1 The Fertility Institute of New Orleans, New Orleans, Louisiana, 2 Section of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Louisiana State University School of Medicine, New Orleans, Louisiana.
*Corresponding author at: The Fertility Institute of New Orleans, 6020 Bullard Avenue, New Orleans, Louisiana 70128. Tel.: 504 246 8971, Fax: 504 246 9778, e-mail: info{at}fertilityinstitute.com
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Abstract |
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Key words: assisted reproductive technology; in vitro fertilization; outcome measures; twin births; singleton births
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Introduction |
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The decision that a twin birth is a complication and that the only acceptable outcome of infertility treatment is a single live birth, is unnecessary, unsympathetic to couples who require ART or ovulation induction (OI) in order to achieve pregnancy, and based on incomplete information. In order to achieve this result, by which the quality of their program is measured, ART clinics would need to perform elective single embryo transfer (eSET) in all IVF cycles, and OI with clomiphene citrate (CC) or urinary and recombinant gonadotropins (GT), would have to be abandoned entirely. A singleton birth policy for ART and non-ART will multiply cost and discomfort for couples who require IVF, desire two children, and have no physical impediment to successful completion of a twin pregnancy. Extension of this policy to OI outside of ART will result in denial of pregnancy to many infertile couples who cannot conceive without OI and who are unable to have IVF because of economic or other reasons.
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Single versus double embryo transfer |
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Triplet and higher order pregnancies are one reason ART singletons and twins are born prematurely
A retrospective analysis of multiple pregnancies, diagnosed by ultrasound before the 7th week of gestation, found that 47% of triplet gestations and 35% of quadruplet gestations had undergone spontaneous reduction or had lost fetal heart activity by the 12th week of gestation, and were continuing as viable singletons or twins (Dickey et al., 2002). Additional unpublished analysis, presented in Table 1, shows that 15% of singleton births and 19% of twin births following IVF began as higher order gestations. Singleton births following IVF that began as single, twin, and triplet or higher order gestations were born 1.8 days, 5.0 days, and 12.4 days earlier, respectively, compared to spontaneous singleton births that began as single gestations. Twin births, due to IVF, that began as twin, triplet, and quadruplet or higher order gestations sacs were born 2.7 days, 6.2 days, and 18 days earlier, respectively, compared to spontaneous twin births that began as twin gestations. In the absence of spontaneous reduction from higher order gestations, the proportion of singletons due to IVF, born before 32 weeks, was not increased compared to spontaneously conceived singletons (1.1 versus 1.3%). Similarly the proportion of premature twins was only slightly increased (10.4 versus 9.5%) compared with spontaneously conceived twins.
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Twins due to ART/ICSI and OI account for a small proportion of all premature births
The increased incidence of perinatal mortality and later developmental abnormalities of twins, compared to singleton births, are principally related to a higher incidence of prematurity. However, twins whether natural or the result of infertility treatment, represent only 12% of all premature births in the US (Gardner et al., 1995). Twins due to ART, therefore, account for only 1.4% of total premature births in the US, and twins due to OI outside of ART account for only an additional 2.5% of total premature births. Furthermore, infants from multiple births have a greater chance of survival than singleton infants, of the same birth weight, gestational age, and ethnic origin (Draper et al., 1999
).
In the United States, babies born at 34 weeks develop normally and have few neonatal problems. Whereas twins as a group are at high risk for preterm birth, some women are clearly able to carry twins to 34 weeks and beyond without difficulty. We suggest that rather than requiring eSET for all ART patients and forbidding OI outside of ART because use of CC and GT might result in multiple pregnancies, it may be possible to identify women who would be at increased risk if they delivered twins so that IVF with eSET can be preferentially provided for those patients. Factors known to be associated with premature birth in multiple pregnancy include nulliparity (Blickstein et al., 2000), short stature (Blickstein et al., 2003
), and cervical length at 2426 weeks gestation (Imseis et al., 1997
).
ESHRE, WHO and ASRM recommendations
It is an encouraging that as yet, neither ESHRE, nor the World Health Organization (WHO) requires eSET for all patients. ESHRE recommendations state, eSET should be performed if a twin pregnancy is contraindicated and/or if a couple wishes to avoid a twin pregnancy at any cost, and eSET should be proposed in a first or second IVF/ICSI cycle in women <36 years of age if at least one good quality embryo is available (Land and Evers, 2003). The WHO recommended in September 2001 that no more than two embryos be transferred per cycle (Vayena et al., 2001
). The American Society for Reproductive Medicine (ASRM) guidelines recommend: transferring a maximum of two embryos for age <35, when there are at least three improved quality embryos and excess embryos available for cryopreservation; transferring a maximum of three embryos for age <35, when there are no more than three good quality embryos with none available for cryopreservation; transferring a maximum of four embryos for age 35 to 40; and transferring a maximum of five embryos for age 40 and above, or for multiple failed cycles (American Society for Reproductive Medicine, 1999
).
