Complications of Ovarian Stimulation: Multiple Pregnancies

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Complications of Ovarian Stimulation: Multiple Pregnancies

Diane De Neubourg

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) included 14 studies reporting on 11,599 cycles; only two studies were randomized controlled trials in contrast to 12 observational studies. The absolute pregnancy rate was 8.4% for monofollicular and 15% for multifollicular growth. The pooled odds ratio (OR) for pregnancy after two follicles as compared to one follicle was 1.6 (99% confidence interval [CI] 1.3–2.0) whereas for three and four follicles the pooled OR was 2.0 (99% CI 1.6–2.5) and 2.0 (95% CI 1.5–2.7), respectively. Compared with monofollicular growth, pregnancy rates increased by 5%, 8%, and 8% when stimulating two, three, and four follicles, respectively. The pooled OR for multiple pregnancies after two follicles was 1.7 (99% CI 0.8–3.6) and increased to 2.8 and 2.3 for three and four follicles, respectively. The risk of multiple pregnancies after two, three, and four follicles increased by 6%, 14%, and 10%. The absolute rate of multiple pregnancies was 0.3% after monofollicular and 2.8% after multifollicular growth. It was concluded that multifollicular growth is associated with increased pregnancy rates in IUI with COS (9) and that one should not aim for more than two follicles because in cycles with three or four follicles the multiple pregnancy rate increased without substantial gain in overall pregnancy rate.

Recently, identification of risk factors for multiple pregnancies has been done on the basis of 3375 gonadotropin-stimulated cycles in 1438 patients (10). Regression analysis revealed that the presence of at least two follicles ≥13 mm at ovulation trigger significantly increased clinical pregnancy rates (OR, 95% CI = 1.45, 1.18–1.78) and multiple pregnancy rates (MPR) (OR, 95% CI = 5.17, 2.16–12.41) and that an estradiol level >400 pg/ml significantly increased MPR (OR, 95% CI = 9.54, 2.31–39.42). A significant decrease in pregnancy rate was observed as age increases beyond 40 years (OR, 95% CI = 0.58, 0.44–0.76), but an association with multiple pregnancy rates could not be observed (10). On the basis of these and other patient-specific and cycle-specific variables, an applet has been developed to calculate the patient’s chance to achieve a pregnancy and risk to develop a multiple pregnancy. However, one should bear in mind that risk estimates are insufficient in a patient population with an absolute contraindication for multiple pregnancies. In the general infertility population, two follicles and the risk of twin pregnancy may be acceptable after careful patient counseling.

Analysis of the Risks of Different Stimulation Protocols for Multiple Pregnancies

In a narrative review, McClamrock et al. (2) compared reproductive outcome after COS with clomiphene citrate, low-dose gonadotropins (≤75 IU), and high-dose gonadotropins (≥150 IU) in combination with IUI. They retrieved data from randomized controlled trials on the different stimulation protocols and analyzed them accordingly but without formal meta-analysis (Table 25.3). The authors (2) concluded first that an increasingly compelling case could be made in support of low-dose (≤75 IU) gonadotropin regimens for which per-cycle pregnancy rates of 8.7%–16.3% and absent high-order gestation have been noted in prospective randomized trials although a more mixed record was noted for the twin gestation category. A second conclusion (2) was that a strong case could also be made for clomiphene for which per-cycle pregnancy rates of 2.0%–19.3% have been noted in prospective randomized trials with virtual absence of high-order gestation and twin gestation rates ranging between 0% and 12.5%. However, these conclusions should be interpreted cautiously because they are based on a nonsystematic narrative review of the literature (2) without accounting for many forms of bias.

In a more thorough systematic Cochrane review (11) on the influence of the type of ovarian stimulation combined with IUI it was concluded that COS using gonadotropins increases pregnancy rates compared with the use of anti-estrogens (OR = 1.8, 95% CI 1.2–1.7). For studies that could be included in the comparison (11), there appeared to be no difference in the multiple pregnancy rates after COS with gonadotropins or anti-estrogens when calculated per patient (OR = 0.53; 95% CI 0.15–1.86) or per pregnancy (OR = 0.96; 95% CI 0.28–3.28). Doubling the starting dose of gonadotrophins did not increase pregnancy rates significantly (OR = 1.2; 95% CI 0.67–1.9) or affect multiple pregnancy rates (OR = 3.11; 95% CI 0.48–20.13). Based on this systematic review, COS with gonadotropins is superior to COS with anti-estrogens in an IUI program without concomitant increased risk in multiple pregnancy rate. Nevertheless, it should be kept in mind that the risk for multiple pregnancy is more dependent on the number of stimulated follicles than on the type of product used for COS (gonadotropins or clomiphene citrate) as reviewed above in the section “Identification of risk factors.”

