Estimating rates of multiple gestation pregnancies: Sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial

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Abstract

Infertility afflicts 15% of couples who wish to conceive. Despite intensive evaluation of both male and female partners, the etiology may remain unknown leading to a diagnosis of unexplained infertility. For such couples, treatment often entails ovulation induction (OI) with fertility medications coupled with intrauterine insemination. Complications of this therapy include ovarian hyperstimulation syndrome and creation of multiple gestation pregnancies, which can be complicated by preterm labor and delivery, and the associated neonatal morbidity and expense of care for preterm infants. The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study is designed to assess whether OI in couples with unexplained infertility with an aromatase inhibitor produces mono-follicular development in most cycles, thereby reducing multiple gestations while maintaining a comparable pregnancy success rate to that achieved by OI with either gonadotropins or clomiphene citrate. These results will provide future guidance of therapy for couples with unexplained infertility, and if comparable pregnancy rates are achieved with a substantial reduction in multiple gestations, the public health benefit will be considerable.

Introduction

Infertility afflicts an estimated 10% to 15% of couples, although this number may underestimate the true incidence because the inability to conceive carries a hidden stigma of shame and secrecy for many couples, and because others cannot afford to seek medical evaluation and treatment [1], [2], [3]. The availability of new treatment methods, including stimulation of ovarian follicular development [commonly called ovulation induction (OI)], intrauterine insemination (IUI) and other assisted reproductive technologies (ART) explain at least in part the observed increase of couples seeking care for infertility (American Society for Reproductive Medicine 1996). Treatment with OI combined with IUI has been applied empirically for different types of infertility including unexplained infertility, male-factor infertility, and anovulatory infertility. This treatment has been shown to be effective in a previous study performed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network (RMN) [4]. Ovulation induction is thought to improve the cycle fecundability rate in part by increasing the number of follicles (and hence oocytes) available for fertilization, and perhaps by correcting subtle, unpredictable ovulatory or endometrial dysfunction. IUI is expected to allow adequate numbers of selected sperm to be deposited into the uterine cavity, thereby circumventing potential cervical problems.

At the present time, primarily two types of medication are used for OI: either an oral selective estrogen receptor modulator, clomiphene citrate (CC), or injectable gonadotropins, each in conjunction with human chorionic gonadotropin (hCG), a surrogate for LH to stimulate ovulation. Administration of these medications, however, is associated with risks for development of ovarian hyperstimulation syndrome (ovarian enlargement, which can be associated with third spacing of fluid, hemoconcentration, and even systemic organ function impairment with the need for hospitalization, sometimes in intensive care units), and initiation of multiple gestation pregnancies, particularly with the use of the more potent gonadotropins. Recently, several descriptive reports have suggested that the use of aromatase inhibitors for ovarian stimulation may be an alternative to CC and gonadotropins, and that such use may be associated with monofollicular development, thereby reducing the rate of multiple gestation pregnancies [5], [6], [7], [8], [9], [10]. The latter is of major concern because of the risk for preterm delivery and its associated fetal morbidity and even mortality, as well as the expense of care for multiple infants. Additionally, it has been suggested that use of aromatase inhibitors may be associated with a better endometrial response, including better blood flow as suggested by significantly lower spiral artery impedance on Doppler, with the use of the aromatase inhibitor letrozole, as compared to CC [11]. This study will be conducted to assess efficacy of an aromatase inhibitor for ovarian stimulation in women with unexplained infertility.

This manuscript will present the protocol and statistical analysis plan of the RMN study entitled the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) trial (Fig. 1). The RMN studies are designed by its Steering Committee composed of the Principal Investigators of the participating sites and data coordinating center, NICHD Project Scientist, and NICHD appointed Steering Committee Chair. Following development by the Steering Committee, each protocol is reviewed independently by both an Advisory Committee and Data Safety and Monitoring Board (DSMB). Studies undertaken by the RMN are chosen to address critical clinical questions in reproductive science, which require multicenter design to allow timely conduct and completion of the protocol. Access to the clinical data from the AMIGOS trial will be made available to non-RMN investigators for conduct of secondary analyses, as will access to biorepository specimens collected at baseline and throughout the trial, following approval by the RMN Steering Committee. Consequently, knowledge of the design, inclusion criteria, and exclusion criteria of the AMIGOS study are of value to investigators with interest in the reproductive sciences.

Section snippets

Materials and methods

The AMIGOS study is a multi-center, randomized clinical trial of gonadotropin or clomiphene citrate (CC) vs. letrozole, an aromatase inhibitor (AI), in the treatment of 900 couples with unexplained infertility. While originally designed to be completely double blinded including sham injections in women assigned to the CC or AI arms, inability to identify a financially feasible placebo to the gonadotropin injection resulted in a final study design in which the study will be double-blind with

Results

It is difficult to identify estimates of pregnancy and multiple gestation rates in infertile couples with a regularly ovulating female receiving empiric ovulation induction. For the determination of sample size calculations for the AMIGOS study, the RMN has utilized a recent report of a cohort study of women who underwent 3045 cycles of ovulation induction using a variety of agents for OI, including gonadotropins alone, CC alone, and AI alone [5] in which choice of treatment agent was based on

Discussion

The occurrence of multiple gestational pregnancy is one of the most common problems associated with OI. While the rate of spontaneous twin pregnancy has been estimated to range from 1% to 1.35% and that of a triplet pregnancy from 0.01% to 0.017%, the incidence of multiple gestational pregnancies is more than 10–20 times higher with OI and IUI, ranging from 7.5% to 29% per couple [18], [19]. In the last decade, the significant increase in the incidence of multiple births in most countries is

Conclusion

The occurrence of multiple gestations after ovulation induction in couples with unexplained infertility remains a major concern of infertility therapy. The AMIGOS study will evaluate whether the use of an aromatase inhibitor for recruitment of multiple follicular development will lower the rate of multiple pregnancy without detrimentally affecting the likelihood of establishing a pregnancy.

Acknowledgements

The authors express their thanks to the other members of the Cooperative Reproductive Medicine Network (RMN), as well as the RMN Advisory Committee and Data Safety Monitoring Board for their critical review of the AMIGOS protocol.

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    Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5U10 HD 039005, 3U10 HD 039005-S1, 5U10 HD 038992, 3U10 HD 038992-S1, 5U10 HD 055942, 3U10 HD 055942-S1, 5U10 HD 055944, 3U10 HD 055944-S1, 5U10HD055925, 5U10HD055925-S1).

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