The ketogenic diet, which is characterised by a drastic reduction in carbohydrate intake and an increase in the proportion of fat in the diet, is increasingly being used as a therapeutic measure for various diseases such as epilepsy, diabetes and even neurological disorders. However, the effects of such a diet during pregnancy have so far been little researched. This study provides new insights into the potential risks and benefits of a ketogenic diet during prenatal development.
Fewer female offspring and lower birth mass
The ketogenic diet was administered for 10 days during pregnancy (G8.5 to G18.5), a critical phase of organogenesis during which most of the embryo's organs develop. The diet consisted of 84% fat, 11% protein and 5% carbohydrate. After birth, the lactating females and later the offspring after weaning were kept on a standard diet to separate the effects of the prenatal diet from postnatal influences. The study included two cohorts of mice reared under different housing conditions in France and Austria. The results were consistent in both cohorts, which emphasises the robustness of the data.
The researchers found that a 10-day ketogenic diet (KD) led to a reduction in litter size and an imbalanced sex ratio, with male offspring surviving more frequently. Female embryos were more susceptible to the negative effects of the diet, possibly leading to increased embryonic mortality. In addition, female offspring in the KD group had a lower birth weight, but this normalised by day 16 of life. ‘Our results show that female offspring are particularly sensitive to the metabolic changes induced by a ketogenic diet during pregnancy,’ explains Sarah M. Zala, lead author of the study and researcher at the Konrad Lorenz Institute of Ethology at the Vetmeduni.
The study emphasises that the increased susceptibility of female embryos may be due to the specific sensitivity of female placentas to dietary changes. Previous studies have shown that female placentas react more strongly to the fat composition of the diet, which could lead to increased vulnerability.
Shortened lifespan in male offspring
In the long term, male offspring in the KD group were found to have increased body mass and a significantly shorter lifespan in later life. Female offspring were less affected. ‘The fact that male offspring had a shorter lifespan in later life is concerning and suggests that the effects of a ketogenic diet during pregnancy may extend well beyond birth,’ says Sarah M. Zala.
The researchers found that the male offspring in the KD group had significantly higher body mass from around two and a half years of age, which persisted until their natural death. Interestingly, this mass gain was not due to obesity, as no excessive fat accumulation was observed. However, the exact causes of the increased body mass remain unclear and require further investigation.
No long-term metabolic or behavioural changes
Despite the differences in lifespan and body mass, the researchers found no evidence of long-term metabolic changes or behavioural abnormalities such as anxiety or depression in the offspring. The offspring's metabolic profiles, including blood glucose and ketone body levels, remained within the normal range, and no differences were found in spontaneous activity or in tests of anxiety and depression susceptibility. ‘Our results suggest that the ketogenic diet during pregnancy has no lasting metabolic or behavioural effects on the offspring, at least not in the parameters tested,’ says Diana Zala, last author of the paper from the Institute of Psychiatry and Neuroscience of Paris, France.
Pathological examinations and reproductive capacity
Pathological examinations showed no differences in the incidence of tumours between the KD and control groups. This is particularly noteworthy as previous studies have indicated that ketogenic diets can reduce the incidence of certain types of tumours in adult mice. The reproductive capacity of the offspring was also unaffected by the diet.
According to the researchers, further studies are needed to better understand the underlying mechanisms and to more accurately assess the risks of a ketogenic diet during pregnancy. In particular, future studies should investigate the epigenetic changes that could be triggered by the diet, as well as the potential effects on brain development and ageing.
The article “Sex-dependent effects of a gestational ketogenic diet on offspring birth and lifespan” by Sarah M. Zala, Renata Santos, Eva Strasser, Alice Schadder, Sarah Kugler, Verena Strauss, Anna Kübber-Heiss and Diana Zala was published in PLOS One.