**1. Introduction**

Assisted Reproductive Technology (ART) has, since its inception, been associated with increased rates of multiple pregnancy as the treating doctors struggled to balance an acceptable live birth rate with the risk of multiple pregnancy. A multiple pregnancy results in increased rates of both maternal and neonatal morbidity compared with a singleton pregnancy. Further, multiple pregnancy is associated with increased rates of prematurity, especially an increased

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

rate of severe prematurity, low birth weight, neonatal death and longer term developmental concerns [1]. Women with a multiple pregnancy are at risk of nearly every complication of pregnancy in comparison to women pregnant with a singleton pregnancy. Pre-eclampsia, gestational diabetes and operative delivery are all associated with significant increased maternal morbidity in multiple pregnancies.

without strict tracking protocols. Hence it is believed that ovulation induction accounts for up

Judicious Fertility Treatment to Minimise the Risk of Multiple Pregnancy

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Ovulation induction agents are usually divided into oral and injectable agents with the historical belief being that injectable agents, usually recombinant or urinary derived follicular stimulating hormone (FSH), being associated with higher rates of both multiple pregnancy

Clomiphene citrate was until recently the first line fertility treatment for anovulatory women undergoing ovulation induction [6]. Clomiphene is a selective oestrogen receptor modulator that blocks negative feedback of rising oestrogen levels at the level of the hypothalamus thereby resulting in ongoing FSH secretion and follicular development. Clomiphene citrate has historically had rates of multiple pregnancy quoted at 7%, with higher order multiple pregnancies rates occurring in less than 1% of confirmed pregnancies. [7] Newer data however suggests that multiple pregnancy rates with the use of clomiphene may be as high as 9% and higher order multiple pregnancy rates closer to 2%, as often ultrasound monitoring of the stimulated cycles is not performed [8]. Clomiphene, unlike other ovulation induction agents, does not have a higher rate of multiple pregnancy rates with higher dosing. The anti-oestrogenic properties exhibited by clomiphene on both the cervical mucus and endometrial lining with increased dosing have a negative impact on the rate of conception and implantation. Hence, although ovulation rates may increase, successful pregnancy, including multiple pregnancy, are not necessarily increased. Thus, for clomiphene, unlike other ovulation induction agents, simply prescribing lower doses

Letrozole is an aromatase inhibitor that is now recommended as a first line ovulation induction agent [6]. It is associated with higher rates of mono-ovulation than clomiphene and thus lower rates of multiple pregnancy, at around 3.5% [9], but with overall similar if not higher live birth rates [10]. It has a shorter half-life than clomiphene and, unlike clomiphene, during treatment endogenous FSH is suppressed by rising oestrogen levels thus reducing the risk of multiple follicles developing. Due to the benefit of increased live birth rates and a reduction in the rates of multiple pregnancy letrozole should be the oral agent for first line use in anovulatory women undergoing ovulation induction. However, letrozole must be used under informed consent as ovulation induction is not an approved indication for the drug.

Metformin has, over the last few years, been increasingly used for the management of women with PCOS, having potential benefits with regard to its metabolic consequences [11] and androgenic side-effects [12]. However, with respect to anovulatory infertility as a sole agent the benefit of increasing the chance of a live birth is not clear, other than perhaps as an adjuvant to clomiphene citrate in overweight women [13], or as an adjuvant to FSH ovulation induction [14].

to 65% of the world's higher order multiple pregnancies [5].

of the agent will do little to reduce multiple pregnancy rates.

and ovarian hyper-stimulation syndrome.

**2.1. Clomiphene citrate**

**2.2. Letrozole**

**2.3. Metformin**

A multiple pregnancy, for patients who have suffered through months or years of infertility and treatment, can often be seen as a "double blessing" and may indeed result in a successful outcome for many patients. For many years rates of multiple pregnancy for women undergoing ART were accepted as a necessary part of treatment. With ongoing development of fertility treatment, employing better processes and therapies, the success rate of ART has improved, and thus the impetus for using methods that also run the risk of high rates of multiple pregnancy are no longer warranted or accepted. Now when determining the success of an ART technique or an ART service provider, the rate of singleton, term, live birth should be seen as the gold standard of measurement and the aim of successful treatment [2]. Strategies to achieve this are now the cornerstone in research, development and guidelines in ART techniques and stricter regulations and protocols are in place to implement safer methods.

This chapter will explore ways in which ART, in particular ovulation induction, super-ovulation and intra-uterine insemination (IUI) and in-vitro fertilisation (IVF), can be delivered to ensure low rates of multiple pregnancy and make ART and the pregnancy that results safer for mother and baby.
