The choice of culture media for nurturing embryos before implantation in assisted reproduction procedures had no major impact on live birth rates, but did affect pregnancy rates and birth weight in a Dutch randomized trial.
The G5 media formulation was not only linked to significantly higher rates of implantation and clinical pregnancy, but significantly lower birth weights than the HTF formulation, reported Sander H.M. Kleijkers, MSc, of Maastricht University Medical Center in the Netherlands, and colleagues, writing in Human Reproduction.
"Understandably, there are multiple environmental influences which will also have an effect on embryo growth, pregnancy success and delivery outcome, but emphasis needs to be placed on the selection of the tiny drop of 'growth-support fluid' which inevitably has a vital role," Matthew VerMilyea, PhD, of Ovation Fertility, a national fertility service provider, told MedPage Today via email. VerMilyea was not involved with the research.
Kleijkers and colleagues performed a multi-center, double-blind clinical trial of 836 couples -- with 417 randomized to G5 and 419 to HTF embryo culture media. The culture media were used in all treatment cycles, including frozen transfer cycles, for up to 1 year of treatment.
Live birth rates in the G5 group were higher than in the HTF group but the difference fell short of statistical significance (44.1% versus 37.9%, P=0.08).
However, the G5 group showed significant differences in other IVF/ICSI outcomes compared to the HTF group: rates of clinical pregnancy were significantly higher (47.7% versus 40.1%, P=0.03), as were the number of embryos transferred or cryopreserved per cycle (2.8 versus 2.3, P<0.001).
There were also significant differences in birth outcomes, with infants in the G5 group born with significantly lower birth weights versus the HTF group, albeit with a wide confidence interval (mean difference 158 g, 95% CI 42 to 275 g, P=0.008). Multivariable-adjusted analyses showed similar results.
"Despite the absence of a statistical significance in the difference in live birth rate, we conclude that G5 provides better treatment success than HTF, as other outcomes that are relevant for IVF and correlate to live birth rate, all significantly favored G5," the authors wrote. However, they also noted that more than 20 other media formulations for embryo culture are currently on the market.
Implications for Child Health
The potential clinical implications of culture media to impact birth outcomes were examined in a separate review of literature by Arne Sunde, PhD, of St. Olav's University Hospital in Trondheim, Norway, and colleagues. They investigated the impact of assisted reproductive technology on birthweight, specifically citing the "developmental origin of health and disease" hypothesis, which suggested that birthweight can impact a child's cardiometabolic health years down the road.
But the results from this review were inconclusive. Sunde's group said that a number of caveats exist about specifically linking culture media to birth outcomes. Still, they found that there have been certain differences in assisted reproductive technology treatment linked to differences in outcomes -- in the case of fresh versus frozen embryos. Prior research showed that children born following frozen embryo transfer were linked to higher mean birth weight and were at increased risk of being large for gestational age.
The authors noted that a prior evidence review had attempted to investigate the association between birthweight and the type of culture medium used, and found decidedly mixed evidence -- five studies suggested an association, while six studies did not. Sunde and colleagues concluded that the relationship between the two is "unclear," and more research may be needed to explore any potential impact of different ART treatments on children.
"If a relationship between the culture medium used and certain perinatal outcomes ... such as birthweight is found to be true, it is still too early to know the long-term effect on health," they wrote.
Call for Increased Regulation
The results of this study also raised a larger issue -- namely that manufacturers in the European Union are not required to list all the ingredients in culture media, which have the potential to influence birth outcomes. In the EU, culture media are considered a class III medical device.
Hans Evers, MD, Human Reproduction's editor-in-chief, told MedPage Today via email that the laws governing the marketing of culture media differ greatly from drug companies, where regulations on new medicines are much tougher.
"For me, as a doctor, it is of great concern that companies marketing culture media do not have to disclose the exact composition of their media," said Evers. "Drug companies have to detail all components of new drugs and have to provide proof from RCT's that their drugs really offer an added value to those on the market already, [but] so far, companies making embryo culture media do not have such an obligation. It's high time for some legal rules in this respect."
Evers argued further in an accompanying editorial that the composition of culture media varies by manufacturer, with products showing "high degrees of variability." He also said that because their exact composition is unknown, this limits the option to link specific ingredients with IVF outcomes.
"[We] therefore advocate that the complete formulation of culture media should be disclosed ... and all subsequent changes should be justified, validated and communicated at once to their end-users by the manufacturers," Evers wrote. "Changes should be made to the existing regulatory system to achieve transparency and improve monitoring of outcomes to the long-term benefit of ART children."
The FDA did not respond to a request for comment from MedPage Today, but VerMilyea said that in his experience, there is no requirement to list the ingredients of culture media in the U.S., but some manufacturers do. However, the relative proportions of ingredients are heavily guarded and proprietary.
"As there are multiple commercially available culture media on the market, these findings should lead to an increase awareness of the selection and implementation of products into the IVF laboratory and a more transparent approach from the manufacturers as to specific ingredients," VerMilyea argued.