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Research Letter |

Safety of Assisted Reproductive Technology in the United States, 2000-2011 FREE

Jennifer F. Kawwass, MD1; Dmitry M. Kissin, MD, MPH2; Aniket D. Kulkarni, MBBS, MPH2; Andreea A. Creanga, MD, PhD2; Donna R. Session, MD1; William M. Callaghan, MD, MPH2; Denise J. Jamieson, MD, MPH2 ; for the National ART Surveillance System (NASS) Group
[+] Author Affiliations
1Division of Reproductive Endocrinology and Infertility, Emory University School of Medicine, Atlanta, Georgia
2Division of Reproductive Health, US Centers for Disease Control and Prevention, Atlanta, Georgia
JAMA. 2015;313(1):88-90. doi:10.1001/jama.2014.14488.
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Published online

Use of assisted reproductive technology (ART) continues to increase in the United States and globally. In an effort to improve patient safety, stimulation protocols have become less aggressive, oocyte retrieval has transitioned from laparoscopic to transvaginal, and pregnancy rates have improved.1 However, limited data exist regarding the incidence of maternal complications.2 We explored incidence and trends in reported patient and donor complications in fresh ART cycles using the US Centers for Disease Control and Prevention National ART Surveillance System (NASS).

NASS is a federally mandated reporting system that collects cycle-level ART procedure information.3 As of 2011, NASS included 97% of cycles and 94% of all US ART clinics.4 Annually, 7% to 10% of reporting clinics undergo data validation (does not include complication variables).4

Reported complications (defined as having been directly related to ART and occurring within 12 weeks of cycle initiation) include infection, hemorrhage requiring transfusion, moderate or severe ovarian hyperstimulation syndrome (OHSS), medication adverse event, anesthetic complication, hospitalization, patient death within 12 weeks of stimulation, and other complications. We report severe OHSS and severe or moderate OHSS in a single category because the delineation between categories is subjective. We also report maternal death prior to infant birth.

Separate analyses using SAS version 9.3 (SAS Institute Inc) and SUDAAN version 11.0 (RTI International) were performed for autologous and donor cycles. We report complications (absolute numbers and rates/10 000 cycles annually) and maternal death prior to infant birth/100 000 ART-conceived live births from 2000-2011. The 2-sided α level was .05. Bivariable linear regression (complication rate as outcome, calendar year as explanatory variable) was used to assess trends over time.

The Centers for Disease Control and Prevention institutional review board approved this study; a waiver of informed consent was obtained.

Among 1 135 206 autologous cycles, the most commonly reported patient complications were OHSS (peak of 153.5/10 000 autologous cycles; 95% CI, 146.0-161.3) and hospitalizations (peak of 34.8/10 000 autologous cycles; 95% CI, 30.9-39.3); rates of other complications remained below 10/10 000 cycles (Table 1). Rates declined from 2000-2011 for reported medication adverse events (P = .02) and hospitalizations (P < .001); no other significant trends were detected among reported infections, hemorrhages, OHSS, severe OHSS, anesthetic-related complications, and deaths within 12 weeks of stimulation start or during pregnancy (P > .10 for trend for all tests).

Table Graphic Jump LocationTable 1.  Patient Complications in Fresh, Autologous ART Cycles as Reported to the US CDC National ART Surveillance System, 2000-2011

Fifty-eight total deaths were reported (18 stimulation-related and 40 maternal deaths prior to infant birth). No temporal patterns were noted. Of the 40 maternal deaths, 16 women carried a singleton, 16 carried twins, 2 carried triplets or higher-order multiples, and 6 did not report plurality. The maternal death rate ranged from 1.6 per 100 000 ART-conceived live births in 2008 to 14.2 in 2004.

Reported complications following donor ART cycles (n = 112 254) were less frequent; none showed a significant trend (P > .05 for trend for all tests; Table 2). The most common donor complications were OHSS (peak of 31.0/10 000 cycles; 95% CI, 22.9-44.3) and hospitalizations (peak of 10.5/10 000 cycles; 95% CI, 5.5-20.1). Rates of other complications remained below 5/10 000 cycles. No donor deaths were reported; 13 maternal deaths prior to infant birth were reported among oocyte donor recipients.

Table Graphic Jump LocationTable 2.  Oocyte Donor Complications in Fresh, Donor ART Cycles as Reported to the US CDC National ART Surveillance System, 2000-2011

In the United States from 2000-2011, autologous and donor ART procedures were associated with low reported stimulation and surgical complication risks; no concerning trends or patterns were identified. The most frequently reported complication among autologous and donor cycles was OHSS, though less frequent in donor cycles. Obstetric mortality was rare.

