Laird Harrison

February 18, 2013

SAN FRANCISCO, California — A large population-based trial has shown that using frozen/thawed embryos produces good overall outcomes. In fact, by some measures, the outcomes are better than with fresh in vitro fertilization (IVF).

These findings, from the Committee on Nordic Assisted Reproductive Technology and Safety (CONARTAS) trial, support the practice of transferring 1 embryo at a time and freezing surplus embryos for later use.

"I think the primary message should be that cryopreservation is safe for most infants," lead researcher Ulla-Britt Wennerholm, MD, from Sahlgrenska University in Göteborg, Sweden, told Medscape Medical News.

In contrast, transferring more than 1 fresh embryo at a time carries a much higher risk for twin pregnancies, which leads to a higher incidence of preterm birth, low birth weight, small size for gestational age, mortality, and risks to the mother, she explained.

It is not clear why frozen/thawed embryos are healthier than fresh ones, said Dr. Wennerholm during her presentation here at the Society for Maternal-Fetal Medicine 33rd Annual Meeting.

Cryopreservation is safe for most infants.

"It is estimated that the number of children born after IVF now exceeds more than 5 million," she said. "Worldwide, the use of frozen embryo replacement has increased since the first child in 1984."

For this large population-based study, Dr. Wennerholm and colleagues collected data from all IVF treatments in Denmark, Norway, and Sweden from 1982 to 2007.

They compiled data on 6647 babies born after frozen/thawed embryo replacement, 42,222 born after conventional IVF, and more than 288,000 born to the general population.

The mothers who underwent cryopreservation were older than the mothers who underwent conventional IVF, who were older than the mothers who conceived naturally. When comparing outcomes, the researchers made adjustments for maternal age, parity, child sex, and year of birth.

The odds ratios were significantly lower in the cryopreservation group than in the fresh IVF group for preterm and very preterm birth, low birth weight, and low for gestational age. "But higher odds ratios were found for post-term birth, large for gestational age, macrosomia, and perinatal mortality, with a borderline increased risk of infant mortality," Dr. Wennerholm reported.

Table. Adjusted Odds Ratios for Outcomes After Frozen/Thawed Embryo Replacement, After Conventional IVF, and in the General Population

Outcome Frozen/Thawed vs General Population Frozen/Thawed vs Conventional IVF
Preterm birth 1.49 0.84
Very preterm birth 2.68 0.79
Low birth weight 1.27 0.81
Very low birth weight 1.69 0.87
Large for gestational age 1.29 1.45
Small for gestational age 1.18 0.72
Macrosomia 1.29 1.58
Perinatal mortality 1.39 1.58
Infant mortality 1.92 1.50

At first glance, the higher risk for mortality in the cryopreservation group appears to make this a more dangerous procedure. However, Dr. Wennerholm told Medscape Medical News that this statistic is misleading because not very many of the embryos or infants died in either group.

"I think it is very important to look at the absolute risk in figures, not only the relative risk," she said. "It is a very small difference, but because of the large sample size we get a statistical significance. The perinatal mortality in the cryopreservation group was 0.71% and in the fresh IVF group was 0.61%," she explained.

Dr. Wennerholm noted that it is not clear what is causing the differences between frozen/thawed embryos and fresh IVF, but she outlined some hypotheses.

"It may be a positive selection of a better quality of embryos or healthier women," she said. "But several studies show higher birth weight in cryo-singletons than in fresh IVF [singletons born to] the same woman."

Another explanation could be the use of natural cycles in cryopreservation, in contrast to the controlled ovarian stimulation often used in conventional IVF, she said. In addition, cryoprotectants or the culture media could cause epigenetic modifications.

Study Limitations

Dr. Wennerholm acknowledged some study limitations. Notably, the researchers were not able to collect data on variables such as body mass index, socioeconomic status, smoking, or years of infertility. They also did not have information on vitrification or cleavage stage.

After her presentation, an audience member called for a return to old-fashioned conception. "Shouldn't we take action?" he asked. "Many of these indications could be replaced by something we call home conception.... We're creating another problem."

Dr. Wennerholm agreed that more children should be conceived naturally.

Another audience member wondered if the researchers noted any trends over time. According to Dr. Wennerholm, "the trend toward gestational age was significantly increased over time, but nothing else."

This study, although interesting, should not discourage anyone from conventional IVF, said Robert Silver, MD, professor of obstetrics and gynecology at the University of Utah, Salt Lake City, when asked by Medscape Medical News to comment.

"The absolute risk is low, so families undergoing IVF should be assured that it's a safe procedure," he said.

The researchers and Dr. Silver have disclosed no relevant financial relationships.

Society for Maternal-Fetal Medicine (SMFM) 33rd Annual Meeting: Abstract 30. Presented February 14, 2013.