Raikkonen K, Martikainen S, Pesonen A-K et al. (2017) Maternal licorice consumption during pregnancy and pubertal, cognitive and psychiatric outcomes in children. Am J Epidemiol 185(5): 317-328 http://bit.ly/2ornFJT

In a nutshell
This longitudinal cohort study, conducted in Finland, found that high maternal consumption of liquorice during pregnancy was associated with poorer cognitive performance and higher prevalence of behaviour problems in the adolescent offspring at a mean age of 12.5 years. Advanced pubertal maturation in girls at this age was also found to be associated with high maternal liquorice consumption during pregnancy.

Background
It is now well accepted that the quality of the maternal diet and exposure to adverse events (such as illness or stress) during pregnancy can increase the risk of negative health outcomes in the offspring across the lifespan. However, much more research is required to understand the specific aspects of the maternal diet and life experiences that influence this ‘programming’ of life-long health in the growing fetus, and the mechanisms underpinning these effects.

Fetal exposure to maternal cortisol – the ‘stress hormone’ – is thought to be the mechanism by which maternal stress impacts negatively on fetal neurodevelopment. Liquorice contains the natural compound glycyrrhizin, which is known to inhibit breakdown of maternal cortisol and thus increase fetal exposure. The implication is that maternal liquorice consumption may have negative effects on fetal neurodevelopment by increasing exposure to cortisol in the same way as maternal stress. Evidence in support of this hypothesis was found in an earlier study by Raikkonen and colleagues who examined the cognitive abilities and prevalence of behavioural issues of the same cohort as the present study when the offspring were aged 8 years (Raikkonen et al. 2009). This follow-up study was conducted to see if the effects of high maternal liquorice consumption during pregnancy on offspring cognition and behaviour persist into early adolescence and also to examine whether high maternal liquorice consumption during pregnancy was associated with earlier puberty in the offspring, evidence for which has been found in animal studies but not previously explored in humans.

Study objective
The study examined whether high maternal consumption of liquorice during pregnancy was associated with earlier pubertal maturation in the offspring and also if the associations with cognitive performance and prevalence of behaviour problems previously found when the offspring were 8 years of age persisted through to the adolescent period.

Study design
This longitudinal cohort study involved mothers and their offspring, born in 1998 in Helsinki, Finland where liquorice is a popular snack. Data were collected from 1049 women on their weekly liquorice consumption during pregnancy just after their babies had been born, using a retrospective food frequency questionnaire specific to liquorice-containing foods. Between 2009 and 2011, these women were followed up and 378 agreed to have their child’s (mean age 12.5 years) pubertal maturation, cognitive abilities, cortisol levels and any behavioural problems assessed, which were the main outcome measures of the present study. Data were also collected about a variety of maternal, paternal, neonatal and adolescent background factors which were included as covariates in the analyses. Of the 378 participants followed-up, based on the mother’s intake of liquorice during pregnancy, 327 were classified as ‘zero-to-low’ consumers of glycyrrhizin (0-249 mg/week; mean 47 mg/week) and 51 as ‘high’ consumers (≥500 mg/week; mean 845 mg/week) and differences between the offspring of these two groups in the main outcome measures were assessed.

Key results
Adolescent boys and girls whose mothers were classified as high consumers of glycyrrhizin during pregnancy, compared to those whose mothers were classified as low-to-zero consumers, were found to:

  • score an average of 7 points lower (on a 100 point-scale) on tests of intelligence quotient;
  • have threefold higher odds of attention deficit/hyper-activity disorder problems (self-reported by the mother);
  • have similar cortisol levels.

These findings were generally consistent with the children’s cognitive performance and behavioural issues examined when they were 8 years of age (Raikkonen et al. 2009).

Adolescent girls whose mothers were classified as high consumers of glycyrrhizin during pregnancy, compared to those whose mothers were classified as low-to-zero consumers, were found to:

  • have a higher Body Mass Index (BMI) by 2.2 points, on average;
  • be heavier by 8.1 kg, on average;
  • be closer to their expected adult target height;
  • be more advanced in puberty (self-reported by the mother).

Boys showed no consistent associations between maternal glycyrrhizin consumption and pubertal maturity.

Authors’ conclusions
‘The present findings suggest that pregnant women should be informed that consumption of licorice and other food products containing glycyrrhizin may be associated with harm for their developing offspring’.

Limitations
The study was observational in design and therefore provides evidence for associations between high maternal glycyrrhizin consumption during pregnancy and poorer cognitive performance and higher prevalence of behavioural issues, and early pubertal maturation, in the adolescent offspring but further research is required to determine whether high maternal glycyrrhizin consumption during pregnancy caused these effects. It is possible that there are factors, such as the families’ socioeconomic status, not controlled for in the analyses, which might explain the reported associations.

