INTRODUCTION — Following assisted reproductive technology (ART), the ideal outcome is the delivery of a single, healthy child. However, one side effect of both ovulation induction and fertility procedures (eg, in vitro fertilization) is multiple gestation pregnancy, including twin, triplet, and higher order multiples. To reduce the incidence of multiple gestation following all types of ART, refinements in embryo evaluation and patient selection have been made. In cases where high order multiples occur, patients have the option of pregnancy reduction.
This topic will review the incidence and risk factors for multiple gestation following ART as well as multifetal pregnancy reduction. Related content on fertility treatments and outcomes can be found elsewhere.
●(See "In vitro fertilization: Overview of clinical issues and questions".)
●(See "Overview of ovulation induction".)
●(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
INCIDENCE AND TRENDS — The incidence of multiple gestation has risen significantly over several decades, primarily due to increased use of fertility drugs for ovulation induction, superovulation, and assisted reproductive technologies, such as in vitro fertilization (IVF) [1]. In 1960, before the commercial availability of drugs for treatment of infertility, there were approximately 4.3 million births in the United States, with 1244 triplets and higher order multiples [2]. In 2018, the total number of births was slightly lower (3.8 million), and there were 3525 triplet and higher order multiples, the lowest number reported since 1991; these numbers do not include those high order multiple gestations (ie, pregnancies with at least three fetuses) reduced naturally or iatrogenically [3,4].
For comparison, past studies have reported the following:
●Society for Assisted Reproductive Technology (SART) data from 2019 reported that from 2010 to 2019, the percentage of embryo transfers resulting in singleton births increased from 22.6 to 34.4 percent, the percentage of twins decreased from 9.0 to 2.7 percent, and the percentage of triplets or more decreased from 0.4 to 0.06 percent [5].
●From 2019 to 2020, the twin birth rate fell 3 percent to 32.1 per 1000 live births, and the triplet and higher-order multiple birth rate decreased 9 percent to 79.6 per 100,000 births [6].
IMPACT OF MULTIPLE GESTATION — Multiple gestations are at significantly increased risk of fetal, neonatal, and maternal complications, as well as complete pregnancy loss, when compared with singleton pregnancies (table 1) [7]. As an example, in one review, the risk of delivery <32 weeks of gestation for singleton, twin, triplet, and quadruplet pregnancies was 2, 8, 26, and >95 percent, respectively [7]. In another study that compared twin pregnancy outcome with outcome of two successive singleton pregnancies delivered by the same mother, adverse pregnancy and neonatal outcomes were significantly increased for in vitro fertilization (IVF) twins compared with two successive IVF singleton pregnancies [8].
RELEVANT SOCIAL ISSUES
●Impact of insurance coverage – The lack of insurance coverage for assisted reproductive technologies (ART) in most of the United States, as well as competition among ART programs, has generated pressure to achieve success in a minimal number of cycles [9,10]. One strategy was to increase the number of embryos transferred per in vitro fertilization (IVF) procedure. An analysis of 1998 Society for Assisted Reproductive Technology (SART) data reported that providers in states without insurance coverage for IVF transferred more embryos per cycle, had a higher percentage of cycles resulting in pregnancy, and encountered an increased frequency of high order gestations compared with providers in states with IVF insurance coverage [9]. This finding was confirmed in a similar analysis of 2007 to 2011 SART data [11].
●Patient acceptance of, or desire for, multiple gestation – Patients with infertility often consider the birth of twins acceptable, or even desirable, since it may result in a completed family after (sometimes) years of infertility [12-16]. Nevertheless, there is a need for effective patient education and methods to reduce the frequency of multiple gestation, particularly high order pregnancies.
●Impact of multiple gestation on family well-being – The economic and psychologic impact on families raising children of a multiple gestation is also important [17-20]. In one study, for example, 22 percent of mothers of multiples had Parenting Stress Index scores indicating severe parenting stress compared with 5 percent of mothers of IVF singletons and 9 percent of mothers of naturally conceived singletons [19]. Another study found that each additional child more than tripled the odds of not being able to meet basic material needs and doubled the odds of a lowered quality of life for the family [20]. (See "Neonatal complications of multiple births", section on 'Family/caregiver support'.)
●Local and national policies – Several strategies attempting to control the frequency of high order multiples have been implemented, sometimes on a national scale. The overriding aim of these strategies is to transfer fewer embryos of higher quality to maximize the pregnancy rate and minimize the risk of high order multiple gestation.
