Background In vitro fertilization is associated with a highrisk of multiple births, which is a direct consequence of thenumber of embryos transferred. However, other factors that contributeto the risk are not well defined.
Methods Using the data base established by the Human Fertilisationand Embryology Authority in the United Kingdom, we studied thefactors associated with an increased risk of multiple birthsin 44,236 cycles in 25,240 women. The factors included the woman'sage, the cause and duration of infertility, previous attemptsat in vitro fertilization, previous live births, number of eggsfertilized, and number of embryos transferred.
Results Older age, tubal infertility, longer duration of infertility,and a higher number of previous attempts at in vitro fertilizationwere all associated with a significantly decreased chance ofa birth and of multiple births. Previous live birth was associatedwith an increased chance of a birth but not of multiple births.The higher the number of eggs fertilized, the higher the likelihoodof a live birth. When more than four eggs were fertilized, therewas no increase in the birth rate for women receiving threetransferred embryos as compared with those receiving two, butthere was a considerable increase in the rate of multiple birthswhen three were transferred (odds ratio, 1.6; 95 percent confidenceinterval, 1.5 to 1.8).
Conclusions Among women undergoing in vitro fertilization, thechances of a live birth are related to the number of eggs fertilized,presumably because of the greater selection of embryos for transfer.When more than four eggs are fertilized and available for transfer,the woman's chance of a birth is not diminished by transferringonly two embryos. Transferring more embryos increases the riskof multiple births.
The high rate of multiple births resulting from in vitro fertilizationis a major health issue.1,2,3 The medical, social, and financialconsequences are considerable, chiefly because of the excessivemorbidity among the survivors of high-order multiple births(triplets or more).4,5,6,7,8 The problem exists because of thelarge number of embryos transferred in treatment cycles, frequentlythree or even more. Clinicians and couples are under considerablepressure to maximize pregnancy rates, but there is a view thatmultiple gestation is an unacceptable consequence of these pressures.5,9Some have suggested that no more than two embryos need be transferred,10,11arguing that doing so will not necessarily result in a reductionin pregnancy rates. Others have indicated that transferringonly two embryos would be unduly restrictive and would in manyinstances reduce the chance of success.12,13,14,15
To address this issue, we examined the factors, including thenumber of embryos transferred, that predispose women undergoingin vitro fertilization to multiple gestation. This study extendsa previous analysis of treatment outcomes,16 and like the outcomestudy it was carried out with the data base established by theHuman Fertilisation and Embryology Authority that has recordedall cycles of in vitro fertilization carried out in the UnitedKingdom since 1991.
Methods
Subjects
We previously studied the factors affecting the outcome of invitro fertilization treatment, using data from 36,961 cyclesin 26,389 women registered in the Human Fertilisation and EmbryologyAuthority data base from 1991 to 1994. Using an extended database of all 78,325 cycles (in 34,430 women) initiated betweenAugust 1991 and April 1995, we analyzed in the current studythe factors affecting the likelihood of multiple births.
We excluded from this analysis 2478 cycles with donated eggsin 1689 women, 566 cycles with donated embryos in 398 women,10,611 transfers of frozen embryos in 7113 women, 4608 unstimulatedcycles in 3370 women, and 23,151 cycles in 15,051 women in whichone embryo or no embryo was transferred. Because of overlapbetween the categories, the total numbers of excluded cyclesand women were 34,089 and 9190, respectively. Thus, we analyzed44,236 cycles in 25,240 women. Of these women, 63 percent hadone treatment cycle, 20 percent had two, 8 percent had three,and 9 percent had more than three. Their mean (±SD) agewas 34±4 years (range, 18 to 52), and the mean durationof infertility was 6±4 years (range, 0 to 20). The indicationsfor in vitro fertilization were tubal disease (50 percent),unexplained infertility (35 percent), endometriosis (10 percent),and other conditions (12 percent); some women had more thanone indication. The factors analyzed were the woman's age, theduration and cause of infertility, previous in vitro fertilizationtreatment, previous live births and whether these were the resultof in vitro fertilization, number of eggs fertilized, and numberof embryos transferred. The outcome measures were rates of births(live births and perinatal deaths) and multiple births per embryotransfer. Seventy-eight centers contributed both treatment andoutcome data for the 44,236 cycles that formed the basis ofthis analysis. Permission to review the data was granted bythe information committee of the Human Fertilization and EmbryologyAuthority.
