer. A clinical pregnancy was defined by fetal cardiac activity on ultrasound examination 6 weeks after oocyte retrieval.

Patients were asked if they felt any side-effects during the treatment and these were scored by the patients on a scale of 1–4 according to severity (French Drug Agency, 1994Go). Thickness and ultrasonographic patterns of the endometrium were noted (Grunfeld et al., 1991Go). Blood flow velocity, expressed as the pulsatility index (PI), was calculated automatically according to the formula: PI = (peak systolic velocity/mean velocity) – (end diastolic velocity/mean velocity). The mean pulsatility indices of the left and right uterine arteries were calculated. We used the standard cut-off point from the literature (Steer et al., 1992Go; Wada et al., 1994Go; Bied-Damon et al., 1995Go): a PI >3 was considered to indicate high uterine resistance.

Data analysis used the {chi}2 and Fisher’s exact tests, with P < 0.05 considered to indicate statistical significance. The Mann–Whitney or Wilcoxon rank-sum test was used as appropriate. Bonferroni method was also used in the trial for multiple comparisons.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
During a 14 month period (November 1998 through January 2000), 164 patients were initially enrolled in this study. When considering only transfers of at least two good quality embryos, we excluded 26 patients with only one embryo available. A total of 138 patients was randomized (Figure 1Go), 70 patients were treated with NTG and 68 with placebo. No patient refused to be treated. Doppler was performed for 53 patients treated with NTG and 49 with placebo. Table IGo summarizes the characteristics of the population and Table IIGo the characteristics of IVF procedures for each group. On the day of embryo transfer, the endometrial thickness was comparable in both groups. Secretory changes of the endometrium had occurred from the day before in 30.6% of patients in the NTG group versus 43.2% in the placebo group (P = not significant): the endometrium became totally hyperechogenic, indicating a mid-luteal phase. The mean PI was similar in both groups, both on the day before and the day of embryo transfer.



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Figure 1. Flow diagram of the progress through the phases of the randomized trial. ET = embryo transfer; NO = nitric oxide.

 

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Table I. Characteristics of the population in the nitric oxide (NO) donor and placebo groups
 

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Table II. IVF features in the nitric oxide (NO) donor and placebo groups
 
The results of IVF procedures for the NTG group and for the placebo group are summarized in Table IIIGo. The number of oocytes retrieved, the number of metaphase II oocytes and the cleavage rate were equivalent in both groups, as well as the number of ‘good quality’ embryos transferred. The pregnancy rate was 28.6% in the NTG group and 27.9% in the placebo group. Neither this difference nor the difference in the implantation rate (10.6 versus 11.6%) was significant.


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Table III. IVF–embryo transfer outcome in the nitric oxide (NO) donor and placebo groups
 
Table IIIGo summarizes the pregnancy outcomes. The groups did not differ for delivery or abortion rates. No pregnancy ended in a second-trimester abortion. No significant difference was noted for the mean weight of the newborns, although among twins (six pregnancies, three in each group), the mean weight was higher in the NO donor group.

There was one malformation and one third-trimester intrauterine death, both involving mothers in the placebo group. One baby girl, with a birthweight of 3760 g, was born with blepharophimosis, epicanthus inversus and ptosis (BPES syndrome) associated with anal imperforation. The fetal death occurred to one of a pair of twins. A healthy and premature 31 week boy of 1320 g was born.

Outcome according to PI on the day before embryo transfer was also studied. We measured the change in PI from the day before to the day of implantation and identified a subgroup with initially high uterine resistance. In this subgroup, there were five pregnancies (33%) in the NTG group, compared with none in the placebo group.

From a safety point of view, only one patient in the placebo group reported side-effects. She complained of nervousness, insomnia, constipation and a feeling of weakness and discontinued the treatment after one only patch.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In our study, neither placebo nor NTG improved pregnancy rates in patients with poor outcomes following IVF.

To our knowledge, this is the largest multicentre study to assess the accuracy of an NO donor in an IVF programme. However, some limitations must be discussed. Fewer patients were included than initially planned because of the slowness of recruitment. Another limitation is that Doppler measurements could not be performed for all the patients because a Doppler device was not always available.

