**2.3. Metformin**

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].

#### **2.4. Follicular stimulation hormone (FSH)**

Injectable agents, usually recombinant FSH, have historically been associated with higher rates of multiple pregnancy. When first described dosing regimes in the realm of 225 IU of FSH were used to induce ovulation in anovulatory women with multiple pregnancy rates of around 25% [15]. As greater experience was gained using FSH and with a clear distinction being made between dosing for the aim of mono-ovulation in ovulation induction, versus ovarian hyper-stimulation for IVF cycles initial dosages fell dramatically. Low dose, step up protocols are now the recommended regime with close monitoring to observe response [16]. Unlike oral agents that are given for a limited number of days in the early follicular phase, FSH can be given for an extended period until follicular development is seen. With this method rates of multiple pregnancy can be as low, or lower, than with oral agents and can be achieved with higher live birth rates. In countries with good health insurance and state funding for fertility treatments out of pocket costs to patients are comparable to oral agents and are thus often used as a first line treatment due to their increased success rates.

More judicious care can be taken to actively avoid multiple pregnancy by ensuring monoovulation by very closely monitoring oestrogen levels and follicular development on ultrasound. By cancelling cycles when more than 2 follicles of greater than 10 mm are present has been shown to actively reduce multiple pregnancy rates. Oestrogen levels above 600 pg/ mL have been associated with increased rates of multiple pregnancy [20] and higher than 2000 pg/mL with higher order multiple pregnancy. [21] Using both ultrasound follicle tracking and serum oestradiol measurements to carefully track cycles is imperative to minimise

Judicious Fertility Treatment to Minimise the Risk of Multiple Pregnancy

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51

As a general rule, younger women, women with a greater antral follicle count or higher antimullerian hormone (AMH) levels are more likely to have a greater response to a lower dose of induction agent and thus should be started at a minimum dose on the first cycle and tracked

All couples should be worked up prior to embarking on ovulation induction to confirm tubal patency and adequate semen analysis, and to ensure a more invasive form of ART may not be a better first line therapy. The group of women for who ovulation induction is most widely used is those with anovulation secondary to poly-cystic ovarian syndrome (PCOS.) This is often a group of patients that are of a younger age than the average infertility patient and have a high antral follicle count and in reflection of that, often a high AMH. These women may also benefit from the additional use of metformin during their stimulation to improve outcomes [14]. It is critical that these women are identified as high risk for responding excessively to even small doses of ovulation induction agents and should be started on very low doses of ovulation induction agents and very carefully monitored. Being younger also means the rate of fecundity per ovulation is high and therefore every effort should be made to aim

Options available when development of an excessive number of follicles is observed include cancelling the cycle, aspirating the excess follicles or switching to an egg collection and IVF cycle. None of these options are ideal for a patient hoping to achieve a pregnancy but need to be discussed with the patient before embarking on treatment. Cancellation of the cycle can be devastating to the patient from a financial and emotional cost, however a cancelled cycle due to hyper-stimulation of the ovary gives valuable information to the practitioner for management of the next cycle in regard to dosing and monitoring. Follicular aspiration for either reduction in follicle number, or for transfer to an IVF cycle is difficult if it has not been discussed as an option pre-treatment, and has ethical implications in regard to informed consent for a patient who is now being faced with either cancellation of the cycle or conversion to a more complicated and costly treatment. It is imperative that as part of the consent process for ovulation induction the risk of multiple follicle development is discussed and the options and recommendations when an excessive number of follicles develop are considered. Having an absolute maximum cut off of 2 follicles, and for high risk couples one follicle, will be a huge step forward in reducing the multiple pregnancy rates with ovulation induction. Such an approach has been associated with multiple pregnancy rates below 5% and no higher order multiple pregnancies [22]. This compares with rates up to 30% if no intervention is made until follicular numbers reach more than three [23]. High risk couples, for whom more than one follicle should be the threshold for cancellation include young women undergoing

multiple pregnancy.

for mono-ovulation.

accordingly.

In our unit, after exclusion of other potential infertility factors, we aim to induce mono-ovulation with a low dose step up protocol. We start all women on a low dose of gonadotropin, on average 25 IU FSH, and monitor women with oestrogen levels and ultrasound tracking of developing follicles. Dosing is increased if no response is seen after 10 days, with dose increments of 12.5 IU, until a threshold is reached whereby mono-follicular development occurs and the dose is not increased further. If more than 2 follicles of 10 mm are noted the cycle is cancelled, and in patients under 35 years consideration is given to cancelling with two follicles. Review of our data has showed that our rate of multiple pregnancy using this method for ovulation induction is below 4% [17]. This is with a cumulative live birth rate of close to 50% over 3 cycles and a cycle cancellation rate of around 10%. After 3 cycles the live birth rate per cycle falls significantly as the patients with additional reproductive pathology start to make up a greater percentage of remaining patients. If after 3 cycles a successful pregnancy has not occurred we give consideration to switching to IVF treatment. This allows a low rate of multiple pregnancy and a close to 50% rate of successful pregnancy for our patients without exposing them to the increased risk of IVF unless it is warranted.

