Birth Outcome in Relation to Licorice Consumption during Pregnancy
Timo E. Strandberg1,
Anna-Liisa Järvenpää2,
Hannu Vanhanen1 and
Paul M. McKeigue3
1 Department of Medicine, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
2 Department of Pediatrics and Neonatology, Helsinki City Maternity Hospital for Children and Adolescents (Kätilöopiston sairaala), Helsinki, Finland.
3 Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom.
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ABSTRACT
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A role for glucocorticoids is suspected in the etiology of low birth weight. The authors tested whether maternal consumption of glycyrrhizin (an inhibitor of cortisol metabolism) in licorice affects birth weight in humans. A sample of 1,049 Finnish women and their healthy singleton infants was studied in 1998. Glycyrrhizin intake was calculated from detailed questionnaires on licorice consumption. Glycyrrhizin exposure was grouped into three levels: low (<250 mg/week; n = 751), moderate (250499 mg/week; n = 145), and heavy (
500 mg/week; n = 110). Birth weight and gestational age (from ultrasound measurements) were obtained from hospital records. Babies with heavy exposure to glycyrrhizin were not significantly lighter at birth, but they were significantly more likely to be born earlier: The odds ratio for being born before 38 weeks' gestation was 2.5 (95% confidence interval: 1.1, 5.5; p = 0.03). Although the effect of heavy glycyrrhizin intake on mean duration of gestation was small (2.52 days) when expressed as an effect on the mean, this shift to the left of the distribution of duration of gestation was sufficient to double the risk of being born before 38 weeks. The association remained in multivariate analyses. In conclusion, heavy glycyrrhizin exposure during pregnancy did not significantly affect birth weight or maternal blood pressure, but it was significantly associated with lower gestational age.
gestational age; glycyrrhiza; glycyrrhizic acid; hydroxysteroid dehydrogenases; pregnancy
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INTRODUCTION
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Associations of reduced size at birth with raised blood pressure and glucose intolerance in adult life have been demonstrated in several populations (1
3
). One possible mechanism is exposure of the fetus to maternal cortisol. This is normally prevented by the action of the placental enzyme 11ß-hydroxysteroid dehydrogenase 2, which converts cortisol to inactive cortisone (4
, 5
). Administration of carbenoxolone, an inhibitor of 11ß-hydroxysteroid dehy-drogenase 2, to pregnant rats reduces birth weight by 20 percent (6
). Carbenoxolone is a synthetic analogue of glyc-yrrhizin (3ß-D-diglucuronyl-18ß-glycyrrhetinic acid), which is a natural constituent of licorice (7
9
). If the effects demonstrated in rats apply to humans, we would predict that heavy consumption of licorice by pregnant women would affect birth weight. To test this hypothesis, we studied births in Finland, where consumption of large quantities of licorice is common among young women.
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MATERIALS AND METHODS
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Participants
The study was approved by the ethical committee of the City of Helsinki Health Department. The survey was carried out at the Helsinki City Maternity Hospital (Kätilöopiston sairaala). The hospital is the principal maternity hospital of Helsinki, with approximately 4,500 births per year.
Between March and November of 1998, questionnaires were distributed by midwives in four regular maternity wards to women who had delivered in the hospital. The midwives were instructed to give the questionnaire to all women with singleton healthy births in which both parents were of Finnish origin. Sick or very preterm babies (<32 weeks) were treated in the pediatric ward or in the university hospital, and their mothers did not participate (n = 250). During this period, there were 2,746 women who would have been eligible for the study. While only 30 women actually refused to participate, others failed to receive their questionnaires, especially during the summer months when the regular midwives were on vacation. Consequently, during the more active months (SeptemberMay), questionnaires were received from 61 percent of women. It is not likely that this involved a selection bias, since the midwives were unaware of the exact aims of the study and the questions about licorice were embedded in the questionnaire. Moreover, in a pilot study undertaken in antenatal clinics with consecutive visits and anonymous questionnaires, the distribution of data on licorice consumption was almost identical to that in the main study.
