20 April 2009.

A pregnancy rate of approximately 15% per cycle renders the process of human reproduction inefficient. The cycle-dependent expression of molecules involved in the embryo-endometrial dialogue has lead to the identification of a 'window of implantation'. This is the unique temporal and spatial expression of factors that allows the embryo to implant (via signalling, appositioning, attachment and invasion) in a specific time frame of 48 h, 7-10 days after ovulation. Integrin molecules, L-selectin ligands, mucin-1, heparin-binding epidermal growth factor and pinopodes are involved in appositioning and attachment. The embryo produces cytokines and growth factors [interleukins, prostaglandins, vascular endothelial growth factor (VEGF)] and receptors for endometrial signals (leukaemia inhibitory factor receptor, colony stimulating factor receptor, insulin-like growth factors and heparin binding epidermal growth factor receptor). The immune system plays an important role. Immunomodulatory factors such as glycodelin, inhibin and interleukin prevent a graft-versus-host reaction. Angiogenesis controlled by VEGF and prostaglandins is needed for formation of a receptive endometrium and a placenta. Identification of these factors has led to their use as markers of implantation that may identify defects causing subfertility. An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation. Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.

Objectives To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. Design Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. Setting 17 centres in the Netherlands. Participants Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. Interventions Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. Main outcome measures The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality Results 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). Conclusions In vitro fertilisation with single embryo transfer an...

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Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.