LIMITING THE MULTIPLE GESTATION RISK OF ASSISTED REPRODUCTIVE TECHNOLOGY — Restricting the number of embryos transferred during in vitro fertilization (IVF) increases the proportion of singleton births. National legislation in several European countries restricting the number of embryos transferred has proven to be effective in reducing the high order pregnancy rate, although there has been a trade-off in terms of lower delivery rates (table 2) [21,22].
Beginning in 1998, the American Society for Reproductive Medicine (ASRM) issued practice guidelines on the number of embryos to transfer [23] and has periodically revised the guidelines, most recently in 2017 (table 3) [24]. These guidelines suggest limiting the number of embryos transferred based upon maternal age, embryo quality, euploidy, as well as the availability of high-quality embryos for cryopreservation.
The ASRM guidelines have had a significant impact on practice patterns and outcomes, resulting in a shift toward transfer of fewer embryos [25]. Between 2003 and 2019, the percentage of single embryo transfers has markedly increased from 0.1 to 82.4 percent in patients <35 years and from 0.2 to 73.3 percent in patients 38 to 40 years of age [25]. There are no legal regulations in the United States limiting the numbers of embryos transferred, but improvements in embryo culture technology and shifting perceptions among patients in addition to refinements in ASRM guidelines have contributed to fewer embryos being transferred.
Factors affecting multiple gestation risk — The optimum number of embryos to transfer depends on several factors, which are discussed below.
Maternal age — Studies consistently demonstrate that live birth rates after ART decrease with advancing age. The importance of maternal age on the risk of multiple gestation after embryo transfer is illustrated by ART surveillance data (2006) reporting multiple birth rates after transfer of three or two embryos in women of various age groups (table 4) [26]. Live birth rates and twin rates were comparable for all age groups whether three or two embryos were transferred, but transfer of two embryos resulted in substantial reductions in the incidence of high order multiple births, especially among younger women.
Embryo quality — The ability to select only the highest quality embryos would allow transfer of fewer of them while achieving acceptable birth rates. Embryo quality is assessed in a number of ways, with morphologic evaluation remaining the first-line method for assessment [27].
Number of eggs fertilized — The importance of embryo quality was demonstrated in a study that found higher pregnancy rates when more than four eggs fertilized and two embryos were transferred than when only two eggs fertilized and two embryos were transferred [28]. Presumably fertilization of four eggs provided a higher chance of selecting quality embryos for transfer. In all maternal age groups up to age 40 years, when four eggs fertilized, the transfer of two, rather than three, embryos reduced the risk of high order birth without decreasing the chance of live birth.
Similarly, a CDC study of 35,554 IVF transfers showed that for all age groups, increased availability of embryo choice (indicated by the cryopreservation of at least one embryo) resulted in higher live birth rates despite fewer transferred embryos [26].
Morphology — Morphologic criteria associated with improved embryo quality are used to identify developmentally competent embryos for transfer. The human zygote should undergo the first cleavage division by 24 to 27 hours postinsemination, the second cleavage division by approximately 44 hours, and the third cleavage division to the 8-cell stage by 68 to 72 hours (figure 1). Embryos developing more slowly than described in this timeline are less likely to implant [29,30]. Determining a cumulative embryo score encompassing the three characteristics of cell number, fragmentation, and embryo symmetry can help to select the most viable embryos, thereby maintaining implantation rates while reducing the need to transfer many embryos and the concomitant risk of multiple gestation [27,31].
Additional morphologic criteria that have been developed for assessing embryo quality include fragment distribution among the blastomeres, morphology of the first polar body, pronuclear orientation, pronuclear morphology, time of initial cleavage, and mononucleate blastomeres [32-43]. Independently, each of these characteristics have been found to enhance implantation and pregnancy rates when used to select embryos for transfer.
While numerous studies have evaluated the utility of multiday embryo assessment for selection of embryos for day 3 transfer [44], one study showed that day 2 or day 3 evaluations alone are sufficient for morphologic assessment of cleavage stage embryos [45]. As culture systems have progressed, there has been an increasing trend to perform embryo transfer at the blastocyst stage on day 5 or 6. (See 'Day 5 or 6 (blastocyst stage)' below.)
