Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

21. Multiple Pregnancies

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

The problem of multiple pregnancies hangs like a millstone around the neck of ovulation induction and ovarian stimulation for IUI and for IVF/embryo transfer. Multiple pregnancies carry an increased risk of premature delivery (×5), perinatal morbidity and mortality and psychological (and financial) implications for the parents. In ovulation induction the predisposing factor is multiple follicular development as it is for gonadotrophin stimulation before IUI whereas in IVF/embryo transfer, it is purely a reflection of the number of embryos transferred. The use of low-dose gonadotrophin protocols minimizes the risk of multiple pregnancies in ovulation induction and stimulation for IUI whereas in IVF/embryo transfer, the high multiple pregnancy rate can be considerably reduced by employing a selective single embryo transfer (eSET) policy without seriously affecting pregnancy rates in suitable candidates especially when frozen/thawed embryos are utilized in subsequent cycles.

Elective single embryo transfer will hopefully be more widely adopted as methods for embryo selection improve as it is the obvious solution for the reduction of the present unacceptable multiple pregnancy rates.

Keywords

Multiple PregnanciesOvulation inductionOvarian stimulationIUIIVFICSIEmbryo transferPerinatal morbidityMortalityGonadotrophinIatrogenicAssisted reproductive technologiesMultiple embryo transfersSelective single embryo transfereSETMature follicleshCGClomipheneDominant follicleOHSSAnovulatory patientsPCOSIntra-uterine inseminationMale infertilityControlled ovarian stimulationMild stimulationMonofollicular ovulationFreezingEmbryosFrozen-thawed SETFoetal reduction

The problem of multiple pregnancies hangs like a millstone around the neck of ovulation induction and ovarian stimulation for IUI and for IVF/embryo transfer. While a multiple pregnancy may be regarded by some patients as a blessing or a way of completing their family “in one go”, if they knew of the increased risk of premature delivery (×5), perinatal morbidity and mortality and the psychological (and financial) implications for the parents, their joy may be quelled.

The annoying point regarding the high multiple pregnancy rates in all forms of gonadotrophin driven ovarian stimulation is that it is very largely iatrogenic and preventable. The driving ambition of both doctor and patient to achieve a pregnancy (and this is pressure emanating from either or both sides) often encourages caution to be thrown to the winds with an “all or nothing” mentality. In ovulation induction the predisposing factor is multiple follicular development as it is for gonadotrophin stimulation before IUI whereas in IVF/embryo transfer, it is purely a reflection of the number of embryos transferred. In all of these treatment modes, particularly in IVF/embryo transfer, the high multiple pregnancy rate can be reduced by taking the correct measures which, on the whole, will not significantly reduce the overall pregnancy rate.

21.1 Incidence of Multiple Pregnancies

The incidence of spontaneous multiple pregnancies is about 1 in 80. Predisposing factors are familial and a later reproductive age. These factors are hardly preventable.

With the inception of gonadotrophin induction of ovulation and then various assisted reproductive technologies, twinning and, more disturbingly, high order multiple pregnancy rates grew remarkably. It is only in the last few years that it has been realized that inducing multiple pregnancy cannot necessarily be regarded as a “success”.

Regarding ovulation induction with gonadotrophins, a collection of data from 14 large published series which was reported in 1990 [1] revealed a mean multiple pregnancy rate of 34 %. All women in these series had undergone gonadotrophin induction of ovulation, using a conventional protocol, due to either WHO Group I or Group II anovulation. This multiple pregnancy rate has been drastically reduced to below 6 % by the introduction of the low-dose protocol for gonadotrophin induction of ovulation (See Chap. 9).

Results for IUI preceded by gonadotrophin stimulation of the ovaries are a cause for concern. Whether the indication is unexplained infertility or a mild sperm deficiency, multiple pregnancy rates for IUI with gonadotrophin stimulation in 2001 ranged from 18.1 to 29 % [23]. In one of these studies it was specifically noted that multiple pregnancy was a frequent result when more than four mature follicles were induced. This fact gives the clue to their prevention. Taking heed of this in Europe, in 2009 the twin and triplet rates from IUI were 10.4 and 0.6 % respectively [4].

Data collections for IVF/ICSI for all indications in Europe demonstrate an impressive reduction in multiple birth rates due to a decrease in the number of multiple embryo transfers and the adoption of a selective single embryo transfer (eSET) policy in a number of countries. In 1999 the multiple birth rate in Europe from IVF procedures was 26.3 %, made up of 24 % twins, 2.2 % triplets and 0.1 % higher order [5]. Ten years later, the multiple birth rate was 20.2 %, made up of 19.4 % twins and 0.8 % triplets [4]. The U.S.A. still lags way behind Europe. In 2010, in the USA, 46.4 % of ART infants were multiples made up of 43.4 % twins and 3.0 % triplets and higher order [6].

21.2 Preventative Methods

21.2.1 In Ovulation Induction

The prevalence of multiple pregnancy during ovulation induction is almost entirely dependent on the number of large, mature follicles that develop as a result of ovarian stimulation. The problem is that, the larger the number of follicles over 15 mm on the day of hCG, usually the higher the pregnancy rate (Table 21.1) and this tempts many practitioners to ‘go for it’ and hope for the best. However, from the table, it can be seen clearly that the prevalence of multiple pregnancy increases from 5.1 % with 1 large follicle, 11.7 % with 2, 20 % with 3 and so on. The first course of action, apparent from this data, is that if hCG is withheld when 3 or more large follicles develop or intercourse postponed, the multiple pregnancy rate during any form of ovulation induction, be it with clomiphene or gonadotrophins, can be severely reduced.

Table 21.1

Multiple birth rate related to the number of follicles >15 mm on hCG day

No. of follicles on dhCG

No. of cycles

Clinical pregnancies

Births

Multiple birth rate (%)

No.

Rate/cycle (%)

No.

Twins

1

277

47

17.1

39

2

5.1

2

77

20

26.0

17

2

11.7

3

32

11

34.4

10

2

20.0

>3

19

5

26.3

4

2

50.0

Ares-Serono (1995), with permission

The second course of action would be to encourage the growth of one dominant follicle only. This can be largely achieved today by using a chronic low dose protocol in preference to the conventional protocol widely used up to some years ago. This regimen, the rationale behind it and the results achieved have been described in detail in Chap. 9 so will only be dealt with very briefly here. Conventional ‘step-up’ treatment involving relatively high starting doses and frequent incremental dose rises with gonadotrophins characteristically induces multiple follicular development by overstepping the FSH threshold and results in a high frequency of multiple pregnancies and OHSS. Chronic low-dose gonadotrophin therapy demands the attainment and maintenance of follicular development with exogenous FSH without exceeding the threshold requirement of the ovary. The principle of the classic chronic low dose regimen, shown in Fig. 9.​1, is to employ a low starting dose for 14 days and then use small incremental dose rises (25–37.5 IU) when necessary, at intervals of not less than 7 days, until follicular development is initiated [7]. The dose that initiates follicular development is continued until the criteria for giving hCG are attained. A single dominant follicle, rather than the development of many large follicles, can be achieved in at least 70 % of cycles so completely avoiding OHSS and keeping the multiple pregnancy rate below 6 % while maintaining a good pregnancy rate [8]. The majority of patients on a low dose protocol develop a single large follicle meeting hCG administration criteria within 14–16 days without any change in the initial dose for 14 days.

There is now sufficient evidence to demonstrate that low dose, step-up gonadotrophin therapy should be the only treatment of choice for anovulatory patients and particularly for those with PCOS. Small starting doses in the first cycle for a 14-day initial period without a dose change and then a small incremental dose rise if required, are the secrets for success as they produce the best results.

21.2.2 In Ovarian Stimulation Preceding Intra-uterine Insemination (IUI) (See Also Chap.​ 15)

The overly high multiple pregnancy rate presently being obtained in ovarian stimulation protocols for IUI, whether for idiopathic infertility or for a minimal sperm deficiency, can be overcome in two possible ways:

1.

2.

Multiple pregnancy rates for IUI in a natural cycle with no stimulation are obviously at an absolute minimum level. However, the majority of large studies and meta-analyses [910], have shown the superiority of ovulation stimulation in terms of pregnancy rates but this has been at the expense of very much increased multiple pregnancy rates compared with IUI on a natural cycle. There is an ascending pregnancy rate and ascending multiple pregnancy rate, in order, from natural cycles, clomiphene stimulated to gonadotrophin stimulated. However, two studies, both well controlled, the first treating mild male factor infertility [11] and the other [3] both idiopathic and mild male infertility, found no significant difference in the pregnancy rate between natural and gonadotrophin stimulated cycles for IUI. In my own experience, gonadotrophin stimulated cycles are preferable regarding pregnancy rates for unexplained infertility. The ideal then, would seem to be a cross between the two, i.e. our second alternative to lower multiple pregnancy rates, minimal stimulation with gonadotrophins. For mild male infertility, gonadotrophin stimulation adds little to the results obtained using a natural cycle.

Mild, controlled ovarian stimulation (COH) before IUI sounds something of a paradox as one of the explanations why the combination of COH yields results in idiopathic and mild male factor infertility is an increased production of large mature follicles. However, the additional theories explaining why gonadotrophin adds to the success include correction of a subtle, undiscovered ovulatory defect, improved endocrine environment and uterine receptivity. If, therefore, we can keep the number of large mature follicles on the day of hCG below 3 or 4, we may be able to reap the benefits of stimulation without an unacceptable multiple pregnancy rate. This can be achieved by using a low daily dose (50–75 IU), at least in the first cycle and increasing by only one half of this amount in the next cycle if monofollicular ovulation only was achieved in the first attempt. While this approach may seem cautious and certainly not foolproof, it must surely improve multiple pregnancy rates in IUI treatment cycles without significant detriment to pregnancy rates. As I have repeated several times in this book, taking a further month or so to achieve a healthy singleton pregnancy is preferable to the possible agonies involved in a multiple pregnancy, especially if it is of high order.

21.2.3 IVF/Embryo Transfer

The aetiology of multiple pregnancies following IVF is completely different from that of ovulation induction or stimulation for IUI. The way to reduce multiple pregnancy rates in IVF is, therefore, also completely different. In IVF the number of embryos transferred has a direct bearing on the number of resulting multiple pregnancies – the more embryos transferred, the more multiple pregnancies result. It follows that a reduction in the number of embryos transferred will bring down the multiple pregnancy rate. Although many countries have implemented strict laws regarding the number of embryos that may be transferred, at least in the under 40 year-olds, the tardiness in arriving at the ideal, elective single embryo transfer, is due to the accompanying reduction in pregnancy rates. Much of this suspicion has been overcome thanks to pioneering schemes in Scandinavia and Belgium where eSET is being applied successfully for young, good prognosis patients with a consequent dramatic reduction in multiple pregnancy rates. However, logic dictates that for eSET to produce good results, superior methods to select the single embryo to be transferred must be found. This is now the subject of intensive research, much of it directed at time-lapse imaging of embryo growth (see Chap. 22), and, more controversially, revolving around methods of pre-implantation genetic survey.

While single embryo transfer (SET) is the obvious solution to reduce multiple pregnancy rates, the question remains whether, while obviously drastically reducing multiple pregnancy rates, it can produce results similar to that of a two-embryo transfer. An old systematic review of the literature [12] involving three randomized trials and 17 cohort studies did indeed show that SET is associated with a decreased incidence of clinical pregnancy. However, when considering singleton pregnancy or singleton life birth as the end-points, then SET did not alter this likelihood compared with transfer of two or more embryos. In other words, the difference in pregnancy rates is mostly made up by the addition of the number of multiple pregnancies from the transfer of two or more embryos. This point is well illustrated from a model comparing single with double embryo transfer [13] in which the assumption was that with SET the chance of having a child was 21 % with virtually no multiples compared with a 24.8 % chance of a singleton child and a 7.8 % chance of twins when two embryos are transferred.

A sensible suggestion [14] seems to be to select for eSET those patients who are at the highest risk for a multiple pregnancy i.e. young, first or second cycle of IVF with a good number of high quality embryos.

When eSET is performed in young, good prognosis patients, almost invariably embryos are available for freezing. This could be a game changer as there is no evidence of a significant difference in the cumulative live birth rate when a single cycle of double embryo transfer is compared with a repeated frozen-thawed SET cycle [15]. This policy minimizes the risk of multiple pregnancy without substantially reducing the likelihood of achieving a live birth.

It is easy to foresee that eSET will be become a much more acceptable, and, therefore, more widespread practice with the enormous benefit of a drastic reduction in multiple pregnancies.

21.3 Foetal Reduction

The availability of methods for the culling of foetuses in utero, euphemistically named foetal reduction, is not in any shape or form, an excuse for ‘taking a chance’ and replacing an inordinate number of embryos to increase the chances of pregnancy. If ever there was a case for ‘prevention is better than cure’ this is it! The procedure, in addition to being repulsive and psychologically damaging, whether performed at 8 or 14 weeks or later, often presents an agonising choice of which foetus(es) are to be destroyed. The chances of losing the whole pregnancy as a result of the procedure are not small. While realizing the inevitability of having to use such a procedure in some exceptional cases, the preventative measures detailed here will, hopefully, severely limit its use in future.

21.4 Conclusions

1.

2.

3.

4.

5.

References

1.

Hamilton-Fairley D, Franks S. Common problems in induction of ovulation. Baillieres Clin Obstet Gynaecol. 1990;4:609–25.PubMedCrossRef

2.

Khalil MR, Rasmussen PE, Erb K, Laursen SB, Rex S, Westergaard LG. Homologous intrauterine insemination. An evaluation of prognostic factors based on a review of 2473 cycles. Acta Obstet Gynecol Scand. 2001;80:74–81.PubMedCrossRef

3.

Goverde AJ, McDonnell J, Vermeiden JW, Schats R, Rutten FH, Schoemaker J. Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertilit: a randomized trial and cost effectiveness analysis. Lancet. 2002;355:13–8.CrossRef

4.

Ferraretti AP, Goossens V, Kupka M, et al. Assisted reproductive technology in Europe, 2009. Results generated from European registers by ESHRE. Hum Reprod. 2013;28:2318–31.PubMedCrossRef

5.

Nygren KG, Andersen AN. Assisted reproductive technology in Europe, 1999. Results generated from European registers by ESHRE. Hum Reprod. 2002;17:3260–74.PubMedCrossRef

6.

Assisted reproductive technology surveillance – United States, 2010. MMWR Surveill Summ. 2013;62:1–24.

7.

Polson DW, Mason HD, Saldahna MBY, Franks S. Ovulation of a single dominant follicle during treatment with low-dose pulsatile FSH in women with PCOS. Clin Endocrinol (Oxf). 1987;26:205–12.CrossRef

8.

Homburg R, Howles CM. Low dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, reflections and refinements. Hum Reprod Update. 1999;5:493–9.PubMedCrossRef

9.

Guzick DS, Sullivan MW, Adamson GD, et al. Efficacy of treatment for unexplained infertility. Fertil Steril. 1998;70:207–13.PubMedCrossRef

10.

Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod. 1997;12:1865–72.PubMedCrossRef

11.

Cohlen BJ, te Velde ER, van Kooij RJ, Looman CW, Habbema JD. Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled trial. Hum Reprod. 1998;13:1553–8.PubMedCrossRef

12.

Dare MR, Crowther CA, Dodd JM, Norman RJ. Single or multiple embryo transfer following in-vitro fertilization for improved neonatal outcome: a systematic review. Aust N Z J Obstet Gynaecol. 2004;44:283–91.PubMedCrossRef

13.

Wolner-Hanssen P, Rydhstroem H. Cost-effectiveness analysis of in-vitro fertilization: estimated costs per successful pregnancy after transfer of one or two embryos. Hum Reprod. 1998;13:88–94.PubMedCrossRef

14.

Hunault CC, Eijkmanans MJ, Pieters MH, et al. A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer. Fertil Steril. 2002;77:725–32.PubMedCrossRef

15.

Pandian Z, Marjoribanks J, Oztrk O, Serour G, Bhattacharya S. Number of embryos fro transfer following in vitro fertilization or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev. 2013;(7):CD003416.