Cryopreserved embryo transfer is an independent risk factor for placenta accreta

Cryopreserved embryo transfer is a strong predictor of placenta accreta among patients using in vitro fertilization and/or intracytoplasmic sperm injection. This increased risk may be associated with the thinner endometrial linings and lower estradiol levels characteristic of these cycles.

Daniel J. Kaser, M.D., Alexander Melamed, M.D., M.P.H., Charles L. Bormann, Ph.D., Dale E. Myers, Sc.M., Stacey A. Missmer, Sc.D., Brian W. Walsh, M.D., Catherine Racowsky, Ph.D., Daniela A. Carusi, M.D., M.Sc.

Volume 103, Issue 5, Pages 1176-1184


To explore the association between cryopreserved embryo transfer (CET) and risk of placenta accreta among patients utilizing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI).

Case-control study.

Academic medical center.

All patients using IVF and/or ICSI, with autologous or donor oocytes, undergoing fresh or cryopreserved transfer, who delivered a live-born fetus at ≥24 weeks of gestation at our center, from 2005 to 2011 (n = 1,571), were reviewed for placenta accreta at delivery.

Cases of accreta (n = 50) were matched by age and prior cesarean section to controls (1:3) without accreta. The association between CET and accreta was modeled using conditional logistic regression, controlling a priori for age and placenta previa. Receiver operating characteristic curves were used to determine thresholds of endometrial thickness and peak serum E2 levels related to accreta.

Main Outcome Measure(s):
Placenta accreta.

Univariate predictors of accreta were non-Caucasian race (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.25–6.47); uterine factor infertility (OR 5.80, 95% CI 2.49–13.50); prior abdominal or laparoscopic myomectomy (OR 7.24, 95% CI 1.92–27.28); and persistent or resolved placenta previa (OR 4.25, 95% CI 1.94–9.33). In multivariate analysis, we observed a significant association between CET and accreta (adjusted OR 3.20, 95% CI 1.14–9.02), which remained when analyses were restricted to cases of accreta with morbid complications (adjusted OR 3.87, 95% CI 1.08–13.81). Endometrial thickness and peak serum E2 level were each significantly lower in CET cycles and those with accreta.

Cryopreserved ET is a strong independent risk factor for accreta among patients using IVF and/or ICSI. A threshold endometrial thickness and a “safety window” of optimal peak E2 level are proposed for external validation.

  • Shvetha Zarek

    This study has attracted attention in the pediatric/neonatology field as one explanation for increasing placenta accreta. However, of the 50 cases of placenta accreta, 33 were defined by the obstetrician, not by a histopathology sample, stating that the placenta was “adherent”, a highly subjective term. Could the authors kindly comment on how confident they are (based on perhaps additional descriptors in the medical charts) that the descriptive term “adherent” correlates to placenta accreta? How did the obstetricians come to this conclusion? If it is based on the duration of the third stage of labor, this may be more operator dependent, especially in a teaching institution. Any additional information the authors have is greatly appreciated.

    • Daniel Kaser

      Thank you for this important question. Placenta accreta as a histologic vs. clinical diagnosis has been an important issue in the area of research (of surgical obstetrics?). In the absence of hysterectomy with an in-situ placenta, a firm pathologic diagnosis may not be obtainable. Therefore, researchers have used clinical diagnoses, including difficulty creating a separation plane between the placenta and uterus (“adherent”), or excessive bleeding encountered in an attempt to remove an adherent placenta. We used both of these definitions in addition to histopathology (when available). If review of a surgeon’s operative note was not clear, we spoke directly with those surgeons whenever possible to obtain their intended meaning. Ultimately, it is hard to conceive of another condition that will cause a placenta to “adhere” to the uterus other than some level of cellular myometrial invasion.
      With some clinically-defined as well as histopathologically-confirmed accretas, we found that the outcomes were not always morbid for the patients (in terms of hemorrhaging or requiring additional surgical procedures). Given that some readers may find only the morbid cases to be clinically relevant, we separately analyzed the results using only morbid accreta cases, and obtained the same results observed the same association between accreta and cryopreserved embryo transfer. Thus, we hypothesize that simple “adherence,” marked difficulty removing a placenta, and pathologic diagnosis of accreta lie on a single pathophysiologic spectrum.

      From: Daniela Carusi, MD, MSc, Brigham & Women’s Hospital, Boston, MA

      • Shvetha Zarek

        Thank you for the additional information and the due diligence on the authors’ part in confirming with the primary obstetrician on the diagnosis of an adherent placenta. Thank you for your comments.

  • ranjithrama

    This is an interesting study suggesting risk of cryopreserved ET for placenta accreta. Can the authors propose a mechanism for why CET and not FET would cause this increased risk?

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