The hallmark of reducing rates of multiple pregnancy with ovulation induction is to closely monitor follicular development both with hormone levels and ultrasound tracking to ensure only a single dominant follicle, or a maximum of two, will develop and ultimately ovulate. It would be assumed that with close monitoring a clinician could predict when a patient was at risk of releasing more than one oocyte and could act prudently to avoid conception in such cases. Existing guidelines surrounding risk adverse practice in regard to tracking are sparse and not overly cautious. The American College of Obstetricians and Gynaecologists (ACOG) guideline recommends abandoning an ovulation induction cycle if there are more than 3 follicles measuring more than 15 mm [18]. Studies have shown that follicles as small as 7 mm at time of trigger can result in successful ovulation and impact the multiple pregnancy rate, although it is generally believed that follicles of 14 mm in size or greater will have a mature oocyte [19]. Capping the recommended maximum number of follicles before cancellation of the cycle at more than 3 is doing little to reduce the rate of multiple pregnancy and indeed risks, not just a multiple pregnancy but a higher order multiple pregnancy.

More judicious care can be taken to actively avoid multiple pregnancy by ensuring monoovulation by very closely monitoring oestrogen levels and follicular development on ultrasound. By cancelling cycles when more than 2 follicles of greater than 10 mm are present has been shown to actively reduce multiple pregnancy rates. Oestrogen levels above 600 pg/ mL have been associated with increased rates of multiple pregnancy [20] and higher than 2000 pg/mL with higher order multiple pregnancy. [21] Using both ultrasound follicle tracking and serum oestradiol measurements to carefully track cycles is imperative to minimise multiple pregnancy.

**2.4. Follicular stimulation hormone (FSH)**

50 Multiple Pregnancy - New Challenges

of IVF unless it is warranted.

Injectable agents, usually recombinant FSH, have historically been associated with higher rates of multiple pregnancy. When first described dosing regimes in the realm of 225 IU of FSH were used to induce ovulation in anovulatory women with multiple pregnancy rates of around 25% [15]. As greater experience was gained using FSH and with a clear distinction being made between dosing for the aim of mono-ovulation in ovulation induction, versus ovarian hyper-stimulation for IVF cycles initial dosages fell dramatically. Low dose, step up protocols are now the recommended regime with close monitoring to observe response [16]. Unlike oral agents that are given for a limited number of days in the early follicular phase, FSH can be given for an extended period until follicular development is seen. With this method rates of multiple pregnancy can be as low, or lower, than with oral agents and can be achieved with higher live birth rates. In countries with good health insurance and state funding for fertility treatments out of pocket costs to patients are comparable to oral agents and are

In our unit, after exclusion of other potential infertility factors, we aim to induce mono-ovulation with a low dose step up protocol. We start all women on a low dose of gonadotropin, on average 25 IU FSH, and monitor women with oestrogen levels and ultrasound tracking of developing follicles. Dosing is increased if no response is seen after 10 days, with dose increments of 12.5 IU, until a threshold is reached whereby mono-follicular development occurs and the dose is not increased further. If more than 2 follicles of 10 mm are noted the cycle is cancelled, and in patients under 35 years consideration is given to cancelling with two follicles. Review of our data has showed that our rate of multiple pregnancy using this method for ovulation induction is below 4% [17]. This is with a cumulative live birth rate of close to 50% over 3 cycles and a cycle cancellation rate of around 10%. After 3 cycles the live birth rate per cycle falls significantly as the patients with additional reproductive pathology start to make up a greater percentage of remaining patients. If after 3 cycles a successful pregnancy has not occurred we give consideration to switching to IVF treatment. This allows a low rate of multiple pregnancy and a close to 50% rate of successful pregnancy for our patients without exposing them to the increased risk

The hallmark of reducing rates of multiple pregnancy with ovulation induction is to closely monitor follicular development both with hormone levels and ultrasound tracking to ensure only a single dominant follicle, or a maximum of two, will develop and ultimately ovulate. It would be assumed that with close monitoring a clinician could predict when a patient was at risk of releasing more than one oocyte and could act prudently to avoid conception in such cases. Existing guidelines surrounding risk adverse practice in regard to tracking are sparse and not overly cautious. The American College of Obstetricians and Gynaecologists (ACOG) guideline recommends abandoning an ovulation induction cycle if there are more than 3 follicles measuring more than 15 mm [18]. Studies have shown that follicles as small as 7 mm at time of trigger can result in successful ovulation and impact the multiple pregnancy rate, although it is generally believed that follicles of 14 mm in size or greater will have a mature oocyte [19]. Capping the recommended maximum number of follicles before cancellation of the cycle at more than 3 is doing little to reduce the rate of multiple pregnancy and indeed

risks, not just a multiple pregnancy but a higher order multiple pregnancy.

thus often used as a first line treatment due to their increased success rates.

As a general rule, younger women, women with a greater antral follicle count or higher antimullerian hormone (AMH) levels are more likely to have a greater response to a lower dose of induction agent and thus should be started at a minimum dose on the first cycle and tracked accordingly.

