Wednesday February 11 2015
Obesity can increase the risk of complications in pregnancy
“Damaging effect of obesity on a woman’s eggs can now be reversed,” is the potentially misleading headline from the Mail Online today.
The over-egged headline refers to a mouse study showing that signs of lower fertility due to obesity could be reversed using experimental drugs. This was not tested in humans, however.
Maternal obesity is known to lower the chance of successful conception, as well as increasing the risk of miscarriage.
The study compared the fertility of mice before and after they became obese due to a genetic condition that makes them overeat. When given IVF drugs, their fertility at the start was similar to mice of a healthy weight, but as the mice became obese, their fertility reduced. They became less able to develop eggs, and any eggs produced were less likely to be fertilised. The researchers also found that once obese, there was reduced activity of mitochondria (the part of the cell that converts food to energy) in the eggs.
All of these effects were reversed if the obese mice were given either a drug called Salubrinal or BGP-15. BGP-15 is an experimental, unlicensed drug that is being trialled for use in people with type 2 diabetes.
The study does not prove that the reduced mitochondrial activity causes obesity in the offspring, but it is a plausible explanation that will require further research.
The immediate impact of this research to women is minimal, as this is very early stage research. However, the study does reinforce the message that women should maintain a healthy weight before pregnancy.
Where did the story come from?
The study was carried out by researchers from the University of Adelaide, Monash University, and the Baker IDI Heart and Diabetes Institute in Melbourne. It was funded by the National Health and Medical Research Council of Australia, the Operational Infrastructure Support Program of the Government of Victoria, and the Women’s and Children’s Hospital Foundation.
The study was published in the peer-reviewed journal Development.
In general, the media headlines implied that these drugs have been tested on women, when this is not the case. For example, the Mail Online’s article did not mention that the research was carried out on mice, and had not actually been tested for this use in humans. This means we don’t know if the drug would have the same effect in people as it does in mice.
The Independent’s coverage was more balanced. It acknowledged the mouse origins of the research, but could have done more to spell out why this was a limitation. The article usefully included a quote from Professor Adam Balen, “a leading expert in reproductive medicine at the University of Leeds, and chair of the British Fertility Society” who said: “while any drug treatment was a long way off, the findings were ‘very interesting’”. He added that the important message to take away from this study is that: “women [need] to be nutritionally healthy before they get pregnant”.
What kind of research was this?
This was an animal study looking at the effect of obesity on fertility in mice.
Previous animal studies have indicated that obesity affects the metabolism and growth of offspring, and rat studies have shown that obesity alters the egg before fertilisation. The authors also highlight that overweight women are more likely to require assisted reproduction, and the success rates are lower.
The researchers had already done studies using obese female mice to investigate what biological changes obesity might be causing. They found that mice fed high-fat diets had eggs with signs of intracellular stress. This included higher fat content, increased reactive oxygen species and altered mitochondria. Mitochondria are the parts of the cell that convert food to energy and feature heavily in the debate on whether three-parent fertility technology can or should be used in the UK.
In this study, they wanted to see whether this alteration in mitochondria was associated with reduced fertility, whether it is passed on to the offspring, and whether it affected the weight of the growing foetus. They also wanted to find out if the use of two experimental drugs that reduce intracellular stress could reverse these changes.
What did the research involve?
The researchers compared the fertility of obese mice with healthy-weight mice in a variety of experiments.
Mice with a genetic disorder similar to Alstrom syndrome in humans were used, and compared to mice of a healthy weight. This syndrome causes overeating that leads to severe obesity, increased insulin and diabetes, despite eating a low-fat diet.
The mice were given IVF drugs to stimulate their eggs to become ready for fertilisation. The following aspects were measured, comparing mice before and after they had become obese with healthy-weight mice:
- the number of eggs stimulated by IVF drugs
- the level of mitochondria activity in the eggs
- the number of eggs able to be fertilised
- weight of the growing foetus when implanted into mice of a healthy weight
The researchers then repeated the experiments after giving obese mice an experimental drug once per day for four days, to see if this could reverse the effects of obesity on the eggs and their development. The drug was either:
- Salubrinal – an experimental drug that reduces cell stress responses
- BGP-15 – an experimental drug that has been shown to protect against obesity-induced insulin resistance in mice. It is currently undergoing human trials for type 2 diabetes
What were the basic results?
Before the mice were obese, the same number of eggs developed after stimulation with IVF drugs as in healthy-weight mice. After they were obese, a reduced number of eggs were produced. This indicated that the fertility of the mice was affected by obesity, rather than the syndrome.
When obese mice were given either Salubrinal or BGP-15 for four days before the IVF drugs, the number of eggs developed more than doubled and was almost the same as for the healthy-weight mice. The number of eggs also increased when these drugs were given to healthy-weight mice.
The eggs of obese mice had indications of higher levels of intracellular stress and decreased mitochondrial activity. Obese mice given either drug did not have reduced mitochondrial activity.
Fewer fertilised eggs from obese mice survived compared to healthy-weight mice by four hours after fertilisation, or two days later. The same numbers survived if they were given IVF before they had become obese, or if obese mice had been given either Salubrinal or BGP-15.
When they implanted the fertilised eggs into normal-weight mice, compared to foetuses from healthy-weight mice:
- foetuses from obese mice were significantly heavier
- foetuses from obese mice given Salubrinal or BGP-15 were the same weight
How did the researchers interpret the results?
The researchers concluded that eggs from obese mice give rise to foetuses that are heavier and have reduced mitochondrial activity. They say that obesity causes intracellular stress in the eggs. They found that if either of two experimental drugs were given before fertilisation, this could reverse the following effects of obesity:
- reduced response to IVF drugs
- reduced mitochondrial activity
- reduced fertilisation rate
- developing foetus of increased weight
This mouse study has shown that obesity reduces fertility, but the exact mechanism remains unclear. It found that eggs from obese mice had reduced mitochondrial activity compared to when the mice were of a healthy weight, and this reduced mitochondrial activity is evident in the growing foetus. The researchers give a plausible explanation that it is the damaged mitochondria that causes the reduced fertility and increased weight; however, this is just a theory. The study does not prove that obesity causes reduced mitochondrial activity or that this would cause the offspring to be obese. The weight of the growing foetuses of obese mice was greater, but none were born.
Strengths of the study include the type of obese mice used (which are known as “Blobby mice” in Australia). Mice with this syndrome become obese regardless of the type of food they eat, because of the volume they consume. In this experiment, the researchers did not want to compare healthy-weight mice with obese mice that had become so because of just eating a high-fat diet, as this could confound the results.
While studies of other mammals such as mice are useful, they cannot tell us exactly what happens in humans. It is known that fertility rates improve when women who are overweight or obese lose weight, and this can be achieved through small changes such as increasing your activity levels and reducing your intake of calories.
The drugs in this trial are not yet available for humans, other than BGP-15 in a trial for type 2 diabetes. Neither of them have been tested in any fertility trials on humans. For further tips on improving your fertility, see our fertility pages.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.