**2.1. Clomiphene citrate**

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

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

Ovulation induction involves stimulating the ovary with the aim to induce mono-follicularovulation in a sub-fertile woman who is anovulatory. A trigger injection, to mimic the midcycle luteinising hormone (LH) surge, is given to initiate release of the ovum and timed

Multiple pregnancy may occur with ovulation induction secondary to unintended overstimulation of the ovary and the development of more than one follicle and the release and subsequent fertilisation of more than one oocyte. Rates of multiple pregnancy with ovarian stimulation depend greatly on the treatment protocol used, but for all methods has been

A recent 5-year review of multiple pregnancy rates in the United States revealed 22% of the nation's twin pregnancies were due to ovulation induction and 40% of triplet pregnancies were as a result of ovulation induction treatment [4]. The rates of multiple pregnancy secondary to ovulation induction are falling as better techniques and practices are introduced however, not as quickly as is being seen with more invasive ART techniques such as IVF. Stricter controls and more stringent regulations are being enforced in many countries towards IVF treatments in the hope of stalling the multiple pregnancy rate, however this has not been replicated in the field of ovulation induction, as this is often performed outside of large fertility clinics, or

approximated at up to 9 times the rate of natural conception in fertile women [3].

maternal morbidity in multiple pregnancies.

48 Multiple Pregnancy - New Challenges

and baby.

**2. Ovulation induction**

intercourse is advised.

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