Abstract

1. INTRODUCTION

Intrauterine insemination (IUI) is one of the most popular infertility treatments worldwide. ^{1 , 2} In many centers, it is the primary treatment modality in cases of unexplained infertility and mild‐to‐moderate female and male factor infertility, with typical per‐cycle pregnancy rates (PRs) ranging from 10% to 20%. ³ It has the advantage of being a simple, non‐invasive technique and is relatively cheap. ¹

In the ESHRE register published in 2020, almost 190 000 IUI with husband's semen (IUIH) and almost 50 000 IUI with donor's semen (IUID) cycles were performed in Europe. The rates of twins and triplets were 8.9% and 0.5% in IUIH and 7.3% and 0.6% in IUID. ⁴ One of the major challenges in current assisted reproductive techniques (ART) is preventing multiple pregnancies. ^{5 , 6 , 7 , 8}  Nowadays, this can be achieved relatively easily in IVF, since ovarian response, ⁹ one of the most important favorable prognostic factors, can be completely isolated from multiple pregnancy risk as a result of single embryo transfer policies and frozen embryo programs. ¹⁰ In contrast, in IUI, ovarian response is directly related to both PR overall ¹¹ and multiple PR, including high‐order multiple pregnancies. ^{11 , 12 , 13}

In a meta‐analysis, the PR in IUI cycles with monofollicular growth was 8.4% compared with 13.4%, 16.4%, and 16.4% in cycles with two, three, and four follicles. ¹¹  The risk of multiple pregnancy in cycles with monofollicular growth was 3.7% compared with 6%, 14%, and 10% in cycles with two, three, and four follicles. ¹¹

One strategy to regulate the number of follicles is to use lower doses of gonadotropins. ^{14 , 15} Despite this measure, however, multiple follicular response can still happen occasionally. ¹⁶  The standard course of action in IUI cycles with hyperresponse is cycle cancellation. Other options are converting the cycle into IVF ^{17 , 18} or even continuing the cycle, and, in cases of multiple pregnancy, performing embryo/fetal reduction, ¹⁹ with notable ethical and psychological implications.

One possible alternative is excess follicle aspiration before insemination (EFABI). This consists of ultrasound‐guided vaginal puncture of the excess follicles before insemination. A similar approach has been used in women undergoing ovarian stimulation, ^{20 , 21 , 22} especially those with polycystic ovarian syndrome (PCOS), mainly to prevent multiple pregnancy and ovarian hyperstimulation syndrome (OHSS).

Four previous reports of EFABI exist in the literature, published between 12 and 26 years ago. ^{23 , 24 , 25 , 26} In them, the timing of the EFABI procedure was markedly heterogeneous, ^{23 , 24 , 25 , 26} and two of them included both IUI and timed‐intercourse cycles. ^{23 , 24 , 25 , 26}

The aim of our study was to analyze the impact of EFABI on PR, multiple PR, and cancellation rates, when performed systematically on the day of hCG administration, in IUI high responders, in a setting in which cycles of extremely high responders were converted to IVF.

2. MATERIALS AND METHODS

The study population consisted of all the women who underwent EFABI in the reproduction unit of our university hospital, between July 1, 2016, and December 31, 2019. The results of the EFABI population were compared with those of patients in the same period not undergoing EFABI. A second analysis was performed, comparing all IUI results (with and without EFABI) from the period when EFABI was available (July 1, 2016–December 31, 2019) with the 3.5 previous years in which EFABI was not used (January 1, 2013–June 30, 2016).

Institutional board approval was obtained (code CEIC EI8/12), and written informed consent forms were given to all women and, in case of couples, their partners also.

The inclusion criteria for our IUI program were as follows: (1) for IUIH, age <38 years, at least one normal patent tube as assessed by hysterosalpingography (HSG) or laparoscopy, anti‐Müllerian hormone (AMH) >0.1 ng/ml, sperm with >5 million motile sperm recovered and (2) for IUID, age <40 years and at least one normal patent tube regardless of AMH level. Exclusion criteria for our IUI program were as follows: body mass index (BMI) >35 kg/m²; endometriosis III‐IV; myoma type 1–3; and uterine malformation.

The main indications for IUIH were as follows: idiopathic infertility (46%); PCOS (19%); mild‐to‐moderate male factor (14%); low ovarian reserve (12%); unilateral tubal factor (7%); and endometriosis I‐II (2%). The main indications for IUID were azoospermia/cryptozoospermia (23%) and women without a male partner (77%).

Our IUI work‐up has been described previously. ^{3 , 27 , 28}  The female work‐up included at least pelvic examination, blood chemistry, measurement of hormone levels (including AMH levels), HSG, and pelvic ultrasound (US). A laparoscopic study was performed when HSG findings suggested any abnormality (however minor). Women with at least one normal patent tube were considered eligible for IUI. Couples with male factor infertility were considered to be potentially eligible for IUI when, despite some seminogram parameters being subnormal according to World Health Organization standards, ²⁹ it was possible to obtain 5 × 10⁶ motile sperm/ml after semen preparation.

