Children conceived by frozen embryo transfer are significantly more likely to be large for gestational age at birth than those conceived naturally or by fresh embryo transfer.

Population-based studies from both France and Denmark have come to the same conclusion: Compared with fresh embryos, frozen embryos are up to 60% more likely to develop into large for gestational age (LGA) infants.

No one can yet be sure of the mechanism behind this finding, which also has been observed in Asian studies, Dr. Anja Pinborg said at the annual meeting of the European Society of Human Reproduction and Embryology. It may be related to the oocyte transfer, to keeping the embryo an extra day in the culture media, or even to something in the culture media itself.

"It may also be [an] example of epigenetic changes in the very early embryos caused by freezing and thawing," said Dr. Pinborg of Rigshospitalet, Copenhagen. "At this point all we have are theories. We need much more data to understand this. But I think it is important that we do understand more."

Dr. Pinborg presented the results of the Danish study, which included data on 910 singleton pregnancies conceived by frozen embryo transfer, 9,603 from fresh embryo transfer, and 4,656 conceived naturally.

The rate of LGA infants was 17% in the frozen embryo group – significantly higher than the 10% rate in the fresh embryo group and 11% rate in the natural conception group.

After adjusting for maternal age and parity, and the babies’ gender and birth year, frozen embryo infants were 60% more likely to be LGA than fresh embryo infants.

The number of infants with a birth weight of more than 4,500 g also was significantly higher in the frozen embryo group (6%) than in the fresh embryo and naturally conceived group (3% each).

"When we look at it from the other end – babies who are small for gestational age (SGA) – we see the reverse pattern," Dr. Pinborg said. The rate of SGA infants was 9% in the frozen embryo group, 15% in the fresh embryo group, and 11% in the naturally conceived group. After adjusting for the confounding factors, frozen embryo infants were 40% less likely to be SGA than fresh embryo infants.

The group also looked at the incidence of placenta previa – a factor associated with SGA infants. The incidence was 0.5% in the frozen embryo group, 1.5% in the fresh embryo group, and 0.3% in the naturally conceived group. The adjusted odds ratio of placenta previa was 2.8 for the frozen versus natural conception group and 5.0 for the fresh versus natural conception group.

Dr. Pinborg said the study has three key messages. "The first is a positive message: Children born after frozen embryo transfer have obstetrical outcomes similar to naturally conceived children. But our study also shows that these children are at a significantly increased risk of being large for gestational age and having a birth weight of more than 4,500 g. At this point, we don’t know the implications of this message. But in general, all children born by assisted reproductive technology do very well and have no problems."

The French study, presented by Dr. Sylvie Epelboin of the Bichat-Claude Bernard Hospital, Paris, came to similar conclusions about birth weight.

The French cohort consisted of 16,002 singleton pregnancies conceived by assisted reproductive technology (ART); 2,140 (13%) were frozen embryo transfer. The control group consisted of the 13,862 fresh embryo transfer pregnancies.

The gestational age at birth was slightly, but not significantly, younger in the frozen embryo group (39.1 vs. 39.3 weeks). The rate of preterm birth was also similar (8.6% in the frozen group and 8.3% in the fresh group). Neonatal mortality was less than 0.25% in each group.

Measures of weight were the only statistically significant between-group differences, Dr. Epelboin said.

The mean birth weight was 102 g higher in the frozen embryo group than in the fresh embryo group, while the incidence of low birth weight (less than 2,500 g) was significantly lower in the frozen embryo group.

Using the 90th percentile, the incidence of LGA births was significantly higher in the frozen embryo than the fresh embryo group (13% vs. 9%). The difference was also significant when comparing the 95th percentile (7% vs. 5%).

The good news, Dr. Epelboin said, is that embryo freezing does not adversely affect neonatal outcome, particularly in the risk of giving birth to a SGA infant.

Again, she said, there are only theories about the mechanism behind larger babies from frozen embryos. The finding may be related to the process of freezing and thawing, or perhaps to differences in the hormonal environment and its effect on the endometrium.

The study was sponsored by the ART Follow-Up Scientific Board. Dr. Epelboin said she had no relevant financial disclosures. Dr. Pinborg also reported no relevant financial disclosures.

Frozen Embryos More Likely to Develop Into Bigger Babies