Luke, B., Brown, M. B., Wantman, E., Lederman, A., Gibbons, W., Schattman, G. L., Lobo, R. A., Leach, R. E., & Stern, J. E. (2012). Cumulative birth rates with linked assisted reproductive technology cycles. The New England journal of medicine, 366(26), 2483-91. https://doi.org/10.1056/NEJMoa1110238
Luke B, Brown MB, Wantman E, Lederman A, Gibbons W, Schattman GL, Lobo RA, Leach RE, Stern JE. Cumulative birth rates with linked assisted reproductive technology cycles. The New England journal of medicine. 2012;366(26):2483-91. doi:10.1056/NEJMoa1110238
Luke, B., et al. "Cumulative birth rates with linked assisted reproductive technology cycles." The New England journal of medicine, vol. 366, no. 26, 2012, pp. 2483-91.
For EndNote, Zotero or Mendeley:
Open access
Free to read
No reuse license
Open Access
Free full text on PubMed Central (PMC3623697)
Abstract
Background
Live-birth rates after treatment with assisted reproductive technology have traditionally been reported on a per-cycle basis. For women receiving continued treatment, cumulative success rates are a more important measure.
Methods
We linked data from cycles of assisted reproductive technology in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for the period from 2004 through 2009 to individual women in order to estimate cumulative live-birth rates. Conservative estimates assumed that women who did not return for treatment would not have a live birth; optimal estimates assumed that these women would have live-birth rates similar to those for women continuing treatment.
Results
The data were from 246,740 women, with 471,208 cycles and 140,859 live births. Live-birth rates declined with increasing maternal age and increasing cycle number with autologous, but not donor, oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates with autologous oocytes had declined from 63.3% and 74.6%, respectively, for women younger than 31 years of age to 18.6% and 27.8% for those 41 or 42 years of age and to 6.6% and 11.3% for those 43 years of age or older. When donor oocytes were used, the rates were higher than 60% and 80%, respectively, for all ages. Rates were higher with blastocyst embryos (day of transfer, 5 or 6) than with cleavage embryos (day of transfer, 2 or 3). At the third cycle, the conservative and optimal estimates of cumulative live-birth rates were, respectively, 42.7% and 65.3% for transfer of cleavage embryos and 52.4% and 80.7% for transfer of blastocyst embryos when fresh autologous oocytes were used.
Conclusions
Our results indicate that live-birth rates approaching natural fecundity can be achieved by means of assisted reproductive technology when there are favorable patient and embryo characteristics. Live-birth rates among older women are lower than those among younger women when autologous oocytes are used but are similar to the rates among young women when donor oocytes are used. (Funded by the National Institutes of Health and the Society for Assisted Reproductive Technology.).
Abstract Is conception using in vitro fertilization (IVF) associated with the multiple congenital anomaly pattern referred to as VACTERL? Children conceived through IVF were more than twice as likely to develop VACTERL compared to those naturally conceived (OR 2.57, 95% CI 1.93-3.39). VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) is a multiple congenital anomaly pattern with a likely multifactorial origin, as few genetic or non-genetic risk factors have been identified. Some studies have suggested a potential link between IVF and VACTERL, yet this relationship has not been thoroughly investigated while accounting for other maternal characteristics. Given the rarity of VACTERL, large datasets with comprehensive information on fertility treatment parameters, maternal characteristics, and birth outcomes are essential to better understand this association. Study design, size, duration
We performed a population-based study of live births in four U.S. states (Massachusetts, New York, North Carolina, and Texas) between 2004 and 2018, linking birth records and birth defect data to IVF cycles reported in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Naturally conceived births were selected as controls at a 10:1 ratio during the same period as the IVF birth. The study included a total of 1,315,867 live births. Participants/materials, setting, All study children were linked to state birth defect registries, with defects classified using British Pediatric Association codes. VACTERL cases were identified by code 759.890 or the presence of at least three associated anomalies. Children with known chromosomal or other genetic syndromes were excluded. Logistic regression was used to assess the association between IVF conception and VACTERL. Covariates included maternal age, race/ethnicity, education, and state. Main We identified 363 cases of VACTERL - 78 conceived through IVF (0.053%) and 285 naturally conceived (0.024%). Of these, 232 cases were identified using the diagnostic code 759.890, while 131 additional cases were identified by at least three of the six VACTERL associated anomalies. The most frequent VACTERL congenital anomalies were cardiac defects (54%), followed by renal anomalies (50%) and anal atresia (32%). In unadjusted analysis, IVF was significantly associated with an increased prevalence of VACTERL (OR 2.27, 95% CI 1.75-2.89). After adjusting for maternal socio-demographics, the association was further strengthened (OR 2.57, 95% CI 1.93-3.39) and supported in sensitivity analyses restricted to 1,226,080 singletons (OR 2.74, 95% CI 1.92-3.83). Evaluation of specific IVF treatment parameters (n = 141,882) revealed the highest prevalence of VACTERL in 58 of 102,099 births from fresh embryos (0.057% vs. 0.050% from thawed embryos), 41 of 69,765 births from ICSI (0.059% vs. 0.052% without ICSI), and 27 of 48,629 births from male infertility (0.056% vs. 0.055% without male infertility). Refining our multivariable model of IVF, we found that use of ICSI without a diagnosis of male infertility had the strongest association with VACTERL of all IVF groups (OR 3.04, 95% CI 1.90-4.65) compared to natural conceptions. Limitations, We were unable to assess familial clustering and terminations in the prevalence of VACTERL. However, our analyses are representative of live births and we accounted for maternal characteristics associated with both birth defect risks and the use of fertility treatment. The use of IVF is associated with VACTERL in offspring, but the absolute risk for VACTERL in IVF-conceived offspring remains low. The mechanisms underlying this association are unclear, but altered DNA methylation patterns have been implicated in both IVF and VACTERL etiology. No