Ovarian stimulation was performed with hMG (Menopur) or recombinant FSH (Gonal; Merck, Spain or Bemfola). Monitoring of ovarian stimulation was performed with plasma estradiol, progesterone, and ultrasound.

The starting dose of gonadotropins was based on AMH, antral follicle count (AFC), the woman's age, BMI, and cause of infertility. The following median starting doses (IU/day) were administered in IUIH patients: 150 [150–206] (interquartile range) when AMH ≤ 0.4 ng/ml; 150 [102–150] when AMH = 0.5–0.8 ng/ml; 110 [81.2; 150] when AMH = 0.9–1.2 ng/ml; 75.0 [75.0; 110] when AMH = 1.3–2.4 ng/ml; and 75.0 [50.0; 75.0] when AMH ≥ 2.5 ng/ml. Starting doses in IUID were somewhat lower: 150 [150; 150], 100 [93.8; 150], 75.0 [75.0; 150], 75.0 [75.0; 100], and 50.0 [37.5; 75.0].

Semen samples for IUI were prepared with density gradients (Origio^® Gradient 100, Universal IVF Medium with Phenol Red). A single insemination with 0.3–0.5 ml was performed per cycle 38 h after the administration of 250 mcg of rec‐hCG (Ovitrelle, Merck Laboratories). A total of five cycles of IUI were performed if pregnancy was not obtained earlier. The luteal phase was supplemented with vaginal micronized progesterone (200 mg/12 h for the 14 days following insemination).

2.1. Management of hyperresponder patients

Women with ≥7 follicles ≥14 mm were advised to switch to IVF, and if they declined, the cycle was canceled. Women who had between 4 and 6 follicles between 14 and 18 mm on the day of hCG administration or the day before were advised to undergo EFABI, and if they declined, the cycle was canceled. The exclusion criteria for EFABI were plasma estradiol levels >1500 pg/ml, progesterone levels >1.6 ng/ml, having undergone EFABI previously, and gonadotropins administered at a dose of >150 UI/day (Figure 1).

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FIGURE 1

Flow chart. Flow chart of the distribution of patients who have come for IUI between 2016 and 2019, grouped according to the number of follicles and the clinical decision taken

3. RESULTS

4. DISCUSSION

IUI is a low‐complexity, low‐cost technique, which has well‐known efficacy in certain conditions such as idiopathic infertility, PCOS, failing to conceive with ovulation induction and timed‐intercourse, mild‐moderate male factor, and donor insemination. ^{31 , 32 , 33 , 34} However, in recent years, although the number of IUI cycles has risen in absolute terms, the increase in IVF cycles has been more pronounced, ^{4 , 14} and the main factor responsible for this relative decrease in IUI is the risk of multiple pregnancy. ³⁵ In IVF, rates of multiple pregnancies, especially high‐order pregnancies, have markedly decreased due to the almost complete disappearance of transfers of three or more embryos and the increasing adoption of single embryo transfer policies. The adoption of these restrictive practices in terms of the number of embryos transferred has had little influence on per‐cycle PRs, due to improvements in methods of embryo selection, incubation, culture, and freezing, among others. ^{4 , 14 , 36}

In contrast, to date, there are only two widespread strategies to prevent multiple pregnancy in IUI. The first is the use of milder stimulation; however, with milder stimulation, PRs are significantly lower ^{15 , 37 , 38} and monofollicular cycles are associated with a pregnancy rate of 8.4% ³⁹ compared with 15% in multi‐follicular cycles. ¹¹ Furthermore, even with smaller doses, the hyperresponse risk cannot be avoided completely. In an Italian retrospective study, despite initial doses of 50 IU, the multiple PR was still 9.5% and 5% of cycles were cancelled due to hyperresponse. ¹⁶

The second prevention strategy is the cancellation of the IUI cycle. This cancellation may be complete, that is to say, the IUI cycle is cancelled, and no other reproductive treatment is used. Cancellation rates due to hyperresponse in IUI with gonadotropins are not always reported, but they seem to range from 5% to 12.7%, varying with population, starting dose, and cancellation criteria. ^{16 , 40 , 41} Logically, this leads to considerable frustration among couples and also requires patients not to have sexual relations or to use barrier contraceptive methods to avoid a multiple pregnancy through natural intercourse. Additionally, there may be some risk of OHSS. Moreover, the money invested in the cycle and the medication has been spent with no chance of success.

A further form of cancellation is conversion of the IUI cycle into an IVF cycle, which has been reported to have good results. ^{7 , 17 , 18 , 37}  Nonetheless, this strategy poses some problems. On the one hand, there is the unanticipated additional cost to the infertile couple, and the requirement for an ongoing IVF program, which limits the use of this approach to IVF centers. ⁷ Additionally, there is an issue in cases that reach a number of follicles considered too high for an IUI cycle, but still relatively few for an IVF cycle. For example, 4–6 follicles of 14–16 mm will often yield markedly fewer mature oocytes than what is deemed desirable for a standard IVF cycle, taking into account that the ideal response in IVF is between 10 and 15 oocytes, and that fewer than 4 is considered insufficient. ^{42 , 43}  Therefore, such converted cycles would presumably have significantly lower PRs than if these patients had undergone IVF from the outset, using higher stimulation doses, and thus greater follicular responses, larger numbers of embryos, and the possibility of cryotransfers later on.