Chromosomally normal and abnormal embryos have different developmental kinetics. Time lapse morphokinetics analysis has been studied for its effectiveness in selecting chromosomally normal embryos for transfer and thus allowing transfer of fewer embryos [46]. However, a comprehensive review of the literature on the ability of morphokinetic parameters to predict embryo ploidy status concluded that no single or combined parameter was consistently predictive of embryo ploidy status [47].
Preimplantation genetic testing — Preimplantation genetic testing (PGT) has been used to test for aneuploidy (PGT-A) but does not improve live birth rates. The rationale for this procedure is that the ability to transfer chromosomally normal embryos should increase the overall success rate of ART. However, injury to the embryo during biopsy, misdiagnosis due to mosaicism, and indeterminate genetic results may contribute to loss of normal embryos. A noninferiority trial comparing pregnancy rates of single embryo transfer (SET) of a euploid embryo and of double embryo transfer (DET) of morphologically graded embryos reported similar ongoing pregnancy rates beyond 20 weeks (60.7 percent [54 in 89] versus 65.1 percent [56 in 86]) [48]. The multiple pregnancy rate was significantly lower in the SET group than in the DET group (0 percent [0 in 54] versus 53.4 percent [31 in 56]). The authors determined that transfer of a single euploid blastocyst was noninferior compared with transfer of two blastocysts with unknown ploidy status in terms of ongoing pregnancy rates. If PGT-A is not covered by insurance, the additional cost of PGT-A may exceed that of having a second SET with a frozen/thawed embryo without PGT-A after an initial failed SET without PGT-A. The risk of possible miscarriage should be factored in as well. Data from randomized trials and prospective controlled studies have also shown that PGT-A does not improve live birth rates in women of any age or in women with unexplained recurrent miscarriage, and may in fact lower them [49]; there are also no data that it improves IVF success rates in women with repeated implantation failure [50]. A large multicenter randomized controlled trial of PGT-A (STAR trial) in 661 women aged 25 to 40 years showed no increase in ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer with PGT-A and no significant increase in OPR in a subgroup of women aged 35 to 40 years with two or more embryos that could be biopsied when analyzed by intention to treat. (See "Preimplantation genetic testing".)
Assessment of noninvasive biomarkers — Methods to determine embryo competence through noninvasive techniques, including the assay of spent culture medium, are an active area of investigation. However, none of these noninvasive biomarker approaches have yet proven efficacious for embryo selection.
Day 2 or 3 (cleavage stage) — As improvements in IVF culture media in the late 1980s permitted longer duration of embryo culture, it was noted that not all early cleavage stage embryos continued to develop normally. The additional 24 hours in culture from day 2 to day 3 allowed identification of embryos that arrested at the 4-cell stage (figure 1). A general movement toward transferring human embryos on day 3 rather than on day 2 resulted in enhanced success rates with transfer of fewer embryos and, ultimately, fewer multiple gestations. Initially, however, there was a spike in high order multiple gestation after day 3 transfer was implemented because embryo transfer guidelines had not been revised to transfer fewer embryos to correct for better success rates [51].
Day 5 or 6 (blastocyst stage) — The metabolic requirements of the human embryo demand culture media that support development as the genome switches on at the 8-cell stage. The ability to serve these changing metabolic needs with development of either sequential media systems [52,53] or single-step media [54] has permitted culture to day 5 and enabled identification of the most developmentally superior blastocysts (figure 1) [52-54]. There has been an increasing trend to perform embryo transfer at the blastocyst stage on day 5 or 6.
●Blastocyst morphology and grading – Blastocyst morphologic criteria associated with implantation potential include the extent to which the blastocyst has expanded and the quality of the inner cell mass and the trophectoderm. One standard system for blastocyst grading assigns a numerical score from 1 to 6 on the basis of expansion and hatching status (1, an early blastocyst with a blastocoel that is less than half of the volume of the embryo; 2, a blastocyst with a blastocoel that is half of or greater than half of the volume of the embryo; 3, a full blastocyst with a blastocoel completely filling the embryo; 4, an expanded blastocyst with a blastocoel volume larger than that of the early embryo, with a thinning zona; 5, a hatching blastocyst with the trophectoderm starting to herniate though the zona; and 6, a hatched blastocyst, in which the blastocyst has completely escaped from the zona). For blastocysts with grades 3 and above (ie, full blastocysts onward), the inner cell mass is assigned a grade A if tightly packed, many cells are present; B, when several loosely grouped cells are present; or C, if very few cells. The trophectoderm grade is assigned a grade A when many cells forming a cohesive epithelium are present; B, if few cells form a loose epithelium; or C, when there are very few large cells [55].