All couples should be worked up prior to embarking on ovulation induction to confirm tubal patency and adequate semen analysis, and to ensure a more invasive form of ART may not be a better first line therapy. The group of women for who ovulation induction is most widely used is those with anovulation secondary to poly-cystic ovarian syndrome (PCOS.) This is often a group of patients that are of a younger age than the average infertility patient and have a high antral follicle count and in reflection of that, often a high AMH. These women may also benefit from the additional use of metformin during their stimulation to improve outcomes [14]. It is critical that these women are identified as high risk for responding excessively to even small doses of ovulation induction agents and should be started on very low doses of ovulation induction agents and very carefully monitored. Being younger also means the rate of fecundity per ovulation is high and therefore every effort should be made to aim for mono-ovulation.

Options available when development of an excessive number of follicles is observed include cancelling the cycle, aspirating the excess follicles or switching to an egg collection and IVF cycle. None of these options are ideal for a patient hoping to achieve a pregnancy but need to be discussed with the patient before embarking on treatment. Cancellation of the cycle can be devastating to the patient from a financial and emotional cost, however a cancelled cycle due to hyper-stimulation of the ovary gives valuable information to the practitioner for management of the next cycle in regard to dosing and monitoring. Follicular aspiration for either reduction in follicle number, or for transfer to an IVF cycle is difficult if it has not been discussed as an option pre-treatment, and has ethical implications in regard to informed consent for a patient who is now being faced with either cancellation of the cycle or conversion to a more complicated and costly treatment. It is imperative that as part of the consent process for ovulation induction the risk of multiple follicle development is discussed and the options and recommendations when an excessive number of follicles develop are considered.

Having an absolute maximum cut off of 2 follicles, and for high risk couples one follicle, will be a huge step forward in reducing the multiple pregnancy rates with ovulation induction. Such an approach has been associated with multiple pregnancy rates below 5% and no higher order multiple pregnancies [22]. This compares with rates up to 30% if no intervention is made until follicular numbers reach more than three [23]. High risk couples, for whom more than one follicle should be the threshold for cancellation include young women undergoing their first few cycles and who have an expected high fecundity per follicle, but also patients for whom multiple pregnancy would be particularly dangerous. This includes women with an independent risk of pre-term birth and women with underlying medical conditions making them more susceptible to the pregnancy complications of multiple pregnancy.

result of an IVF cycle [25]. Like ovulation induction and super ovulation, IVF is associated with increased rates of unintended multiple pregnancy, in comparison to spontaneous conception, plus there is also a greater risk of an embryo splitting and resulting in monozygotic

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While the key to reducing rates of multiple pregnancy with ovulation induction and superovulation and IUI lies with careful monitoring of the cycle and judicious cancellation of cycles when multiple follicles develop, the cornerstone to reducing multiple pregnancy rates in IVF

As IVF technology has developed and successful live birth rates have increased the need to transfer more than one embryo has rapidly declined. There is no significant difference in the live birth rate for women aged under 37 years undergoing a single embryo transfer (sET) compared with a double embryo transfer (dET), only an increase in the multiple pregnancy rate and subsequent increased pregnancy complication rate [26]. For women aged under 37 years the rate of multiple pregnancy with a double embryo transfer is as high as 25% [27], compared

Although implantation rate is not the gold standard by which to measure success of a fertility treatment, when compared with sET, dET has been reported to be associated with lower implantation rates suggesting a deleterious effect on the intrauterine environment when dET is employed [29]. This observation is further supported by the increased rates of poor pregnancy outcome when dET is performed but only one embryo implants. This scenario is associated with increased rates of growth restriction and preterm delivery compared with singleton pregnancies resulting from a single embryo transfer [30]. A review of the American Society for Assisted Reproductive Technology outcomes between 2004 and 2013, of over 180,000 IVF cycles concluded that although the live birth rate may increase with a dET, this is substantially out-weighed by the risk of multiple gestations [31]. They demonstrated that for patients with favourable prognostic factors; including younger maternal age, transfer of a blastocyst, and additional embryos cryopreserved, the gain in the live birth rate from sET to dET was approximately 10–15%, however, the multiple birth rate increased from approximately 2% to

Single embryo transfer is associated with not just a reduction in multiple pregnancy rates, but also a reduction in overall pregnancy complication rates with little effect on the live birth rate compared with double or higher number embryo transfer rates [32]. Double embryo transfer rates are occasionally recommended or supported when a patient has particular barriers to implantation success and thus have a perceived lower rate of risk to multiple pregnancy with dET. These may include advanced maternal age, poor embryo quality or multiple previous

The barrier to implementing universal single embryo transfer appears to lie in the cost of IVF treatment to the patient. In countries or regions where state funded or supported fertility treatment exists, the rates of single embryo transfer are far higher. The factor most influencing the likelihood a patient will undergo a single embryo transfer over a double or greater number embryo transfer is whether or not they have health insurance, a greater influencing

treatment is to ensure single embryo transfer is the norm.

with less than 6% for women undergoing single embryo transfer [28].

almost 50% for both fresh and frozen embryo transfer cycles.

unsuccessful attempts at single embryo transfer.

twinning.