Luke B et al., 2022·Human reproduction (Oxford, England)·Free full text on PubMed Central
Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated wi [truncated]
Stern JE et al., 2022·F&S reviews·Free full text on PubMed Central
Numerous studies have demonstrated that assisted reproductive technology (ART: defined here as including only in vitro fertilization and related technologies) is associated with increased adverse pregnancy, neonatal, and childhood developmental outcomes, even in singletons. The comparison group for many had often been a fertile population that conceived without assistance. The Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART) was initiated to define a subfertile population with which to compare ART outcomes. Over more than 10 years, we have used the MOSART database to study pregnancy abnormalities and delivery complications but also to evaluate ongoing health of women, infants, and children. This article will review studies from MOSART in the context of how they compare with those of other investigations. We will present MOSART studies that identified the influence of ART and subfertility/infertility on adverse pregnancy (pregnancy hypertensive disorder, gestational diabetes, placental abnormality) and delivery (preterm birth, low birthweight) outcomes as well as on maternal and child hospitalizations. We will provide evidence that although subfertility/infertility increases the risk of adverse outcomes, there is additional risk associated with the use of ART. Studies exploring the contribution of placental abnormalities as one factor adding to this increased ART-associated risk will be described.
Spector LG et al., 2019·JAMA pediatrics·Free full text on PubMed Central
In vitro fertilization (IVF) is associated with birth defects and imprinting disorders. Because these conditions are associated with an increased risk of childhood cancer, many of which originate in utero, descriptions of cancers among children conceived via IVF are imperative. To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally. A retrospective, population-based cohort study linking cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System from January 1, 2004, to December 31, 2012, that resulted in live births from September 1, 2004, to December 31, 2013, to the birth and cancer registries of 14 states, comprising 66% of United States births and 75% of IVF-conceived births, with follow-up from September 1, 2004, to December 31, 2014. The study included 275 686 children conceived via IVF and a cohort of 2 266 847 children, in which 10 births were randomly selected for each IVF birth. Statistical analysis was performed from April 1, 2017, to October 1, 2018. In vitro fertilization. Cancer diagnosed in the first decade of life. A total of 321 cancers were detected among the children conceived via IVF (49.1% girls and 50.9% boys; mean [SD] age, 4.6 [2.5] years for singleton births and 5.9 [2.4] years for multiple births), and a total of 2042 cancers were detected among the children not conceived via IVF (49.2% girls and 50.8% boys; mean [SD] age, 6.1 [2.6] years for singleton births and 4.7 [2.6] years for multiple births). The overall cancer rate (per 1 000 000 person-years) was 251.9 for the IVF group and 192.7 for the non-IVF group (hazard ratio, 1.17; 95% CI, 1.00-1.36). The rate of hepatic tumors was higher among the IVF group than the non-IVF group (hepatic tumor rate: 18.1 vs 5.7; hazard ratio, 2.46; 95% CI, 1.29-4.70); the rates of other cancers did not differ between the 2 groups. There were no associations with specific IVF treatment modalities or indication for IVF. This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.
Related research
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
Outcomes of in vitro fertilization (IVF) treatment are traditionally reported as pregnancies per IVF cycle. However, a couple's primary concern is the chance of a live birth over an entire treatment course. We estimated cumulative live-birth rates among patients undergoing their first fresh-embryo, nondonor IVF cycle between 2000 and 2005 at one large center. Couples were followed until either discontinuation of treatment or delivery of a live-born infant. Analyses were stratified according to maternal age and performed with the use of both optimistic and conservative methods. Optimistic methods assumed that patients who did not return for subsequent IVF cycles would have the same chance of a pregnancy resulting in a live birth as patients who continued treatment; conservative methods assumed no live births among patients who did not return. Among 6164 patients undergoing 14,248 cycles, the cumulative live-birth rate after 6 cycles was 72% (95% confidence interval [CI], 70 to 74) with the optimistic analysis and 51% (95% CI, 49 to 52) with the conservative analysis. Among patients who were younger than 35 years of age, the corresponding rates after six cycles were 86% (95% CI, 83 to 88) and 65% (95% CI, 64 to 67). Among patients who were 40 years of age or older, the corresponding rates were 42% (95% CI, 37 to 47) and 23% (95% CI, 21 to 25). The cumulative live-birth rate decreased with increasing age, and the age-stratified curves (< 35 vs. > or = 40 years) were significantly different from one another (P<0.001). Our results indicate that IVF may largely overcome infertility in younger women, but it does not reverse the age-dependent decline in fertility.