Many studies have attempted to improve uterine receptivity to implantation, in particular after failed IVF procedures. Recent studies have shown that NO plays a role in the mechanisms of ovulation, corpus luteum formation and implantation (Cameron and Campbell, 1998Go; Ota et al., 1998Go). NO potently relaxes arterial and venous smooth muscles and, less strongly, inhibits platelet aggregation and adhesion. NO donors, acting as vasodilating agents, are therefore a possible therapeutic approach (Ohl et al., 1995Go). Because of their very short half-life, these agents are rapid and become fully effective in only a few minutes (Campbell and Lees, 1994Go), in contrast to aspirin. No accumulation can occur, avoiding toxic effects. Therefore, we decided in our study to begin therapeutic administration of patches the day before embryo transfer. The lack of a beneficial effect on the pregnancy rate raises questions about this choice. The NO donor patches should have begun in the early follicular phase. If so, a beneficial impact is expected on ovarian response, or failing that, on uterine receptivity. A recent publication reports that Sildenafil, an NO donor, administered on day 3 of the cycle (Sher and Fisch, 2000Go) appeared effective in improving uterine artery blood flow and endometrial development. However, it was used in combination with estradiol valerate only in four patients with prior poor endometrial response during IVF.

Moreover, monoclonal antibody immunostaining has shown a change during the menstrual cycle in the expression of endometrial NO synthase (Ota et al., 1998Go). Expression increased progressively to become most intense in the middle of the luteal (secretory) phase. This finding suggests that NO donors should be used only in the secretory phase, just before implantation. Moreover, good results have followed the late, as-needed administration of NTG in the studies concerning IUGR and pre-eclampsia during pregnancy (Campbell and Lees, 1994Go; Lees et al., 1998Go). Further studies are needed to answer this question.

NTG was also used in a study in an IVF programme (Shaker et al., 1993Go). A total of 120 patients received randomly two sublingual spray emissions or placebo 3 min before embryo transfer. No significant effect was found on any parameter of the transfer procedure. In our study, duration of the treatment was prolonged with long-acting NTG patches in order to improve not only an atraumatic progression of the catheter, but also implantation rates.

Only one patient in the placebo group complained about side-effects during the treatment which were probably related to the stress of the IVF procedure. Thus NGT appeared safe and well tolerated.

A recent study (Luzi et al., 1999Go) used NTG during the third trimester of pregnancy for 10 patients with threatened premature labour, 10 with pre-eclampsia and 10 healthy patients. In both groups of sick patients, the uterine artery PI fell significantly after NO treatment. No change was detected in the control group after NTG treatment.

In our study, neither placebo nor NTG improved the flow resistance in the uterine artery. The treatment did not improve Doppler parameters even among the women with poor uterine perfusion before treatment. The non-measurable effect on PI from use of NO donor could be explained by an insufficient dosage, but similar findings have also been reported when transdermal 10 mg NTG was administered to pregnant patients with impaired uterine perfusion (Lees et al., 1998Go). It induced neither maternal haemodynamic changes nor a change in Doppler parameters. Nevertheless, fewer complications occurred during pregnancy in the active treatment group. Compensatory mechanisms may secondarily take place and counter-balance the effect of the NO donor on PI after 24 h. The PI could have dropped when measured 20 or 30 min after administration of the patch (Luzi et al., 1999Go).

The predictive value of the PI requires careful assessment. Doppler results have been described as markers of uterine receptivity. Nevertheless, several studies have challenged the predictive value of the uterine Doppler (Aytoz et al., 1997Go; Bloechle et al., 1997Go; Chui et al., 1997Go). Uterine PI reflects the vascularization of the whole organ, but probably not the endometrial quality at the potential site of implantation (Schwartz et al., 1997Go). PI measured on the uterine artery has a high negative predictive value but a low positive predictive value.

In conclusion, NTG treatment the day before embryo transfer was not more effective than placebo in improving the implantation or pregnancy rates in a population of IVF patients with a previous history of implantation failures. The NO donor did not affect uterine Doppler values.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors thank the Multicentre Trialists from the GROG for their clinical contribution. The assistance of Dr Antonio Delgado (Schwarz Pharma, Boulogne, France), Dr Hans-Theo Forst (Schwarz Pharma, Monheim, Germany), Dr Francioise Truong and Pascale Pinck (Serono, Boulogne, France) is gratefully acknowledged.