TABLE 25.3

Pregnancy and Multiple Pregnancy Rates with Clomiphene Citrate and Gonadotrophins Combined with IUI, according to Narrative Review (2)

Secondary Preventive Measures

Cancellation of the Cycle

When multifollicular development occurs during OI or COS a risk for (high-order) multiple pregnancies exists. As mentioned previously, on the basis of risk analysis by van Rumste et al. (9), one should aim for a maximum of two follicles in order to avoid high-order multiple pregnancies. Apart from common sense, there are no studies available in which risks of the number of follicles and their size are weighed and evaluated. There is a lack of evidence-based guidelines.

Aspiration of Supernumerary Follicles

Instead of cancellation of the cycle, supernumerary follicles can be aspirated vaginally under ultrasound guidance. In the studies reported, follicular aspiration was performed on the day of hCG administration when four or more follicles ≥14 mm were present. Three studies reported pregnancy rates and multiple pregnancy rates of 25%–27% and 0%–10%, respectively (2). However, patients should be counseled about this “invasive” option before they start with an OI or COS program.

Escape IVF

When many follicles have to be aspirated, it is important to discuss the possibility of a full oocyte aspiration performed as part of an ART treatment. This rescue procedure can certainly increase the chance of achieving a pregnancy with minimal risks for multiple pregnancies provided single embryo transfer is performed. However, the costs associated with ART are much higher than those associated with OI or COS. Furthermore, success of ART treatment can be compromised if oocytes ovulate prematurely, a common problem as most patients are not treated with a GnRH analogue or antagonist in the context of OI or COS. In principle, a GnRH antagonist can be added, but this is not always possible because follicle size usually exceeds 14 mm at the time of the decision to switch from OI or COS to IVF.

Selective Reduction of a Multi-Fetal Pregnancy

High-order multiple pregnancies will be at increased risk for adverse maternal and perinatal outcome. The balance between reducing the number of fetuses in an attempt to decrease maternal and perinatal risks versus continuation of the pregnancy has to be made individually based on patient counseling provided by ultrasound interventionalists, subspecialists in fetal-maternal medicine, neonatologists, and psychologists.

Conclusions

Ovulation induction aims at monofollicular growth. As pregnancy is more likely to occur with two follicles than with one, the risk for multiple pregnancies increases with 6% when two follicles are present instead of one. The risk for multiple pregnancies is independent of the drugs used, but it is recommended to use low-dose gonadotrophins with gonadotrophin stimulation. In case more than two follicles develop, secondary preventive measures should be considered.

TABLE 25.1

Level of Evidence of Statements

TABLE 25.2

Grade of Strength for Recommendations

REFERENCES

1. Kupka MS, Ferraretti AP, de Mouzon J, Erb K, D’Hooghe T, Castilla JA, Calhaz-Jorge C et al. Assisted reproductive technology in Europe, 2010: Results generated from European registers by ESHRE. Hum Reprod. 2014; 29:2099–113.

2. McClamrock HD, Jones HW Jr, Adashi EY. Ovarian stimulation and intrauterine insemination at the quarter centennial: Implications for the multiple births epidemic. Fertil Steril. 2012; 4:802–9.

3. van Santbrink EJ, Eijkemans MJ, Laven JS, Fauser BC. Patient-tailored conventional ovulation induction algorithms in anovulatory infertility. Trends Endocrinol Metab. 2005; 16:381–9.

4. Galazis N, Zertalis M, Haoula Z, Atiomo W. Is ultrasound monitoring of the ovaries during ovulation induction by clomiphene citrate essential? A systematic review. J Obstet Gynaecol. 2011; 31:566–71.

5. National Institute for Health and Clinical excellence. Assessment and treatment for people with fertility problems. NICE clinical guideline 156, February 2013.

6. Wang JX, Kwan M, Davies MJ, Kirby C, Judd S, Norman RJ. Risk of multiple pregnancy when infertility is treated with ovulation induction by gonadotropins. Fertil Steril. 2003; 80:664–5.

7. Misso ML, Wong JL, Teede HJ, Hart R, Rombauts L, Melder AM et al. Aromatase inhibitors for PCOS: A systematic review and meta-analysis. Hum Reprod Update. 2012; 18:301–12.

8. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014; 371:119–29.

9. van Rumste MM, Custers IM, van der Veen F, van Wely M, Evers JL, Mol BW. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: A meta-analysis. Hum Reprod Update 2008; 6:563–70.

10. Goldman RH, Batsis M, Petrozza JC, Souter I. Patient-specific predictions of outcome after gonadotropin ovulation induction/intrauterine insemination. Fertil Steril. 2014; 101:1649–55.

11. Cantineau AE, Cohlen BJ. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without agonists/antagonists) for intrauterine insemenation (IUI) in women with subfertility. Cochrane Database Syst Rev 2007; 2:CD005356.

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