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Complications of Ovarian Stimulation: Multiple Pregnancies
Introduction
Ovarian stimulation (OS) is a common part of fertility treatments all over the world, and drugs, such as clomiphene citrate and gonadotropins, are widely used. These drugs all have their particular pharmacological mode of action, their proper indication, their cost, and pregnancy and live birth rates. However, multiple pregnancies are a well-known complication of ovarian stimulation, and the awareness has increased that these should be accounted for as complications of the therapy rather than as unpreventable side effects, particularly when high-order multiple pregnancies are considered.
A clear distinction should be made between controlled ovarian stimulation (COS) and ovarian stimulation in cases of ovulation disorders in which monofollicular growth is aimed for and which is called ovulation induction (OI). However, although monofollicular growth is the aim, the previous chapters have shown that this is not always easy to achieve in some groups of patients, such as patients with polycystic ovary syndrome (PCOS).
Controlled ovarian stimulation may be used in cases of unexplained infertility, minimal to mild endo-metriosis, or male subfertility often in combination with intrauterine insemination (IUI) in which an increasing amount of follicles should increase the chance of achieving a pregnancy. With COS, normo-ovulatory women are usually involved, and thus even a mild dose of ovarian stimulation may lead to multifollicular growth. In this group of patients, the increase in pregnancy rates should be balanced against the increase in risk of multiple pregnancies.
There are no data on outcomes from COS cycles without IUI in the literature, so reports from IUI cycles—although not entirely comparable—could give an estimate of both risk factors and the incidence of multiple pregnancies. The European IVF Monitoring (1) reported 9.3% twin deliveries and 0.5% triplets in 2009 in women <40 years treated with IUI using their husband’s sperm. In 2005, COS with IUI and COS alone contributed as much as 22.8% to the national multiple birth cohort in the United States (2).
Studies on the factors that influence pregnancy rates are mostly reviews of retrospective studies and are descriptive in nature. Analysis of an important number of cycles may help to define risk factors for multiple pregnancies. However, interventions, such as cancellation of the cycle, aspiration of supernumerary follicles, escape IVF in case of unacceptable number of follicles, or selective reduction of a multifetal pregnancy, cannot be studied appropriately in retrospective cohorts.
In women treated by ovarian stimulation for OI or COS, both the pregnancy rates and also the risk of achieving a (high-order) multiple pregnancy should be considered. Therefore, appropriate ovarian stimulation should be a balance between these two outcome variables with a focus on completely preventing higher order multiple pregnancies and reducing the twin pregnancy rate to the lowest level possible.
Ovulation Induction
As previously mentioned, ovulation induction is the pharmacological treatment with clomiphene citrate, aromatase inhibitors, or gonadotropins and others (see previous chapters) to induce ovulation in a patient suffering from oligomenorrhea or anovulation.
For clomiphene citrate (CC), it is advised to start with the lowest dose of 50 mg daily for 5 days and to increase with 50 mg/day in the subsequent cycle if ovulation did not occur. This was analyzed in 259 normogonadotropic anovulatory patients for whom the cumulative live birth rate over 12 cycles was 41% with a multiple birth rate of 2% (3).
Although the use of CC is common and the availability of ultrasound monitoring is present in large parts of the world, there still is no evidence regarding the value of ultrasound (US) monitoring during CC treatment to reduce multiple pregnancy rates. A systematic review of all studies investigating the effects of US in the treatment of ovulatory dysfunction with CC showed insufficient evidence to suggest that ultrasound monitoring reduces multiple pregnancy rates or improves pregnancy rates (4). On the other hand, no indication that treatment with CC is safe without ultrasound monitoring was identified. The small number of relevant studies and the heterogeneity observed in the methodologies of each study prohibit reliable conclusions to be drawn. The NICE guideline of 2013 (5) advises that, for women who are taking CC, ultrasound monitoring should be offered during at least the first cycle to ensure that patients are taking a dose that minimizes the risk for multiple pregnancies. To summarize, no reliable conclusions can be drawn regarding the value of ultrasound monitoring in OI cycles to prevent multiple pregnancies because of the small number of relevant studies and the heterogeneity in the methodology of each study (LOE C).
In case of CC resistance or CC failure, gonadotropins can be used for OI. A retrospective cohort study of 748 patients in 2179 initiated cycles used a low-dose step-up protocol for OI. When three or more follicles of ≥16 mm were detected on ultrasound, the cycle was cancelled, and it was advised not to have unprotected intercourse. This strategy led to a cancellation rate of 22% of all cycles and to a pregnancy rate of 20% in the completed cycles. The multiple pregnancy rate was 11% (6).
For PCOS patients, aromatase inhibitors, such as letrozole, have been compared to CC for ovulation induction. A meta-analysis demonstrated that letrozole improved ovulation rates per patient but did not show differences in live birth nor multiple pregnancy rates (7) (LOE 1). A recent multicenter randomized trial comparing letrozole to clomiphene in PCOS patients did show a significant higher cumulative ovulation rate and more cumulative live births but did not find any differences in twin pregnancy. There were more major congenital anomalies with letrozole although this did not reach significance (8). However, this issue needs further follow up in larger series.
Controlled Ovarian Stimulation with or without IUI
Although COS with or without IUI is a different treatment option compared with OI, and also different patient populations are subjected to these treatments, lessons might be learned from COS to prevent multiple pregnancies in OI. Therefore, a short summary of evidence is provided here.
Identification of Risk Factors
A meta-analysis on the influence of the number of follicles on (multiple) pregnancy rates after COS in IUI programs performed by van Rumste et al. in 2008 (9