    Notes
 
6 To whom correspondence should be addressed. E-mail: pierre.ohl{at}evc.net Back

* The Multicentre Trialists from the GROG (Groupe de Recherche en Obstétrique et en Gynécologie): Dr Karima Bettahar-Lebugle, Dr Jeanine Ohl, Dr Catherine Rongières (Schiltigheim); Dr Catherine Lefèbvre-Maunoury (Lille); Dr Marie-Christine Laurent (Rennes); Dr Nicole Quénard, Dr Irène Grefenstette, Dr Pascale Hoffman (Grenoble); Dr Catherine Avril, Bois (Guillaume); Pr Michel Herlicoviez (Caen); Dr Stéphanie Dominé (Paris); Dr Renato Fanchin, Dr Nathalie Lédée (Clamart); Pr Bruno Salle (Lyon); Dr Brigitte Lebouvier (Angers). Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Aytoz, A., Nagy, Z.P., Ubaldi, F., Van Steirteghem, A., Tournaye, H. and Devroey, P. (1997) The predictive value of uterine artery blood flow measurements for uterine receptivity in an intracytoplasmic sperm injection program. Fertil. Steril., 68, 935–937.[ISI][Medline]

Bied-Damon, V., Salle, B., Payan, F., Guerin, J.F. and Boulieu, D. (1995) Etude de la vascularisation utérine par le doppler pulsé couleur avant transfert embryonnaire. Contracept. Fertil. Sex., 23, 524–529.[ISI][Medline]

Black, R., Lees, C., Thompson, C., Pickles, A. and Campbell, S. (1999) Maternal and fetal cardiovascular effects of transdermal glyceryl trinitrate and intravenous ritodrine. Obstet. Gynecol., 94, 572–576.[Abstract/Free Full Text]

Bloechle, M., Schreiner, T., Küchler, I., Schürenkämper, P. and Lisse, K. (1997) Colour Doppler assessment of ascendent uterine artery perfusion in an in-vitro fertilization–embryo transfer programme after pituitary desensitization and ovarian stimulation with human recombinant follicle stimulating hormone. Hum. Reprod., 12, 1772–1777.[Abstract]

French Drug Agency [Agence du Médicament] (1994) Bonnes Pratiques de Pharmacovigilance [Good Drug Safety Practice], p. 11.

Cacciatore, B., Simberg, N., Fusaro, P. and Tiitinen, A. (1996) Transvaginal Doppler study of uterine artery blood flow in in vitro fertilization–embryo transfer cycles. Fertil. Steril., 66, 130–134.[ISI][Medline]

Cameron, I. and Campbell, S. (1998) Nitric oxide in the endometrium. Hum. Reprod. Update, 4, 565–569.[Abstract/Free Full Text]

Campbell, S. and Lees, C. (1994) Xè Journées de vélocimétrie sanguine maternelle et foetale. Maternité Port-Royal Baudelocque, Paris, samedi 19 mars, 1994.

Chui, D.K.C., Pugh, N.D., Walker, S.M., Gregory, L. and Whaw, R.W. (1997) Follicular vascularity- the predictive value of transvaginal power Doppler ultrasonography in an in-vitro fertilization programme: a preliminary study. Hum. Reprod., 12, 191–196.[ISI][Medline]

Chwalisz, K., Winterhager, E., Thienel, T. and Garfield, R.E. (1999) Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat. Hum. Reprod., 14, 542–552.[Abstract/Free Full Text]

Coulam, C.B., Stern, J.J., Soenksen, D.M., Britten, S. and Bustillo, M. (1995) Comparison of pulsatility indices on the day of oocyte retrieval and embryo transfer. Hum. Reprod., 10, 82–84.[Abstract]

Cowan, J.C., Bourke, J.P., Reid, D.S. and Julian, D.G. (1987) Prevention of tolerance to nitroglycerin patches by overnight removal. Am. J. Cardiol., 60, 271–275.[ISI][Medline]

Favre, R., Bettahar-Lebugle, K., Grangé, G., Ohl, J., Arbogast, E., Moreau, L. and Dellenbach, P. (1993) Predictive value of transvaginal uterine Doppler assessment in an in-vitro fertilization program. Ultrasound Obstet. Gynecol., 3, 350–353.[ISI][Medline]

Grunfeld, L., Walker, B., Bergh, P.A., Sandler, B., Hofmann, G. and Navot, D. (1991) High-resolution endovaginal ultrasonography of the endometrium: a non invasive test for endometrial adequacy. Obstet. Gynecol., 78, 200–204.[Abstract]

Hata, T., Hashimoto, M., Manabe, A., Aoki, S., Iida, K., Masumura, S. and Miyazaki, K. (1998) Maternal and fetal nitric oxide synthsis is decreased in pregnancies with small for gestational age infants. Hum. Reprod., 13, 1070–1073.[Abstract]

Lees, C. (1996) Nitric oxide donors in obstetrics and gynaecology. Schwarz Pharma Scientific Forum, Cornelius Limbach GmbH, Köln, Germany, March 1996.

