Kate Johnson

November 06, 2014

HONOLULU — The risk for placenta accreta is 3 times higher in pregnancies achieved with in vitro fertilization using frozen embryo transfer than in those using fresh embryos, according to a new study.

This study "is the first to date to show that cryopreserved embryo transfer is indeed a strong independent risk factor for accreta, after controlling for important variables in multivariate analysis," said lead investigator Dan Kaser, MD, from the Brigham and Women's Hospital and Harvard Medical School in Boston.

Only one previous study, conducted in Japan, has demonstrated an association between frozen embryo transfer and placenta accreta (Fertil Steril. 2014;101:128-133). However, "it did not control for known risk factors of accreta, such as placenta previa, previous cesarean delivery, and other uterine surgery," Dr Kaser told Medscape Medical News here at the American Society for Reproductive Medicine 2014 Annual Meeting.

The finding is of particular concern given that some fertility centers are moving away from fresh embryo transfer because of fewer preterm births and low birthweights after frozen embryo transfer.

The study involved 1571 women who delivered at least one viable infant at a gestational age of at least 24 weeks after undergoing either in vitro fertilization or intracytoplasmic sperm injection.

Patients who had undergone in vitro fertilization or intracytoplasmic sperm injection were identified through a medical record review. The 51 women with accreta were matched for maternal age at delivery and history of cesarean delivery with a control group of 149 women without accreta.

On univariate analysis, predictors of accreta were cryopreserved embryo transfer, nonwhite race, uterine factor infertility, previous myomectomy, and placenta previa, the researchers report.

First to date to show that cryopreserved embryo transfer is indeed a strong independent risk factor for accreta.

On multivariate analysis, cryopreserved embryo transfer was a strong independent predictor of accreta after three confounders of frozen embryo transfer and accreta — primigravidity, nonwhite race, and uterine factor infertility — as well as age and previous placenta previa, were controlled for (adjusted odds ratio [aOR], 3.2; P = .03).

When the analysis was restricted to cases of morbid placenta accreta — defined as hemorrhage of more than 1000 mL or any transfusion, major surgical morbidity such as hysterectomy or uterine artery embolization, or minor surgical morbidity — the association was even stronger (aOR, 3.87; P = .04).

"There is currently no clear explanation" for the association, Dr Kaser told Medscape Medical News. "An unresolved question is whether the increased risk of accreta is due to embryo freeze–thaw per se, or rather, more generally, to transfer of an embryo to a nonstimulated uterus," he said.

No Explanation

"We don't think it is related to method of freezing; we exclusively used slow-frozen embryos, and the Japanese study exclusively used vitrified embryos. We also don't think it is the stage of embryo development, because nearly all transfers in our study were at the cleavage stage. The Japanese study included day 3 and day 5 transfers and reported no difference between the two."

But peak serum estradiol was significantly lower in women who developed accreta than in those who did not, and endometrial thickness was an average of 2 mm thinner in accreta cycles, said Dr Kaser.

"The high serum estradiol from fresh stimulation is known to prevent trophoblastic invasion and can lead to pregnancy complications such as pre-eclampsia and fetal growth restriction. We observed the opposite effect; namely, low serum estradiol was associated with excessive trophoblastic invasion and an increased risk of accreta," he explained.

"The study is compelling and adds to other data suggesting an increased risk of placenta accreta with frozen-thawed embryo transfer," said Deirdre Lyell, MD, medical director of the placental disorders program at the Lucile Packard Children's Hospital, Stanford University, in California.

"There appear to be competing perinatal benefits and maternal risks with frozen-thawed embryo transfer. The best approach should be determined individually, between the patient and her doctor, based on the patient's reproductive and medical history and her preferences," she told Medscape Medical News.

Dr Kaser said his group is currently evaluating whether there are potentially modifiable risk factors associated with frozen embryo cycles, such as endometrial thickness, peak serum estradiol, and mode of uterine preparation, that could mediate this observed effect.

Dr Kaser and Dr Lyell disclosed no relevant financial relationships.

American Society for Reproductive Medicine (ASRM) 70th Annual Meeting: Abstract O-298. Presented October 22, 2014.


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