The lack of significant change in most adverse events may reflect the low baseline rate of such occurrences, making it harder to detect temporal change.

This study is the first, to our knowledge, to quantify US ART-associated patient risks. A 1984-2008 report from the Netherlands found a higher ART-related maternal death rate (42.5/100 000 pregnancies) compared with our study (peak of 14.2/100 000 pregnancies).5 Underreporting of complications remains an inherent limitation of surveillance systems6 and must be considered when interpreting our findings. Additionally, our outcomes are cycle-based rather than patient-based, validation does not include complication variables, and available data do not explain the noted trends.

Increased awareness of the most common complication, OHSS, may prompt additional study to characterize predictors of this and other adverse events to inform the development of effective approaches necessary to decrease complication occurrence.

Section Editor: Jody W. Zylke, MD, Deputy Editor.

Group Information: The NASS group are listed at the end of the article.

Corresponding Author: Jennifer F. Kawwass, MD, 550 Peachtree St, Atlanta, GA 30308 (jennifer.kawwass@gmail.com).

Author Contributions: Dr Kawwass had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kawwass, Kissin, Kulkarni, Session, Callaghan, Jamieson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kawwass, Creanga, Callaghan, Jamieson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kulkarni, Creanga.

Administrative, technical, or material support: Kissin, Creanga.

Study supervision: Kissin, Session, Jamieson.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Group Information: The NASS Group is composed of the following additional members (all with the Division of Reproductive Health, US Centers for Disease Control and Prevention [CDC]) who contributed to the data collection but received no financial compensation: Sheree Boulet, DrPH, MPH, Jeani Chang, MPH, Sara Crawford, PhD, Allison Mneimneh, MPH, CPM, Mithi Sunderam, PhD, and Yujia Zhang, PhD. Pedro Moro, MD, MPH (Division of Healthcare Quality Promotion, CDC), participated in the critical revision of the manuscript but did not receive any financial compensation.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

Wang  J, Sauer  MV.  In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Ther Clin Risk Manag. 2006;2(4):355-364.
PubMed   |  Link to Article
de Ziegler  D, Gambone  JC, Meldrum  DR, Chapron  C.  Risk and safety management in infertility and assisted reproductive technology (ART): from the doctor’s office to the ART procedure. Fertil Steril. 2013;100(6):1509-1517.
PubMed   |  Link to Article
Adashi  EY, Wyden  R.  Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures. JAMA. 2011;306(10):1135-1136.
PubMed   |  Link to Article
Centers for Disease Control and Prevention; Society for Assisted Reproductive Technology. 2010 Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta, GA: US Dept of Health and Human Services; 2012.
Braat  DDM, Schutte  JM, Bernardus  RE, Mooij  TM, van Leeuwen  FE.  Maternal death related to IVF in the Netherlands 1984-2008. Hum Reprod. 2010;25(7):1782-1786.
PubMed   |  Link to Article
Schoendorf  KC, Branum  AM.  The use of United States vital statistics in perinatal and obstetric research. Am J Obstet Gynecol. 2006;194(4):911-915.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Patient Complications in Fresh, Autologous ART Cycles as Reported to the US CDC National ART Surveillance System, 2000-2011
Table Graphic Jump LocationTable 2.  Oocyte Donor Complications in Fresh, Donor ART Cycles as Reported to the US CDC National ART Surveillance System, 2000-2011

References

Wang  J, Sauer  MV.  In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Ther Clin Risk Manag. 2006;2(4):355-364.
PubMed   |  Link to Article
de Ziegler  D, Gambone  JC, Meldrum  DR, Chapron  C.  Risk and safety management in infertility and assisted reproductive technology (ART): from the doctor’s office to the ART procedure. Fertil Steril. 2013;100(6):1509-1517.
PubMed   |  Link to Article
Adashi  EY, Wyden  R.  Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures. JAMA. 2011;306(10):1135-1136.
PubMed   |  Link to Article
Centers for Disease Control and Prevention; Society for Assisted Reproductive Technology. 2010 Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta, GA: US Dept of Health and Human Services; 2012.
Braat  DDM, Schutte  JM, Bernardus  RE, Mooij  TM, van Leeuwen  FE.  Maternal death related to IVF in the Netherlands 1984-2008. Hum Reprod. 2010;25(7):1782-1786.
PubMed   |  Link to Article
Schoendorf  KC, Branum  AM.  The use of United States vital statistics in perinatal and obstetric research. Am J Obstet Gynecol. 2006;194(4):911-915.
PubMed   |  Link to Article
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