Lees, C., Valensise, H., Black, R., Harrington, K., Byiers, S., Romanini, C. and Campbell, S. (1998) The efficacity and fetal–maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Ultrasound Obstet. Gynecol., 12, 334–338.[ISI][Medline]

Lees, C., Lojacono, A., Thompson, C., Danti, L., Black, R., Tanzi, P. et al. (1999) Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. Obstet. Gynecol., 94, 403–408.[Abstract/Free Full Text]

Luzi, G., Castera, G., Iammarino, G., Clerici, G. and Di Renzo, C. (1999) Nitric oxide donors in pregnancy: fetomaternal hemodynamic effects induced in mild preeclampsia and threatened preterm labor. Ultrasound Obstet. Gynecol., 14, 101–109.[ISI][Medline]

Morris, N., Sooranna, S., Learmont, J., Poston, L., Ramsey, B., Pearson, J., Steer, P.J. (1995) Nitric oxide synthase activities in placental tissue from normotensive, pre-eclamptic and growth retarded pregnancies. Br. J. Obstet. Gynaecol., 102, 711–714.[ISI][Medline]

O’Bryan, M.K., Zini, A., Cheng, C.Y. and Schlegel, P.N. (1998) Human sperm endothelial nitric oxide synthase expression: correlation with sperm motility. Fertil. Steril., 70, 1143–1147.[ISI][Medline]

Ohl, J., Bettahar-Lebugle, K. and Dellenbach, P. (1995) Le monoxyde d’azote: nouveaux horizons en gynécologie-obstétrique. Contracept. Fertil. Sex., 23, 645–650.[ISI][Medline]

Ota, H., Igarashi, S., Hatazawa, J. and Tanaka, T. (1998) Endothelial nitric oxide synthase in the endometrium during the menstrual cycle in patients with endometriosis an adenomyosis. Fertil. Steril., 69, 303–308.[ISI][Medline]

Rosselli, M., Dubey, R.K., Imthurn, B., Macas, E. and Keller, P.J. (1995) Effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces toxicity. Hum. Reprod., 10, 1786–1790.[Abstract]

Rubinstein, M., Marazzi, A. and Polak de Fried, E. (1999) Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind, placebo-controlled assay. Fertil. Steril., 71, 825–829.[ISI][Medline]

Schwartz, L.B., Chiu, A.S., Courtney, M., Krey, L. and Schmidt-Sarosi, C. (1997) The embryo versus endometrium controversy revisited as it relates to predicting pregnancy outcome in in-vitro fertilization–embryo transfer cycles. Hum. Reprod., 12, 45–50.[ISI][Medline]

Shaker, A.G., Fleming, R., Jamieson, M.E., Yates, R.W. and Coutts, J.R. (1993) Assessments of embryo transfer after in-vitro fertilization: effects of glyceryl trinitrate. Hum. Reprod., 8, 1426–1428.[Abstract]

Sher, G. and Fisch, J.D. (2000) Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve artery blood flow and endometrial development in patients undergoing IVF. Hum. Reprod., 15, 806–809.[Abstract/Free Full Text]

Steer, C.V., Campbell, S., Tan, S.L. and Crayford, T. (1992) The use of transvaginal color flow imaging after in vitro fertilization to identify optimum uterine conditions before embryo transfer. Fertil. Steril., 57, 372–376.[ISI][Medline]

Telfer, J.F., Irvine, G.A., Kohnen, G., Campbell, S. and Cameron, I.T. (1997) Expression of endothelial and inducible nitric oxide synthase in non-pregnant and decidualized human endometrium. Mol. Hum. Reprod., 3, 69–75.[Abstract]

Veeck, L.L. (1991) Typical morphology of the human oocyte and early conceptus. In Atlas of the Human Oocyte and Early Conceptus, Vol. 2. Williams and Wilkins, Baltimore, pp. 3–144.

Wada, I., Hsu, C.C., Williams, G., Macnamee, M.C. and Brinsden, P.R. (1994) The benefits of low-dose aspirin therapy in women with impaired uterine perfusion during assisted conception. Hum. Reprod., 9, 1954–1957.[Abstract]

Submitted on January 4, 2001; resubmitted on May 7, 2002; accepted on June 14, 2002.





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