eSET results in significantly lower birth rates than eDET
An ESHRE Campus Course Report (2001), summarizing published data on eSET showed per cycle clinical pregnancy rates for eSET equal to rates for eDET. In contrast to those findings, the United States national IVF clinic results for 2001, provides unequivocal evidence that birth rates for eSET are significantly lower than for eDET, and also that birth rates are not increased when more that two fresh non-donor embryos are transferred (Centers for Disease Control and Prevention et al., 2003). The live birth rate per transfer, for patients with the most favorable prognosis, because of age less than 35 years with extra embryos cryopreserved for future use, was 30.0% for eSET and 51.7% for eDET. The live birth rate for all 387 clinics and 65,363 transfer cycles, performed during 2001 in the United States, was 11.3% for SET and 37.2% for DET. When three, four, or more than four embryos were transferred the live birth rate was less than 47% for patients with the most favorable prognosis, and less than 35% for all patients. These results indicate that, if eSET had been mandatory, the live birth rate for patients with the most favorable prognosis would have been reduced by 42%, and the birth rate for all patients might have been reduced by 70%. Until results from other national and multi-national databases, that include all patients as well as patients with favorable prognosis, are available, this data must be considered to represent the real consequences if a single embryo transfer policy was enforced for all patients.
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How should we measure ART success? |
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National ART reporting systems
National reporting systems are designed not only to gather health statistics and monitor clinical activity but also to allow couples to determine their own possibility of pregnancy and which ART programs offer them the best chance for success. In Sweden, two independent surveillance systems are employed, the one concerned with clinical specific results, the other concerned with follow-up of the health of IVF children (Nygren 2002). Swedish clinical results include the proportion of singleton, duplex and triplet or higher order deliveries per cycle, per ovum aspiration, and per embryo transfer in five-year age intervals, the number of embryos replaced in relation to pregnancy outcome, and the proportion of children born with low birth weight. In the United States, the national reporting system is similar to Swedens except that the percent of children born with low birth weight, and the clinic specific pregnancy rate per embryo transferred is not reported, and age intervals are different (Schieve et al., 2002
). In the United States, clinic-specific information is available to everyone on the internet at http://www.cdc.gov/nccdphp/drh/art.htm
Comparisons of individual ART programs based on births rates per cycle are subject to bias
In the United States and elsewhere, some ART programs withhold IVF treatment from patients who they believe have a poor prognosis because of age 38 years, low antral follicle counts, or elevated basal FSH levels, and urge oocyte donation or adoption instead (Bansci et al., 2002
). Other programs provide treatment to similar patients even though they are more likely to have cycles cancelled before oocyte retrieval, and are less likely to become pregnant if they do have oocyte retrieval (Fratterelli et al., 2000
; Bansci et al., 2002
). ART programs differ concerning cancellation policies when fewer than four preovulatory follicles develop; some programs proceed to retrieval when there are as few as one or two follicles. Most ART programs in the United States offer a trial of OI with CC or GT and intrauterine insemination (IUI) to patients without tubal obstruction, but other programs take similar patients directly to IVF. The percentage of second, third, and latter ART cycles differs between programs. Success rates per cycle initiated, or per intent to treat, cannot reliably indicate the comparative success of ART programs nor the probability that an individual patient will become pregnant, unless only first ART cycles are compared, both the number of antral follicles and age are identical, patients have received the same treatment previously, and cancellation and transfer policies are similar.
No single measure of ART success is ideal, therefore outcome reports should include as much information as possible
Measurements of ART success that are independent of patient characteristics and patient selection or cancellation policies, are required to compare ART programs. The effect of antral follicle numbers and pretreatment screening, but not previous treatment, can be mitigated to some extent by measuring success as live birth rate per retrieval or per embryo transfer. Other measures that have been proposed are the number of oocytes retrieved (Fratterelli et al., 2000), number of quality embryos per oocyte, and implantation rate. Because none of these are ideal, more than one measure must be used.
Outcome measures should include all healthy live births, both single and multiple, per cycle with the percentage of premature births indicated for each. The percentage of cycle cancellations and number of embryos cryopreserved should be reported, because these indicate the proportion of patients with high and low prognosis for success admitted to treatment. Outcome measures used to compare ART programs must at a minimum be stratified by age and antral follicle number, number of previous ART and non ART cycles, and should exclude patients with excessive FSH levels. The number of mature follicles per cycle initiated, stratified by patient age and antral follicle count, in patients who have not had previous cycles of OI or ART, is possibly the most accurate outcome measure with which to compare drug stimulation regimens. The live birth rate, both twin and singleton, at 34 weeks and later, per first oocyte retrieval cycle, stratified by age, antral follicle count, semen quality, tubal status, and previous treatment, is arguably the most accurate outcome measure with which to compare individual ART programs.
In the future, preimplantation genetic diagnosis (PGD) may make single embryo transfer practical for all patients because it offers the possibility of identifying and transferring only embryos that are chromosomally normal. For the present, only the most serious genetic defects are being diagnosed by PGD and the procedure is as yet too expensive to allow use in all IVF/ICSI (Robertson, 2003). If PGD becomes widely used, it will be necessary to report outcome separately for patients who have PGD before transfer.
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Conclusions |
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References |
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Submitted: 11 November, 2003 ; accepted: 16 December 2003