Data collection
A total of 1,049 mothers completed a questionnaire specifically designed to yield an estimate of glycyrrhizin intake. Weekly glycyrrhizin intake was calculated from the reported quantity (in grams) and frequency (never, seldom, weekly, daily) of consumption from a list of all brands of licorice-containing confectionery available in Finland. The questionnaire also included items on other lifestyle variables.
Participants were asked for permission to examine their hospital maternity records, and 91 percent (947/1,042) consented. Estimates of gestational age obtained by fetal ultrasound measurements of biparietal diameter during the first trimester were available from these records for 90 percent (946/1,049) of the women. If ultrasound measurements were unavailable, gestational age was obtained from the mother's self-report of the last menstrual period. Maternity records also included type of delivery (spontaneous, induced, or cesarean section), birth weight, and maternal blood pressure.
Data on the glycyrrhizin content of licorice confectionery on sale in Finland were obtained from a report prepared by the National Food Administration in 1993 (7
). This list was updated with information from manufacturers. Weekly glyc-yrrhizin intake was calculated from the reported quantity and frequency of consumption of each brand. This was possible for 1,006 of the 1,049 women.
Statistical analyses
Data were analyzed using the Stata 5.0 statistical package (10
). Associations were examined with glycyrrhizin intake analyzed both as a continuous variable and as a categorical variable with three levels: low (<250 mg/week), medium (250499 mg/week), and high (
500 mg/week). Early delivery was defined as a gestational age of less than 38 weeks.
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RESULTS
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Forty-six percent and 2 percent of mothers reported regular weekly consumption and daily consumption of licorice during pregnancy, respectively. Only 2.3 percent never ate licorice during pregnancy. Among consumers, the calculated mean intake of glycyrrhizin was 363 mg/week (standard deviation 348; range, 12,464). The categories low, medium, and high glycyrrhizin intake comprised 75 percent, 14 percent, and 11 percent of births, respectively. Table 1 compares maternal characteristics and birth outcomes in these three categories.
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TABLE 1. Characteristics of mothers and birth outcomes according to glycyrrhizin intake during pregnancy, Helsinki, Finland, 1998
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Regression analyses were performed with birth weight or gestational age (continuous or with a cutpoint of 38 weeks) used as the dependent variable. Birth weight was not significantly related to glycyrrhizin intake either when the three levels of intake were compared (table 1) or when intake was considered as a continuous variable. Adjustment for sex, gestational age, parity, maternal age, and height did not change these results.
With gestational age considered as a continuous dependent variable and glycyrrhizin intake as a continuous predictor variable in a regression analysis with adjustment for sex and maternal age, the slope of the relation was equivalent to a reduction in gestational age of 0.18 weeks or 1.26 days (95 percent confidence interval: 0.31, 2.24; p = 0.009) for every 500-mg/week increase in glycyrrhizin intake. With glycyrrhizin intake grouped into three categories and mothers with low glycyrrhizin intake used as the reference group, the effect of glycyrrhizin consumption was statistically significant only for the high intake category: Mean gestational age was lower by 0.36 weeks or 2.52 days (95 percent confidence interval: 0.63, 4.34; p = 0.01). The effect of glycyrrhizin intake remained statistically significant after additional adjustment for parity, systolic blood pressure, smoking, and coffee consumption and exclusion of the 87 augmented or induced births. Although the effect on the mean duration of gestation was small, the cumulative frequency plot (figure 1) shows that the entire distribution of gestational age was shifted to the left among women with a heavy intake of glycyrrhizin in comparison with the rest of the sample.

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FIGURE 1. Cumulative frequency plot of the distribution of gestational ages according to glycyrrhizin intake during pregnancy, Helsinki, Finland, 1998.
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With delivery at <38 weeks used as the dependent variable and low intake of glycyrrhizin used as the reference group, the odds ratio for earlier delivery associated with a high intake of glycyrrhizin was 2.5 (95 percent confidence interval: 1.1, 5.5; p = 0.03) (logistic regression analysis adjusting for sex, maternal age, parity, smoking, coffee consumption, and systolic blood pressure).
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DISCUSSION
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Contrary to our hypothesis, we did not detect any significant effect of maternal glycyrrhizin intake in the form of licorice confectionery on birth weight. Instead, we found a significant association between heavy glycyrrhizin intake and lower gestational age. Thus, our results do not support the hypothesis (11
) that fetal exposure to maternal glucocorticoids can explain the association of low birth weight with adverse effects in adult life. However, we did not directly measure placental 11ß-hydroxysteroid dehydrogenase 2 activity, and consequently we cannot be absolutely sure that enzyme activity was sufficiently inhibited in the heavy consumption group.
On the other hand, this study shows that heavy consumption of glycyrrhizin was associated with a shortening of the mean duration of gestation by 2.52 days. This small effect on the position of the distribution has a large effect on the proportion of preterm births, as is represented by the left-hand tail of the cumulative frequency plot (figure 1). Because our study was not designed specifically to evaluate preterm birth (<37 weeks) as an outcome, it included only small numbers of preterm births, and we were unable to examine directly the risk ratios associated with heavy consumption of glycyrrhizin at cutoffs more extreme than 38 weeks. If the effect of glycyrrhizin consumption is simply to shift the entire distribution of gestational age to the left, as figure 1 suggests, the risk ratios associated with glycyrrhizin would be even larger for very preterm births.
The etiology of shortened gestation remains poorly understood (12
, 13
). It is interesting to note that licorice has traditionally been reputed to be an abortifacient (14
). One possible explanation for the effect of glycyrrhizin on length of gestation is inhibition of cortisol metabolism. Parturition in sheep is initiated by a rise in fetal cortisol concentrations (15
), but the evidence for a similar mechanism in humans is less clear. In a study of patients with premature rupture of the membranes, elevation of fetal plasma cortisol predicted early onset of preterm labor (16
). Increased placental release of corticotropin-releasing hormone has been suggested to act as a trigger for parturition in humans (17
) and has been implicated in the pathophysiology of preterm labor (18
, 19
). The release of corticotropin-releasing hormone, in turn, is stimulated in the placenta by cortisol (18
).
An alternative mechanism for the effect of glycyrrhizin on gestational age may be an effect on prostaglandin metabolism (18
). Carbenoxolone inhibits prostaglandin-metabolizing enzymes, as well as 11ß-hydroxysteroid dehydrogenase 2 (20
). One of these enzymes, 15-hydroxy-prostaglandin dehydrogenase, is a homologue of 11ß-hydroxysteroid dehydrogenase 2. In the stomach, carbenoxolone treatment causes a local increase in prostaglandin levels in the uterus. If glycyrrhizin has effects similar to those of carbenoxolone, it is possible that glycyrrhizin intake in pregnancy could cause a local increase in prostaglandin levels in the uterus. Such a mechanism is believed to underlie the increased risk of preterm birth in fetal inflammatory response syndrome (21
), in which interleukin-6 is thought to stimulate prostaglandin production (22
, 23
).
The effects of licorice consumption on gestational age were not hypothesized a priori in our study. Despite aforementioned mechanisms, the results may have been confounded by factor(s) associated with licorice consumption, or they may have been spurious. We are currently conducting a case-control study to clarify the matter further.
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ACKNOWLEDGMENTS
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Financial support for this study was received from the Helsinki University Central Hospital.
The authors thank Anita Brink, Annukka Norppa, Tiina Oinonen, Anja Punkka, Pia Sippola, and Heli Tiura for technical assistance and Anja Hallikainen of the National Food Administration of Finland for advice.
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NOTES
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Correspondence to Dr. Timo Strandberg, Faculty of Medicine, University of Helsinki, P.O. Box 340, FIN-00029 Helsinki, Finland (e-mail: timo.strandberg{at}hus.fi).
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Received for publication June 20, 2000.
Accepted for publication September 21, 2000.