Statistical Analysis
The relation between age and birth rate was modeled by the methodof fractional polynomials,17 on the basis of a logistic-regressionanalysis that found that a linear relation with age was themost parsimonious. All other factors influencing the probabilityof a birth or of multiple births were evaluated by logistic-regressionanalysis with adjustment for age.
Age and duration of infertility were analyzed as continuousvariables. Twelve years was taken as the maximal duration; thefew women who had been infertile for more than 12 years wereassigned a value of 12. The number of eggs fertilized (two only,three or four, or more than four) and previous unsuccessfulattempts at in vitro fertilization (no previous attempt, oneto three previous attempts, or four or more previous attempts)were analyzed as categorical variables. Both forward and backwardselection methods were used to obtain the smallest number ofexplanatory variables that provided a well-fitting model; thedifference in deviance was used to assess whether any additionalterm was necessary in the model. The confidence intervals forthe odds of a birth and of multiple births according to thenumber of eggs fertilized and the number of embryos transferredwere derived from the logistic-regression analysis with useof the method of calculating the floating absolute risk.18
Results
Older age, the presence of tubal infertility, four or more previousattempts at in vitro fertilization, and longer duration of infertilityall significantly reduced both the odds of a birth and the oddsof multiple births (Table 1). Having had a previous live birth(whether the result of in vitro fertilization or not) increasedthe odds of a birth but not of multiple births.
Table 1. Factors Affecting the Results of in Vitro Fertilization.
The effect of the number of embryos transferred was analyzedin relation to the number of eggs fertilized (and thus the numberof embryos available for transfer) (Table 1). When only twoeggs were fertilized and available for transfer, the odds ofa birth, whether single or multiple, were reduced. When morethan two eggs were fertilized, the transfer of three embryosdid not significantly increase the chance of a birth (over thetransfer of two embryos), but it did increase the chances ofboth twin and triplet births (Table 2).
Table 2. Number of Single, Twin, and Triplet Births According to the Number of Eggs Fertilized and of Embryos Transferred, Unadjusted for Age or Other Factors.
The odds of a birth were then calculated in relation to theage of the woman, the number of eggs fertilized, and whethertwo or three embryos were transferred. In all age groups, ifmore than four eggs were fertilized, the odds of a birth wereno greater when three embryos were transferred than when twoembryos were transferred (Figure 1). However, the possibilityof multiple births did increase (Figure 2). Overall, when agewas taken into account, the odds of a birth increased significantlywith the number of eggs fertilized, whether two or three embryoswere transferred (Figure 3).
Figure 1. Odds of a Birth in Relation to the Woman's Age, Number of Eggs Fertilized, and Number of Embryos Transferred.
The odds of a birth were calculated as compared with those of a 30-year-old woman with more than four eggs fertilized and two embryos transferred (odds for this woman, 1.0).
Figure 2. Odds of Multiple Births in Relation to the Woman's Age, Number of Eggs Fertilized, and Number of Embryos Transferred.
The odds of multiple births were calculated as compared with those of a 30-year-old woman with more than four eggs fertilized and two embryos transferred (odds for this woman, 1.0).
Figure 3. Odds of a Birth in Relation to the Number of Eggs Fertilized and Number of Embryos Transferred, as Adjusted for Age.
The odds of a birth were calculated as compared with those of a woman with two eggs fertilized. The asterisk denotes P<0.001 for the comparison between two eggs and three or four eggs fertilized, regardless of whether two or three embryos were transferred. The dagger denotes P<0.001 for the comparison between three or four eggs and five or six eggs fertilized, regardless of whether two or three embryos were transferred. The I bars indicate 95 percent confidence intervals.
We used these data to construct a table to aid in clinical decisionmaking (Table 3). For this purpose we assumed that each womanhad tubal infertility, one to three previous attempts at invitro fertilization and embryo transfer, and no previous pregnancies.For ages 30, 35, and 40 years, the rates of births (per embryotransfer) and of multiple births (as a percentage of all births)were related to the number of eggs fertilized (and hence availablefor transfer) and the number of embryos transferred. When threeor four eggs were fertilized, the transfer of three embryos,as opposed to two, resulted in a small increase in the birthrate, but at the expense of an increase in the rate of multiplebirths. However, when more than four eggs were fertilized, thetransfer of three embryos did not improve the overall birthrate, but it did result in an increase in the rate of multiplebirths by 4 to 11 percentage points, depending on age.