It is important to note that the number of children with mothers classified as ‘high’ consumers of glycyrrhizin during pregnancy was relatively small (51) and much lower than those classified ‘low-to-zero’ consumers (327). Furthermore, for the analyses that split the cohort by sex (i.e. for pubertal maturation), the group sizes were as low as 29 in the high consumer group and 142 is the low-to-zero group. The small sample size reduces confidence in the results and calls the generalisability of the findings into question, particularly as the study was carried out on healthy mothers and their babies raised in Finland, where liquorice consumption is typically more common than in the UK.

The relevance of the study findings also depends on whether the data collected on maternal liquorice consumption during pregnancy was a good estimation of their glycyrrhizin intake during this period. Liquorice intake per week during pregnancy was assessed via retrospective self-report after the pregnancy had ended and intake of other foods containing glycyrrhizin (such as sweets and herbal teas) was not measured. Due to this limited methodology, maternal intakes of glycyrrhizin during pregnancy were likely to be under-estimated and this should be considered when interpreting the study findings. Consideration should also be given to the accuracy of the measures of offspring pubertal maturation and attention deficit/hyper-activity disorder problems, as these was based on assessment by the mothers and not trained health professionals.

Relevance
Currently, in the UK, there is no recommendation to avoid liquorice sweets and tea (or glycyrrhizin) during pregnancy and no specific guidance on safe intake levels although, as a precaution, the NHS advises that the herbal remedy liquorice root is avoided (http://bit.ly/2piN1Pb). There is, however, a recommendation for the general population, particularly those aged over 40 years with a history of heart disease and/or high blood pressure, to avoid eating more than 57 g/day of liquorice for 2 weeks or longer as this can increase blood pressure and lead to an irregular heart rhythm (http://bit.ly/2oTywhr).

Similarly, there are no clear guidelines on liquorice or glycyrrhizin intake during pregnancy from the European Union (EU), although foods or drinks containing liquorice at certain levels are required to be labelled ‘contains liquorice’ and ‘people suffering from hypertension should avoid excessive consumption’ may need to follow depending on the level (Commission Directive 2004/77/EC). In 2003, the European Commission (EC) Scientific Committee on Food, the responsibilities of which have since been transferred to the European Food Safety Authority (EFSA), concluded that there was insufficient data to establish an Acceptable Daily Intake value for glycyrrhizin and that an ‘upper limit for regular ingestion of 100 mg/day provides a sufficient level of protection for the majority of the population’ (EC 2003). This is about the amount of glycyrrhizin found in 60-70 g of liquorice (Omar et al. 2012) and more than what was considered to be high exposure in the studies by Raikkonen et al. (2009; 2017). EFSA has emphasised the need for further information on glycyrrhizin consumption and its health effects.

While data from the studies by Raikkonen et al. (2009; 2017) hint that glycyrrhizin intake during pregnancy might impact negatively on offspring development, more research is required to determine how the pattern and quantity of glycyrrhizin intake during pregnancy relates to offspring developmental outcomes, to establish the direction of the relationship, and to examine these effects in other cohorts/populations. Data of this kind is required to determine whether new guidance on liquorice/glycyrrhizin consumption in pregnancy is necessary.

References
Commission Directive 2004/77/EC of 29 April 2004 amending Directive 94/54/EC as regards the labelling of certain foods containing glycyrrhizinic acid and its ammonium salt. Available at: www.eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2004.162.01.0076.01.ENG

EC (European Commission) (2003) Opinion on the Scientific Committee on Food on glycyrrhizinic acid and its ammonium salt. Available at: www.ec.europa.eu/food/sites/food/files/safety/docs/sci-com_scf_out186_en.pdf

Omar HR, Komarova I, El-Ghonemi M et al. (2012) Licorice abuse: time to send a warning message. Therapeutic Advances in Endocrinology and Metabolism 3(4) 125–138.

Raikkonen K, Pesonen A-K Heinonen k et al. (2009) Maternal licorice consumption and detrimental cognitive and psychiatric outcomes in children. Am J Epidemiol 170(9): 1137-1146

Raikkonen K, Martikainen S, Pesonen A-K et al. (2017) Maternal licorice consumption during pregnancy and pubertal, cognitive and psychiatric outcomes in children. Am J Epidemiol 185(5): 317-328

 

Created April 2017. Review due April 2020. If you have any queries about this article, please contact: postbox@nutrition.org.uk