The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility

BACKGROUND Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART. Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate. This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. METHODS/DESIGN We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months. Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded. Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). DISCUSSION Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. TRIAL REGISTRATION Current Controlled Trials ISRCTN 52843371Alexandra J Bensdorp, Els Slappendel, Carolien Koks, Jur Oosterhuis, Annemieke Hoek, Peter Hompes, Frank Broekmans, Harold Verhoeve, Jan Peter de Bruin, Janne Meije van Weert, Maaike Traas, Jacques Maas, Nicole Beckers, Sjoerd Repping, Ben W Mol, Fulco van der Veen and Madelon van Wel

Pharmacokinetics and Pharmacodynamics of Antifungals in Children and Their Clinical Implications

Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas