Assisted Conception and Multiple Pregnancy

Strategies to Reduce Rates

Mariano Mascarenhas and Adam Balen

The Facts

Multiple pregnancy rates are higher following assisted conception than after natural con­ceptions, thus forming, along with ovarian hyper-stimulation syndrome (OHSS), one of the two main iatrogenic risks of treatment for infertility.

A study from our group which attempted to assess the mode of conceptions of all births (n = 7,015) within a span of a week in 2003 in the United Kingdom noted that the multiple birth rate was significantly greater in assisted (13.5%) than in natural conception (1.2%). Of the multiple births following fertility treatment, 17% resulted from clomiphene citrate therapy, 72% from in vitro fertilisation (IVF) or frozen embryo replacements (FET) and 6% from superovulation with intrauterine insemination (IUI).¹ As we describe in this chapter, multiple pregnancy rates following IVF have fallen significantly since that study was performed. The maternal risks due to multiple pregnancy have been covered in Chapter 18 and neonatal risks in Chapter 26 of this volume.

Assisted conception appears to amplify the adverse maternal and fetal outcomes of twin pregnancies. Dichorionic twin pregnancies conceived following IVF have a higher risk of placenta praevia, preterm birth, very preterm birth, low birthweight and congenital malformations.² A retrospective study noted that IVF increases the risk of preterm birth in twin pregnancies complicated with pre-eclampsia and that this increased risk persists after adjusting for confounders, including maternal age.³

For the purposes of discussing strategies to reduce multiple pregnancy rates, infertility treatments have been classified into ovulation induction (OI) (with/without IUI) and IVF as the prevalence, aetiology and risk-reduction strategies for multiple pregnancy differ accord­ing to the infertility treatment strategy employed.

Ovulation Induction for Anovulatory Infertility with/without Intrauterine Insemination

Ovulation induction is the primary infertility treatment for women with World Health Organization (WHO) type 1 (hypogonadotrophic hypogonadism) and type 2 (which includes polycystic ovary syndrome (PCOS)) anovulatory infertility. Women with hypogo- nadotrophic hypogonadism are ideally treated with pulsatile gonadotrophin-releasing hor­mone (GnRH) provided through a mini-infusion pump, which provides a physiological restoration of the cycle with a low risk of multiple pregnancy.⁴ Unfortunately, this method has fallen out of use due to the lack of availability of the medication in recent years. Instead, gonadotrophin preparations with both follicle-stimulating hormone (FSH) and luteinising hormone (LH) bioactivity are used. Ovulation induction for PCOS can be achieved via a spectrum of medications, but the primary drugs in use include clomiphene citrate (CC) (a selective anti-oestrogen), letrozole (an aromatase inhibitor) and gonadotrophins (from either urinary or recombinant sources).⁵

The primary aetiology behind multiple pregnancies in OI (irrespective of whether it is combined with IUI) is the ovulation of multiple follicles, thereby leading to multiple fertilisation events leading to multiple embryos. The multiple pregnancies ensuing from OI are primarily of the multi-zygotic type. There is no clear evidence that OI increases the risk of monozygotic twinning.

The incidence of multiple pregnancies was reported as high as 15% following OI with CC and 30% following OI with gonadotrophins in the 1970s.6 The advent of first real-time and then transvaginal ultrasound monitoring techniques and accumulating clinical expertise has led to a steady decline in the incidence of multiple pregnancies with OI with data from the turn of the century indicating a multiple pregnancy rate of 8% with CC and 11% with gonadotrophins.⁷ This is further illustrated by data from the latest Cochrane reviews on the topic.

The incidence of multiple pregnancy as outlined in the latest Cochrane literature appears to be not significantly different between CC and letrozole (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 17 RCTs; n = 3,579; I² = 0%; high-quality evidence).⁸ There was also no significant difference noted in multiple pregnancy rates between recombinant and urinary gonadotrophins (RR 0.86, 95% CI 0.46 to 1.61; eight RCTs; n = 1,368; I² = 0%; low-quality evidence). Surprisingly, the Cochrane review also did not note a significant difference between gonadotrophins and CC in multiple pregnancy rates, but the data were more limited (RR 0.89, 95% CI 0.33 to 2.44; one RCT; n = 661; P = 0%; moderate-quality evidence).⁹

The principle of minimising multiple pregnancy rates with OI for women with PCOS is relatively straightforward, and the criteria for cancellation can be strict as OI is, in principle, to be used for women with anovulation and therefore uni-follicular ovulation should be all that is required to restore fertility. Current guidelines suggest that ultrasound monitoring is provided for OI with CC and letrozole for at least the first one or two cycles at each dose used or until it can be established that there is an appropriate ovarian response.⁵ Ultrasound monitoring is mandatory for every cycle of gonadotrophin OI, and we propose strict criteria before the administration of the pre-ovulatory trigger of human chorionic gonadotrophin (hCG), which initiates the release of the eggs, namely no more than a total of two follicles greater than 14 mm in diameter, with the largest follicle usually at least 17 mm.⁵ Furthermore, it is necessary to provide at least six-day if not seven-day service for ultra­sound monitoring, as follicle growth can be unpredictable and scans may be required alternate days or even daily once the follicles reach a mature size.

Laparoscopic ovarian diathermy (‘drilling') is a second-line OI method for women with PCOS which commonly involves multiple needle diathermies (usually four per ovary) targeted at the ovarian stroma. The aim of laparoscopic ovarian drilling is to induce spontaneous ovulation without the need for exogenous medications or the attendant monitoring. Randomised controlled trials have suggested that the incidence of multiple pregnancy is lower with laparoscopic ovarian drilling than with gonadotrophins (OR 0.13; 95% CI 0.03 to 0.52; five RCTs; n = 166; I² = 0%).¹⁰

Ovulation Induction with Intrauterine Insemination for Unexplained Infertility

Ovulation induction agents such as clomiphene, letrozole and gonadotrophins have also been employed as ovarian stimulation agents for women with natural ovulation. Ovarian stimulation with IUI is employed as a strategy in unexplained infertility and mild male factor infertility as an alternative to IVF where there are good patient prognostic factors (young age, a moderate duration of infertility) or where resources for IVF are limited and expectant management is not an acceptable option.

There does not appear to be a clear risk of increased multiple pregnancies with ovarian stimulation with IUI as compared with expectant management for unexplained infertility (OR 2.00, 95% CI 0.18 to 22.34; two RCTs; n = 304; moderate-quality evidence), but neither was there a difference in live birth rates (OR 0.82, 95% CI 0.45 to 1.49; one RCT; n = 253; moderate-quality evidence).¹¹ There was insufficient evidence whether ovarian stimulation with IUI made a significance difference to live birth rates or multiple pregnancy rates as compared with expectant management of mild male factor infertility.¹²

A recent three-armed RCT comparing ovarian stimulation with IUI with conventional IVF with single embryo transfer and modified natural cycle IVF noted no significant difference in multiple pregnancy rates.

When it comes to women with unexplained infertility who are already having natural uni-follicular recruitment, the goal of ovarian stimulation is multi-follicular recruitment.¹⁴ A balance therefore has to be found between minimising multiple pregnancy rates and maintaining an acceptable success rate for superovulation. Suggested recommendations have included cycle cancellation when more than two follicles greater than 16 mm are visualised on ultrasound or when the serum estradiol levels are higher than 1,000 pg/ml.¹⁵ However, the published literature indicates that none of these criteria can be effective in eliminating higher-order multiple pregnancy¹⁶ and that intermediate follicles of size 12 mm or greater could contribute to multiple pregnancy.¹⁷

Superovulation for In Vitro Fertilisation

In vitro fertilisation rather than OI (or superovulation) contributes to the majority of multiple births following assisted conception. It is therefore important for multiple birth reduction strategies to maximise focus on this aspect. Multiple births after IVF place an inordinate burden on public health care systems. A 2006 modelling study noted that the cost to the health service was £3,313 for a singleton birth following IVF, but rose to £9,122 for a twin birth. The costs due to a triplet birth following IVF were far higher at £32,354.¹⁸ The authors suggested that redirecting the cost incurred in managing multiple gestations to instead broaden public health funding for IVF to be linked to limiting the number of embryos transferred would be a cost-effective approach. Public funding, including partial reimbursement where single embryo transfer is performed, has been shown to be cost-effective with the savings in birth­admission costs alone recuperating more than half the cost spent on IVF cycles in Australia.¹⁹ Furthermore, the publication of IVF outcomes in the UK by the Human Fertilisation and Embryology Authority (HFEA) presents data per number of embryos transferred, which consequently favours those clinics with a strict elective single embryo transfer policy.

The incidence of multiple pregnancies following IVF is primarily due to the transfer of more than one embryo. Among couples having IVF, there appears to be a preference to have a double embryo transfer as demonstrated in a trial comparing elective single embryo transfer with double embryo transfer where 40% of women in the elective single embryo transfer arm chose to have double embryo transfer instead.²⁰ More than half of infertile couples (58%) surveyed in a 2014 Spanish study stated that they would prefer to have twin pregnancies with the most common reason being ‘to avoid a new IVF attempt'.²¹ However, acceptance of single embryo transfer is improved when patients are educated regarding the risks of multiple pregnancy with oral, written and/or electronic information.²²

Strict regulations by organisations such as the British Fertility Society, the National Institute for Health and Care Excellence (NICE) and the HFEA have resulted in a drop in multiple live birth rates from 24% in 2008 to 10% in 2017.²³ This drop in multiple live birth rates has been primarily due to elective single embryo transfer, the acceptability of which has increased due to two laboratory factors:

1. Better embryo selection through

a. Blastocyst culture

b. Improvement in embryo selection techniques

2. Improvements in embryo cryopreservation techniques so that surplus good-quality embryos can be frozen, thereby enabling further attempts at embryo transfer without the need to go through a full cycle with ovarian stimulation.

Data from RCTs indicate that the cumulative live birth rates are not significantly different between double embryo transfer and transfer of a single embryo with elective cryopreservation followed by frozen embryo transfer of the second embryo at a later date (OR 1.22,95% CI 0.92 to 1.62, three RCTs; n = 811, I² = 0%, low-quality evidence). However, the multiple pregnancy rate is significantly higher with the former approach (OR 30.54,95% CI 7.46 to 124.95, three RCTs, n = 811, I² = 23%, low-quality evidence).²⁴

Based on such evidence, NICE recommends elective single embryo transfer where a top­quality blastocyst is available for transfer.²⁵ In other cases, the recommendation is to consider a single embryo transfer (dependent of embryo quality) for women younger than the age of 40 years having their first or second full cycle of IVF (a full cycle includes all fresh and frozen embryo transfers from a single oocyte retrieval attempt).

Monozygotic Twins

Some of the latest laboratory techniques such as pre-implantation genetic testing²⁶ and extended culture to blastocyst stage²⁷ appear to increase the risk of monozygotic twinning. Monozygotic twins have a poorer prognosis than dizygotic twins. Furthermore, the limited literature on monozygotic twins following IVF appears to indicate that their prognosis may be poorer than the naturally conceived monozygotic twins.^28,29

Twin Pregnancies after Egg Donation

Pregnancies after egg donation (provided to women with premature ovarian insufficiency) have a higher risk of preterm birth and low birthweight as compared with IVF pregnancies using a woman’s own eggs.³⁰ A pilot RCT comparing a single double embryo transfer with two sequential elective single embryo transfer in egg donation cycles noted no significant difference in cumulative live birth rate, but a significant increase in the risk of twin pregnancies.³¹ Therefore single embryo transfer needs to be considered for egg donation cycles, especially for women aged 45 years or older, who have a 65% risk of preterm birth, a 15% risk of early preterm birth (der Veen F, Van Wely M.

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome. Cochrane Database Syst Rev [Internet]. 2019 [cited 2019 Aug 23];( 1). Available from www.cochranelibrary.com/cdsr/doi/ 10.1002∕14651858.CD010290.pub3∕full

10. Farquhar C, Brown J, Marjoribanks J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev [Internet]. 2012 [cited 2019 Aug 23];(6). Available from www.cochranelibrary.com/cdsr/doi/10.1002/ 14651858.CD001122.pub4/full

11. Veltman-Verhulst SM, Hughes E, Ayeleke RO, Cohlen BJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2016;2 (100909747):CD001838.

12. Cissen M, Bensdorp A, Cohlen BJ, Repping S, De Bruin JP, Van Wely M. Assisted reproductive technologies for male subfertility. Cochrane Database Syst Rev 2016 Feb 26;2:CD000360.

13. Tjon-Kon-Fat RI, Bensdorp AJ, Bossuyt PMM, Koks C, Oosterhuis GJE, Hoek A et al. Is IVF - served two different ways - more cost-effective than IUI with controlled ovarian hyperstimulation? Hum Reprod. 2015 Oct 1;30(10):2331-9.

14. Van Rumste MME, Custers IM, Van der Veen F, Van Wely M, Evers JLH, Mol BWJ. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis. Hum Reprod Update 2008 Nov 1;14(6):563-70.

15. Practice Committee of American Society for Reproductive Medicine. Use of exogenous gonadotropins in anovulatory women: a technical bulletin. Fertil Steril 2008 Nov;90(5Suppl):S7-12.

16. Fong SA, Palta V, Oh C, Cho MM, Loughlin JS, McGovern PG. Multiple pregnancy after gonadotropin-intrauterine insemination: an Unavoidable event? ISRN Obstet Gynecol [Internet]. 2011 [cited 2019 Dec 29]. Available from www.ncbi.nlm.nih.gov/pmc/articles/ PMC3255317

17. Giles J, Cruz M, Gonzalez-Ravina C, Caligara C, Prados N, Martinez JC et al. Small-sized follicles could contribute to high-order multiple pregnancies: outcomes of 6552 intrauterine insemination cycles. Reprod Biomed Online 2018 Nov;37 (5):549-54.

18. Ledger WL, Anumba D, Marlow N, Thomas CM, Wilson ECF. Cost of Multiple Births Study Group (COMBS Group): the costs to the NHS of multiple births after IVF treatment in the UK.BJOG Int J Obstet Gynaecol 2006 Jan;113(1):21-5.

19. Chambers GM, Illingworth PJ, Sullivan EA. Assisted reproductive technology: public funding and the voluntary shift to single embryo transfer in Australia. Med J Aust 2011;195(10):594-8.

20. Prados N, Quiroga R, Caligara C, Ruiz M, Blasco V, Pellicer A et al. Elective single versus double embryo transfer: live birth outcome and patient acceptance in

a prospective randomised trial. Reprod Fertil Dev 2015 Jun;27(5):794-800.

21. Mendoza R, Jauregui T, Diaz-Nunez M, De la Sota M, Hidalgo A, Ferrando M et al. Infertile couples prefer twins: analysis of their reasons and clinical characteristics related to this preference. J Reprod Infertil 2018 Sep;19(3):167-73.

22. Sunderam S, Boulet SL, Jamieson DJ, Kissin DM. Effects of patient education on desire for twins and use of elective single embryo transfer procedures during ART treatment: a systematic review. Reprod Biomed Soc Online 2018 Aug;6:102-19.

23. Human Fertilisation and Embryology Authority. Fertility treatment 2017: trends and figures. 2019. www.hfea.gov.uk/ about-us/publications/research-and-data/ fertility-treatment-2019-trends-and-figures

24. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2013 Jul 29;(7):CD003416.

25. National Institute for Health and Care Excellence. (2013). Fertility problems: assessment and treatment (NICE Quality Standard No. 156). Retrieved from www.nice.org.uk/guidance/cg156.

26. Kamath MS, Antonisamy B, Sunkara SK. Zygotic splitting following embryo biopsy: a cohort study of 207 697 single embryo transfers following IVF treatment. BJOG Int J Obstet Gynaecol [Internet]. [cited 2019 Dec 29];n/a(n/a). Available from https://obgyn.onlinelibrary.wiley.com/doi/ abs/10.1111/1471-0528.16045

27. Knopman JM, Krey LC, Oh C, Lee J, McCaffrey C, Noyes N. What makes them split? Identifying risk factors that lead to monozygotic twins after in vitro fertilization. Fertil Steril 2014 Jul;102(1):82-9.

28. Hack KEA, Vereycken MEMS, Torrance HL, Koopman-Esseboom C, Derks JB. Perinatal outcome of monochorionic and dichorionic twins after spontaneous and assisted conception:

a retrospective cohort study. Acta Obstet Gynecol Scand 2018 Jun;97(6):717-26.

29. Mascarenhas M, Kamath MS, Muthukumar K, Mangalaraj AM, Chandy A, Aleyamma T. Obstetric outcomes of monochorionic pregnancies conceived following assisted reproductive technology: a retrospective study. J Hum Reprod Sci 2014;7(2):119-24.

30. Mascarenhas M, Sunkara SK, Antonisamy B, Kamath MS. Higher risk of preterm birth and low birth weight following oocyte donation: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2017 Nov;218:60-7.

31. Clua E, Tur R, Coroleu B, Rodriguez I, Boada M, Gomez MJ et al. Is it justified to transfer two embryos in oocyte donation? A pilot randomized clinical trial. Reprod Biomed Online 2015 Aug;31 (2):154-61.

32. Laskov I, Michaan N, Cohen A, Tsafrir Z, Maslovitz S, Kupferminc M et al. Outcome of Twin pregnancy in women ≥45 years old: a retrospective cohort study. J Matern Fetal Neonatal Med 2013 May 1;26 (7):669-72.