There are both advantages and disadvantages to blastocyst culture and transfer [56]. Transfer on day 5 is more natural as it takes approximately four days for the naturally fertilized egg (zygote) to travel through the fallopian tube and reach the uterine cavity. Blastocysts may be better embryos because they have demonstrated the ability to make the transition from dependency on the maternal genome to the embryonic genome for continued development and undergo cell differentiation to achieve the blastocyst stage [57]. Only one or two blastocysts need to be transferred to maintain overall success rates, while decreasing the high order multiple pregnancy rate [54,58-63]. If only one or two blastocysts are transferred, triplet pregnancy should not occur unless one of the blastocysts divides to form monozygotic twins. In fact, however, the frequency of monozygotic twinning appears to be higher with blastocyst transfer than with cleavage stage transfer (odds ratio [OR] 3.04, 95% CI 1.54-6.01, 1.64 versus 0.41 percent) [64]. Some studies show up to 5 percent monochorionic twinning rates, with a further increase in risk if the embryos were formed following ICSI [65]. Additional concerns about the use of blastocysts include the possibilities of epigenetic effects on the embryo [64]. However, for ongoing pregnancies, most pregnancy outcomes are similar for day 5 versus day 3 transfer [66,67].
Other drawbacks of blastocyst transfer include the potential for loss in extended culture of embryos that may have successfully implanted if transferred on day 3, and the potentially poorer long-term survival of embryos cryopreserved on day 5. This was illustrated in a meta-analysis of randomized trials comparing blastocyst and cleavage stage transfer [68]. The live birth rate per randomized patient was significantly higher in patients who had a blastocyst stage transfer (OR 1.39, 95% CI 1.10-1.76), and the multiple pregnancy rate was similar for both groups when an equal number of embryos was transferred, but the blastocyst stage group also had a higher cycle cancellation rate (OR 2.21, 95% CI 1.47-3.32) and lower cryopreservation rate (OR 0.28, 95% CI 0.14-0.55) compared with the cleavage stage group. Thus, the increased risk of having no embryos to transfer after extended culture may be a reason to restrict patients with suboptimal embryo cleavage to day 3 transfer.
Patients with no 8-cell embryos on day 3 have a significantly lower chance of conceiving after a day 5 transfer than after a day 3 transfer [69]. When cumulative day 3 pregnancy rates include the results of cryopreserved embryo cycles, there may be no advantage of day 5 transfer per controlled ovarian hyperstimulation in patients with good prognosis (defined as either first IVF cycle plus good embryo quality plus sufficient embryos for cryopreservation or previous IVF success). However, survival of cryopreserved blastocysts varies among centers, and can be quite good. In addition, if only patients with a good prognosis or donor egg cycles are selected, some retrospective studies (but not all) reported that prolonging embryo culture to day 5 improved embryo selection and implantation rates and achieved a significant decrease in high order gestations by reducing the number of embryos transferred, without compromising the pregnancy rates from the fresh transfer [59,69-75]. One could argue that there is no reason to transfer more than two embryos in these good prognosis patients, per Society for Assisted Reproductive Technology (SART) guidelines. One [76] of nine randomized trials comparing day 3 versus day 5 transfer reported similar findings [76-84] and none of these trials showed an increase in high order multiple gestation in patients undergoing day 5 embryo transfer.
It may be prudent to restrict day 5 embryo transfer to patients with a minimum number of zygotes or having a minimum number of good-quality embryos (minimum numbers vary from center to center and some centers also use patient age cutoffs for assigning day of transfer). One or two blastocysts are transferred based on the patient's age, embryo quality, and cycle history. This approach attempts to reduce the risk of high order multiple pregnancy without increasing cycle cancellation rates or decreasing implantation rates.