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
Smith ADAC et al., 2015·JAMA·Free full text on PubMed Central
The likelihood of achieving a live birth with repeat in vitro fertilization (IVF) is unclear, yet treatment is commonly limited to 3 or 4 embryo transfers. To determine the live-birth rate per initiated ovarian stimulation IVF cycle and with repeated cycles. DESIGN, SETTING, Prospective study of 156,947 UK women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. In vitro fertilization, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers. Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted, and conservative cumulative live-birth rates were estimated, reflecting 0%, 30%, and 100%, respectively, of women who discontinued due to poor prognosis and having a live-birth rate of 0 had they continued. Among the 156,947 women, the median age at start of treatment was 35 years (interquartile range, 32-38; range, 18-55), and the median duration of infertility for all 257,398 cycles was 4 years (interquartile range, 2-6; range, <1-29). In all women, the live-birth rate for the first cycle was 29.5% (95% CI, 29.3%-29.7%). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65.3% (95% CI, 64.8%-65.8%) of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes, the live-birth rate for the first cycle was 32.3% (95% CI, 32.0%-32.5%) and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (95% CI, 67.8%-68.9%). For women aged 40 to 42 years, the live-birth rate for the first cycle was 12.3% (95% CI, 11.8%-12.8%), with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (95% CI, 29.7%-33.3%). For women older than 42 years, all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner-related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference. Among women in the United Kingdom undergoing IVF, the cumulative prognosis-adjusted live-birth rate after 6 cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4.
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
To examine the cumulative conception rate and live birth rate in women undergoing IVF and to assess the influence of prognostic factors on cumulative conception rate and discontinuation of treatment. Retrospective analysis of data from couples undergoing IVF. Assisted conception unit of a university hospital. PATIENT(S): Two thousand fifty-six patients undergoing 2708 cycles of IVF from April 1992 to March 1999. MAIN OUTCOME MEASURE(S): Cumulative conception rate by age, number of oocytes retrieved, and embryos transferred, and the influence of these factors on dropout rates. RESULT(S): The cumulative conception rate and cumulative live birth rate after four attempts were 75% and 66%, respectively. The cumulative conception rate differed significantly between women 35 years of age or younger and those older than 35 years who had five or more oocytes retrieved (83% vs. 63%). When fewer than five oocytes were retrieved in women 35 years of age or younger, the cumulative conception rate decreased to 33%. Overall, 36% of patients continued treatment after the first attempt; these patients were more likely to have more than five oocytes retrieved and more than two embryos available for transfer. The cumulative conception rate was greater when the female partner was 35 years of age or younger and had more than five oocytes retrieved and more than two embryos were available for transfer. These factors influenced dropout rates.
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
Data on 575 couples undergoing 1057 consecutive cycles of in vitro fertilization (IVF) were used to calculate cumulative pregnancy rates for repeated IVF cycles. Excluding preclinical abortions and couples in whom the male partner had poor semen parameters, calculated cumulative pregnancy rates for cycles 1 to 6 were 13.6%, 24.8%, 37.2%, 47.8%, 52.2%, and 59.6%, respectively. A parametric model used to fit these data yielded a strong correlation between observed and predicted pregnancy rates (r = 0.99, P less than 0.001). Predicted cumulative pregnancy rates after 9 and 12 cycles were 75% and 84%, respectively. Excluding preclinical abortions, the pregnancy rate per cycle was approximately constant, at approximately 15% over repeated cycles. As the cost of IVF declines and as treatment cycles become more easily tolerated, persistence in IVF can lead to successful pregnancy for a large proportion of couples.
Assisted Reproduction › Outcomes and Effectiveness › Cumulative Versus Per Cycle Reporting · Longevity and Reproductive Aging › Age and Fertility › Age and Treatment Outcomes
PMID 22738098 22738098 DOI 10.1056/NEJMoa1110238 10.1056/NEJMoa1110238 Luke et al. 2012, Luke 2012
Cite this article
Luke, B., Brown, M. B., Wantman, E., Lederman, A., Gibbons, W., Schattman, G. L., Lobo, R. A., Leach, R. E., & Stern, J. E. (2012). Cumulative birth rates with linked assisted reproductive technology cycles. The New England journal of medicine, 366(26), 2483-91. https://doi.org/10.1056/NEJMoa1110238
Luke B, Brown MB, Wantman E, Lederman A, Gibbons W, Schattman GL, Lobo RA, Leach RE, Stern JE. Cumulative birth rates with linked assisted reproductive technology cycles. The New England journal of medicine. 2012;366(26):2483-91. doi:10.1056/NEJMoa1110238
Luke, B., et al. "Cumulative birth rates with linked assisted reproductive technology cycles." The New England journal of medicine, vol. 366, no. 26, 2012, pp. 2483-91.