Table 3. Rates of Births per Embryo Transfer and of Multiple Births as a Percentage of All Births, According to Maternal Age, Number of Eggs Fertilized, and Number of Embryos Transferred.
Discussion
In this large study, we found that an increase in the numberof embryos transferred invariably resulted in higher rates ofmultiple births, without necessarily improving the overall successrates of in vitro fertilization. Some studies have suggestedthat the pregnancy rate after the transfer of two embryos differslittle from that when more embryos are transferred.9,10,11 Otherstudies have suggested that the number of embryos transferred,particularly in older women, can be increased with little riskof multiple births. This assertion has been questioned,19,20and it is certainly true that in the United Kingdom women over40 years of age who are undergoing in vitro fertilization andembryo transfer still regularly give birth to twins and triplets.
As previously described in a detailed analysis using the samedata base,16 a number of patient characteristics, chiefly thewoman's age, diminish the likelihood that a pregnancy will occurafter in vitro fertilization. It is now apparent that many ofthese same characteristics also diminish the chances of multiplegestation. These include treatment for tubal infertility, manyprevious attempts at in vitro fertilization and embryo transfer,and long duration of infertility. However, in this study, wefound that in addition to these patient characteristics, thenumber of eggs fertilized, and hence the number of embryos availablefor transfer, was an important factor in determining outcome.
In spite of the wide variation in practices with respect toin vitro fertilization, it appears that in almost all circumstances,and certainly when more than four eggs have been fertilized,the number of embryos available is more important in determiningoutcome than the number of embryos actually transferred intothe uterus. When more than four eggs had been fertilized, thebirth rate was similar whether three or two embryos were transferred.Transfer of more embryos, however, increased the risk of multiplebirths. A 30-year-old woman choosing to have two embryos transferredrather than three reduced her risk of multiple birth from 39percent to 29 percent and nearly avoided altogether the riskof triplets (Table 3). Similarly, for a 40-year-old woman therewas no advantage in transferring three rather than two embryos.All that was achieved was an increase in the rate of multiplebirths from 23 percent to 27 percent.
These results come from centers with wide variations in clinicalpractice. The low success rate when only two eggs were fertilizedreflects the lack of choice among embryos for transfer, whereasthe increased choice when more than four eggs were fertilizedis reflected in higher pregnancy rates. Thus, the ability toselect embryos remains an important determinant of the outcomeof in vitro fertilization, despite the limitations of gradingthe quality of embryos according to morphologic criteria, asis done in current clinical practice. When three or even moreembryos selected from a larger number are transferred, therewill inevitably be a higher rate of multiple births.
The data presented here are also consistent with the suggestionthat uterine receptivity is likely to be an all-or-nothing effect.21When the uterus is receptive and the embryos have good implantationpotential, as seems more likely when they are chosen from alarge number, transfer of three will result in a higher chanceof twins or triplets than transfer of two. On the other hand,if the uterus is not receptive, a pregnancy will not occur,no matter how many embryos are transferred. Centers in whichthe embryos have a higher potential for implantation may bemore likely to reduce the number of embryos transferred in orderto minimize the rate of multiple births, whereas centers withlower pregnancy rates may continue to transfer three embryosin order to increase their pregnancy rates. However, this patterndoes not explain the significantly higher rates of multiplebirths when three embryos were transferred, nor was there anyevidence that this effect was a contributing factor when thetransfer policies of the individual centers were reviewed.
The implications of these results for clinical practice areclear. When more than four embryos are fertilized and available,transfer of only two embryos will not diminish the woman's chanceof becoming pregnant, but it will reduce her chance of multiplebirths. This is true for women of all ages. When only threeor four embryos are fertilized and the woman is about 40 yearsold, there may be a slight increase in the pregnancy rate whenthree embryos are transferred, but the risk of multiple birthswill also increase. When only two embryos are available fortransfer, these issues do not arise, but the couple should beprepared to accept a much lower pregnancy rate.
We are indebted to the staff of the Human Fertilisation andEmbryology Authority for providing the data for this analysis,in particular to Mr. Bill Parslow, Miss Joanne Thompson, andMr. Richard Baranowski; to Dr. Anne McLaren for her review ofthe manuscript and helpful comments; and to the individual clinicsregistered with the Human Fertilisation and Embryology Authorityfor data collection.
Source Information
From the Human Fertilisation and Embryology Authority, London (A.T.); and the Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, London (J.K.M.).
Address reprint requests to Professor Templeton at the Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Cornhill Rd., Aberdeen AB25 2ZD, Scotland.
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