Single embryo transfer — The most effective method of avoiding high order multiple pregnancy is single embryo transfer [7,85]. Elective single embryo transfer (eSET) is defined as transfer of one good-quality embryo in cases where at least two good-quality embryos are available. Practice committee guidelines of the SART and the ASRM suggest that eSET is most appropriate for women with a good prognosis for conception [85]:
●Age <35 years
●More than one high quality embryo for transfer
●First or second IVF treatment cycle
●Recipients of embryos from donated eggs
Evidence for the efficacy of this approach was provided in a 2013 meta-analysis of 14 randomized trials of single versus double embryo transfer (DET); most of the trials compared cleavage stage transfers [86]. The live birth rate after one cycle of DET was not significantly different from the rate after two cycles of SET (OR 1.22, 95% CI 0.92-1.62, three studies, n = 811); thus, for a woman with a 40 percent chance of live birth following a single cycle of DET, the chance of live birth following two SET cycles would be 30 to 42 percent. However, the multiple pregnancy rate was significantly higher in the DET group (OR 30.54, 95% CI 7.46-124.95, three RCTs, n = 811); therefore, for a woman with a 15 percent risk of multiple pregnancy following a single cycle of DET, the risk of multiple pregnancy following two SET cycles would only be 0 to 2 percent. These data suggest that SET is superior to DET when the number of deliveries with at least one live born child, incremental cost-effectiveness ratio, and maternal and pediatric complications are taken into account [87,88].
Blastocyst transfer is associated with higher pregnancy rates and monozygotic twinning rates than cleavage stage embryo transfer [89,90]. In a randomized trial of blastocyst versus cleavage stage transfer, pregnancy rates were 32 and 21.6 percent, respectively [90]. All of the women in this trial were under 36 years of age; therefore, these results may not apply to older women, who comprise the majority of ART patients. It is also important to understand that when embryo quality is suboptimal at the cleavage stage, further development to the blastocyst stage is likely compromised. Blastocyst transfer is unwise in such cases and may actually result in no viable blastocysts to transfer; hence, in these cases, a cleavage stage transfer should be performed.
Utilization of eSET will likely increase as methods of predicting embryo viability improve and pressure to reduce the incidence of high order pregnancy mounts. Preimplantation genetic testing is one such method that has potential clinical utility. (See "Preimplantation genetic testing".)
A randomized trial found that well-informed and supported patients were more likely to choose eSET than patients receiving usual care [91]. For women under 35 years of age for whom eSET is planned and who meet their center's criteria for day 5 embryo transfer, we suggest transferring a single day 5 blastocyst. If a day 5 embryo is not available, then transfer of a single, high-quality cleavage stage embryo is performed.
Although eSET is associated with a higher rate of singleton pregnancy, the outcomes of these singleton pregnancies are less optimal than those of spontaneously conceived singleton pregnancies. In a systematic review of randomized trials and cohort studies that compared the outcome of eSET-conceived singletons with spontaneously conceived singletons, eSET pregnancies were at higher risk of preterm birth (relative risk [RR] 2.13, 95% CI 1.26-3.61), placenta previa (RR 6.02, 95% CI 2.79-13.01), and ectopic pregnancy (RR 6.40, 95% CI 4.38-9.35) [92]. This finding may be due to factors associated with infertility and/or the process of ART. (See "Assisted reproductive technology: Pregnancy and maternal outcomes", section on 'Low birth weight'.)
LIMITING THE MULTIPLE GESTATION RISK OF OVULATION INDUCTION AND SUPEROVULATION — It is estimated that 39 to 67 percent of high order multiple births are related to ovulation induction without in vitro fertilization (IVF) [7,93], and ovulation induction accounts for essentially 100 percent of multiple pregnancies with six or more fetuses [94]. Thus, ovulation induction and superovulation account for the largest proportion of high order multiple gestations. The contribution of ovulation induction to high order multiple births is rising, while the number of these births from IVF is falling [2].
The number of large follicles present on the day of human chorionic gonadotropin (hCG) administration is a key factor in determining the risk of multiple gestation in superovulation [95]. In one series of 4062 cycles, the incidence of high order multiple pregnancy by number of follicles of diameter ≥10 mm was: 5 to 6 percent with four to six follicles, 14 percent with seven to eight follicles, and 19 percent with nine or more follicles present [96]. Factors associated with the highest risk of high order multiple pregnancies included age <32 years, having seven or more follicles of diameter ≥10 mm, and an estradiol concentration ≥1000 pg/mL (note: this value is assay-dependent). Interestingly, this study also showed that high order multiple pregnancy did not occur after the first cycle unless there were more than seven follicles, and did not occur after the second cycle regardless of follicle number, which suggests that gonadotropin dosing may be safely increased after the first cycle with close monitoring of follicle development [96].
