Letter to the editor |
Reply to: ‘Multiple-birth risk associated with IVF and extended embryo culture: USA, 2001’
1 Women’s Health and Fertility Branch, Division of Reproductive Health, NCCDPHP, Centers for Disease Control and Prevention, Atlanta, USA
2 To whom correspondence should be addressed at: Women’s Health and Fertility Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, 4770 Buford Highway NE, MS K-34, Atlanta, GA 30341-3724, USA. E-mail: Dtk3{at}cdc.gov
Sir,
We appreciate the interest of Surrey et al. in our analyses of multiple-birth risk associated with extended embryo culture.
Dr Surrey and colleagues are concerned that we chose multiple-birth risk and multiple pregnancy risk as outcome measures instead of presenting our results by multiple order (twins, triplets, etc.). We chose not to separate multiple pregnancies and births by the number of fetuses and infants because our focus is on the overall multiple birth problem, as it is one of the major public health issues pertaining to assisted reproductive technology (ART) and because, as Surrey et al. acknowledge, ‘all multiple pregnancies are associated with a higher risk than that associated with singleton pregnancies.’ Twin pregnancies and births, although to a lesser extent than higher order multiples, carry significant risks (Kiely, 1998
; Senat at al., 1998; Martin and Park, 1999; ESHRE Capri Workshop Group, 2000; Martin et al., 2002; Pharoah, 2002; Novak et al., 2003). Furthermore, twin births account for the vast majority (
90%) of the multiple-birth burden among ART patients. Thus, from a public health perspective, the total multiple-birth risk, which combines twin and higher order multiple births, is the appropriate outcome measure.
In our study of ART procedures performed in the USA in 2001, we found that extending culture to the blastocyst stage (day 5) was associated with the transfer of fewer embryos (average: 2.3) compared to transferring at the cleavage stage (day 3, average: 3.0 embryos). This extention of the culture period, however, did not result in a decrease of the total multiple-birth risk. Surrey et al. call attention to the point that blastocyst transfers are associated with a decrease of high-order multiple births. This is an important achievement: the proportion of live-born triplets and higher order multiples was lower when embryos were transferred on day 5 (2.7%) compared to day 3 (4.1%). During the same time period, however, the twin birth rate associated with day 5 transfers (36.4%) was higher than that associated with day 3 transfers (31.2%), as was the total risk of multiple births (39.2 versus 35.3%). Our analyses suggest that transferring more than one blastocyst may not have a clear impact on the multiple-birth problem, despite the reduced risk of high order multiple births. We agree with Surrey et al. that further research is needed to characterize the best candidates for single embryo transfer, a procedure that is still infrequent in the USA, accounting for <10% of all embryo transfers.
We recognize that the criteria used by clinics to determine whether patients undergo a 3 day or a 5 day embryo transfer may vary. However, those clinics that transferred exclusively on day 3 or on day 5 accounted for only 5% of all transfers in our sample, indicating that most clinics have adopted both procedures. Thus, the differences we observed are unlikely to be confounded by this clinic characteristic.
We acknowledged that our data were not from a randomized clinical trial comparing transfer of embryos on day 3 and on day 5. However, the large sample size allowed us to stratify our results by the most important predictors of live birth and multiple birth (i.e. the number of embryos transferred, the patient’s age, the day of embryo transfer, and the availability of supernumerary embryos). The latter variable is a surrogate measure of embryo quality, but it has been shown to be an important predictor of ART outcomes (Templeton and Morris, 1998; Schieve et al., 1999) and has been used as one of the criteria of embryo quality in ART practice guidelines (American Society for Reproductive Medicine, 1999; Practice Committee of SART and ASRM, 2004). To explore the possibility of residual confounding, we further restricted our analyses using such predictors of pregnancy and live-birth rates as the number of oocytes retrieved, the use of assisted hatching, ICSI, FSH level, a diagnosis of diminished ovarian reserve, and the number of previous ART procedures or births. These additional analyses confirmed the pattern of association, suggesting that our original stratification by the key predictive factors had captured most of the variability and is appropriate for use in analyses of ART success rates and multiple-birth risk.
While our analysis was not specifically designed to assess the impact of recent changes in ART practice guidelines, our data may nonetheless serve as the baseline for a future impact assessment. As ART use and the proportion of children born as the result of ART continue to grow in the USA and globally, surveillance of ART success rates and adverse effects will become an increasingly higher public health priority. We hope that our analyses of ART surveillance data in the USA will continue to contribute to the body of evidence used to inform ART practice guidelines and may serve as a tool for assessing their impact.
References
American Society for Reproductive Medicine (1999) Guidelines on Number of Embryos Transferred. A Practice Committee Report: A Committee Opinion. ASRM, Birmingham, AL.
ESHRE Capri Workshop Group (2000) Multiple gestation pregnancy. Hum Reprod 15,1856–1864.
Kiely JL (1998) What is the population-based risk of preterm birth among twins and other multiples? Clin Obstet Gynecol 41,3–11.[CrossRef][Web of Science][Medline]
Martin JA and Park MM (1999) Trends in twin and triplet births: 1980–1997. Natl Vital Stat Rep 47,1–16.[Medline]
Martin JA, Hamilton BE and Ventura SJ (2002) Births: final data for 2001. Natl Vital Stat Rep 51,1–104.[Medline]
Novak E, Blickstein I, Papiernik E and Keith L (2003) Iatrogenic multiple pregnancies. Do they complicate perinatal care? J Reprod Med 48,601–609.[Web of Science][Medline]
Pharoah PO (2002) Neurological outcome in twins. Semin Neonatol 7,223–230.[CrossRef][Medline]
Practice Committee of Society for Assisted Reproductive Technology and American Society for Reproductive Medicine (2004) Guidelines on the number of embryos transferred. Fertil Steril 82,773–774.[CrossRef][Medline]
Schieve LA, Peterson HB, Meikle SF, Jeng G, Danel I, Burnett NM and Wilcox LS (1999) Live-birth rates and multiple-birth risk using in vitro fertilization. J Am Med Assoc 282,1832–1838.
Senat MV, Ancel PY, Bouvier-Colle MH and Breartt G (1998) How does multiple pregnancy affect maternal mortality and morbidity? Clin Obstet Gynecol 41,78–83.[Medline]
Templeton A and Morris JK (1998) Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. New Engl J Med 339,573–577.
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