Selective follicular aspiration has been applied in ovarian stimulation cycles followed by intercourse, especially in PCOS patients, to prevent multiple pregnancy and OHSS. ^{20 , 21 , 22} Previous reports on EFABI differ in methodology from the one we used: None of them considered the option of IVF conversion for extremely high responders; in two cases, EFABI was performed in nearly 50% of all women undergoing IUI ^{23 , 24} vs nearly 5% in our series, and EFABI was performed 36 h after hCG administration ²⁵ or on the day of the first IUI, ^{23 , 24} while the only study in which aspiration was performed on the day of hCG administration included only 26 cases (followed by IUI or intercourse). ²⁶  There were also differences regarding the number of follicles left, as well as the performance of flushing.

Our protocol restricted the use of EFABI to women with 4–6 follicles ≥14 mm, thereby offering IVF if they had >7 follicles. Moreover, we performed EFABI on the day of hCG administration in order to avoid prior ovulation of any of the oocytes, posing a risk of multiple pregnancy. Furthermore, we did not flush the follicles, and we did not recover oocytes (except in one case with premature progesterone rise). Therefore, the decrease in multiple PR should be due to the inability of follicles to ovulate after aspiration of the follicular fluid, and not to the aspiration of oocytes. Moreover, the aim of our protocol was to convert cycles with ≥4 mature follicles to bi‐trifollicular cycles, while cycles with 3 follicles remained unpunctured.

With the use of EFABI and the strategy outlined in the flow chart, we managed to overcome several of the aforementioned problems. Firstly, we were able to prevent cancellation of cycles, which would otherwise have amounted to 9.7% of all the IUI cycles, with the psychological and economic implications this poses. This allows the use of stimulation protocols aimed at the development of 1–3 follicles, which was achieved in 90.3% of cases in our population. Among the other cases, only 3.7% were converted into an IVF cycle, resulting in ovarian responses that were not far from optimal, although EFABI was performed in 5.2% of the cycles, compared with nearly 50% in other reports. ^{23 , 24}

Regarding EFABI outcomes, it should be noted that after EFABI (practiced in patients at high risk of multiple pregnancy because they had 4 to 6 follicles), the rates of twin birth were the same as in non‐EFABI patients (17.8% vs 17.5%). Concerning triplets, although there were no triple pregnancies after EFABI, the sample size was too small for differences to reach statistical significance. Indeed, EFABI transformed cycles with high risk of multiple pregnancy into standard risk IUI cycles. In addition, LBRs were significantly higher in EFABI cycles considering all IUI (25.5% vs 15.2%) and IUID (32.5% vs 18.5%), while in IUIH, although higher, the difference did not reach significance (19.5% vs 12.9%). This means that in patients with hyperresponse in IUI, which would typically require the cancellation of the cycle, not only was the cycle not cancelled, but also the LBR achieved was higher than in the usual cycles. Presumably, this could be explained because after EFABI, there were still 3–2 follicles in IUIH and 2 in IUID, while the number of follicles in standard IUI ranged between 1 and 3. It could also be due to the fact that higher IUI responders have better oocyte quality, which is unaffected by EFABI.

We found an overall multiple PR in IUI of 17.8%, which, despite still being high, is considerably lower than the rate of 31.8% in IUI with gonadotropins described in the most recent meta‐analysis. ³⁸ Furthermore, the triplet pregnancy rate was 1% of pregnancies, representing just 0.2% of all cycles.

When comparing our results since the implementation of EFABI to the historical results prior to the use of EFABI, the following aspects should be considered. First of all, this is not a randomized study, and hence, there are many possible confounding factors, including diagnostic, selection, and cancellation criteria. Nonetheless, we would like to point out that despite the current use of lower doses for initial stimulation, the LBRs were similar in both groups, while current data indicate a significantly higher rate of single births, fewer cancellations due to hyperresponse, and a lower rate of triple pregnancies.

EFABI is a low‐cost, simple, fast, and well‐tolerated technique. Although more studies are needed, EFABI seems to be a good option for minimizing cancellation rates in IUI cycles with hyperresponse in which 4 to 6 mature follicles are produced, converting them into standard IUI cycles in terms of risk of multiple pregnancy, but with higher PRs than standard IUI cycles.

CONFLICT OF INTEREST

B Prieto, M Diaz‐Núñez, L Lainz, A Rabanal, M Iglesias, T Jauregui, B Corcostegui, A Matorras, S Pérez, and R Matorras declare that they have no conflict of interest.

ETHICS STATEMENT

Human rights statements and informed consent: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Institutional board approval was obtained (code CEIC EI8/12), and written informed consent was given to women and, in case of couples, also to their partners.

Notes

Prieto B, Diaz‐Nuñez M, Lainz L, et al. Aspiration of excess follicles before intrauterine insemination in high response cycles. Reprod Med Biol. 2022;21:e12470. 10.1002/rmb2.12470 [CrossRef] [Google Scholar]

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