In the first cycle, however, the dose of gonadotropin and length of stimulation are highly important factors. For example, high order multiples have been reported in 6 to 9 percent of cycles with FSH or hMG dose ≥150 IU, but in ≤1 percent of cycles with doses of 37.5 to 75 IU [2]. Similarly, the frequency of high order multiples fell when the duration of stimulation was lowered from ≥12 days to less than 9 days.
Strategies to reduce the high order multiple gestation rate from ovulation induction include [2,7,97-99]:
●Begin with medication regimens associated with a low incidence of multiple follicles, including clomiphene citrate, aromatase inhibitors, and pulsatile GnRH (where available), followed by the lowest effective gonadotropin dose [7].
●Closely monitor follicle development with a strict cycle cancellation policy for patients with an excessive number of mature follicles (eg, greater than 3 follicles ≥15 mm [100] or ≥16 mm [101]).
●Alternatives to cycle cancellation include aspiration of supernumerary follicles before hCG administration or conversion to IVF.
The authors of one analysis estimated that, depending on the strategy used, 5 to 20 percent of cycles would be canceled, but high order pregnancy rates would be less than 2 percent and pregnancy rates would average 10 to 20 percent per cycle [2]. Pregnancy rates per patient would not be reduced if low gonadotropin doses were continued for four to six cycles. As the majority of patients are paying out of pocket for treatment, this might well be a difficult policy to implement.
These issues are discussed in more detail separately. (See "Overview of ovulation induction".)
MULTIFETAL PREGNANCY REDUCTION — A prospective analysis of ultrasound and birth information on 709 multiple and 5962 singleton pregnancies conceived at a private infertility clinic observed spontaneous reduction of one or more gestational sacs and/or embryos in the first trimester in 36 percent of twin, 53 percent of triplet, and 65 percent of quadruplet pregnancies [102]. For those that do not reduce spontaneously, iatrogenic fetal reduction may be used to lower the risks associated with multiple gestation. However, pregnancy reduction may not be an acceptable option for some patients. The procedure is discussed in detail separately. (See "Multifetal pregnancy reduction and selective termination".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)
SUMMARY AND RECOMMENDATIONS
●Background – Following several decades of increasing incidences of twin and high order multiple gestations (ie, triplets or more) after assisted reproductive technology (ART), including ovulation induction, superovulation, and in vitro fertilization (IVF), the incidence of both twin and high order multiple gestations has declined in the past decade. (See 'Introduction' above.)
●ART goal – The ideal ART outcome is the delivery of a single, healthy child. Progress toward this goal has been made as a result of improvements in embryo evaluation and patient selection, including limiting the number of embryos transferred based on maternal age and embryo quality/availability for cryopreservation. However, additional research is needed to develop more accurate methods of embryo selection. (See 'Limiting the multiple gestation risk of assisted reproductive technology' above.)
●Preferred use of single embryo transfer – The most effective method of avoiding high order multiple pregnancy is single embryo transfer, when appropriate. (See 'Single embryo transfer' above.)
•For woman under 35 years of age for whom single embryo transfer is planned and who meet their center's criteria for day 5 embryo transfer, we suggest transferring a single day 5 blastocyst rather than cleavage stage transfer (Grade 2B). (See 'Day 5 or 6 (blastocyst stage)' above.)
•For programs who do not perform blastocyst transfers, we suggest single rather than double cleavage stage embryo transfer for women under age 35 who have other good-quality embryos available for transfer (table 3) (Grade 2B). (See 'Day 2 or 3 (cleavage stage)' above.)
•For all other women, maternal age and embryo quality/availability for cryopreservation need to be taken into account in determining the optimal number of embryos to transfer (table 3). (See 'Limiting the multiple gestation risk of assisted reproductive technology' above.)
●Approach to ovulation induction
•For individuals undergoing ovulation induction without IVF, we suggest treatment with either clomiphene citrate or aromatase inhibitors, as appropriate, rather than gonadotropins (Grade 2B). The rationale is to reduce the risk of high-order multiple gestation. (See 'Limiting the multiple gestation risk of ovulation induction and superovulation' above and "Overview of ovulation induction".)
•In women with an excessive number of mature follicles, we suggest conversion to IVF or cycle cancellation (Grade 2C). (See 'Limiting the multiple gestation risk of ovulation induction and superovulation' above.)
●Role of fetal reduction – Fetal reduction is an option for reduction of high order multiple gestations. (See 'Multifetal pregnancy reduction' above.)
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