1 Department of Medicine, University of Helsinki, Helsinki, Finland.
2 Department of Pediatrics, University of Helsinki, Helsinki, Finland.
3 Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland.
4 Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Received for publication March 25, 2002; accepted for publication June 19, 2002.
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ABSTRACT |
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gestational age; glycyrrhizic acid; pregnancy
Abbreviations: Abbreviation: SD, standard deviation.
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INTRODUCTION |
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In a previous cross-sectional study on licorice and birth outcome (1), we noticed a statistically significant inverse association of heavy licorice and consequently glycyrrhizic acid (3ß-D-diglucuronyl-18ß-glycyrrhetinic acid) consumption with length of gestation. This finding was interesting, because the etiology of preterm birth is still poorly understood (24), and both glycyrrhizic acid and the mechanism of delivery are associated with glucocorticoid and prostaglandin metabolism (1). However, our previous study, based in a city hospital (secondary level) in which few preterm births occurred, was not designed to detect an association with preterm births. Because the association, if real, might shed light on the mechanism of preterm birth, we decided to reexamine this finding in the university clinic (tertiary level) that, while also handling normal births, treats more preterm deliveries.
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MATERIALS AND METHODS |
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The questionnaire contained demographic items including gestational age (in months and days, for cross-checking purposes), a question about smoking, and detailed questions about licorice consumption during pregnancy. These questions were identical to those in the previous study (1). In that larger study (1, 5), glycyrrhizin intake was not connected with various lifestyle parameters (alcohol, coffee, or tea consumption; maternal stress during pregnancy), body mass index, or blood pressure; therefore, to reduce the size of the questionnaire and to improve compliance, these items were not included in the present questionnaire. Glycyrrhizin intake was calculated from answers to detailed questions on licorice consumption, and glycyrrhizin exposure was grouped into three levels: low (<250 mg/week), moderate (250499 mg/week), and heavy (500 mg/week), as described earlier (1). Because of a threshold effect, in the analyses, heavy consumption was compared with moderate and low levels combined.
NCSS software (Kaysville, Utah; Internet Web site: www.ncss.com) was used for statistical analyses. Continuous variables were compared by using the Mann-Whitney U test, and logistic regression was used for multivariate analyses. In our series, mothers age and length of gestation were correlated positively (r = 0.25, p = 0.0004), with no evidence of a shortening at older ages; consequently, we used mothers age as a continuous variable in the analyses. Parity was used as a dichotomous variable (>1 = 1).
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RESULTS |
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Median glycyrrhizin intakes (interquartile range) among the mothers of cases and controls were 150.0 mg/week (75.0409.0) and 104.0 mg/week (50.0310.0), respectively. The heavy glycyrrhizin intake group included 19/95 (20.0 percent) mothers of cases and 11/107 (10.3 percent) mothers of controls (p = 0.06). The association of heavy intake with preterm (<37 weeks) and early preterm (<34 weeks) delivery was further investigated in multivariate analyses, and the results are shown in table 1. The point estimates for preterm delivery remained over 2 and changed very little when covariates were added to the model. The effect tended to be even larger for early preterm delivery (odds ratio = 3.07, 95 percent confidence interval: 1.17, 8.05 for the fully adjusted model).
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DISCUSSION |
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A possible limitation of this study is that information on licorice consumption during pregnancy was collected retrospectively. However, a pilot study conducted in the antenatal clinics found similar patterns of consumption among pregnant women (unpublished observations). Another limitation is the possibility of confounding. Licorice consumption simply might be associated with some other factor(s) causally related to preterm birth. We have no such evidence, however. A recent social history (6) on a special type of licorice popular in Finland, the Netherlands, and Denmark (salty licorice, "salmiak") was a Christmas bestseller in Finland. That book cited consumer surveys by the industry showing that licorice consumption in Finland is especially popular among those under 35 years of age and among women, that is, females of childbearing age. Licorice consumption is a socially neutral phenomenon; it is not considered to confer either a negative or positive stigma on users. Common knowledge and previous, partly unpublished results from our earlier, larger study (1) suggest that licorice consumption among Finnish women is not related to type of work, socioeconomic status, or various lifestyle factors. A specific association with licorice consumption, rather than a general association with consumption of confectionery, is supported by the finding that chocolate consumption was not related to birth outcome in our earlier study (1). In that study, we also found a significant association between perceived stress during pregnancy and chocolate, but not licorice, consumption (5).
Our finding is also biologically plausible because of the effects of glycyrrhizin on cortisol and prostaglandin metabolism. Glycyrrhizin inhibits the local breakdown of cortisol in placenta, leading to increased cortisol levels that may affect prostaglandins. Carbenoxolone, a synthetic analogue of glycyrrhizin, inhibits prostaglandin-metabolizing enzymes (7) and, in the stomach, causes a local increase in prostaglandin levels. If glycyrrhizin has similar effects, it is possible that intake during pregnancy could cause a local increase in prostaglandins in the uterus and lead to contractions (4). Interestingly, in traditional medicine, licorice has been used as an abortifacient (8), but there is no experimental evidence to support this use. Further elucidation of the pathogenetic mechanisms could contribute to the research on preterm delivery. Measurement of the activities of placental enzymes or maternal plasma concentrations of glucocorticoids, corticotrophin-releasing hormone (CRH) (9, 10), and prostaglandins in heavy licorice consumers might be important.
Preterm birth is a multifactorial state (4), and heavy licorice consumption is only one of the possible factors affecting preterm delivery. In our study, the effect of licorice was clearly stronger than that of smoking, a factor conventionally associated with preterm birth. This finding implies a clinically significant effect of licorice, and the possible connection should be determined. In the present and the earlier (1) studies, approximately 10 percent of the women were considered heavy licorice consumers during pregnancy, and 500 mg of glycyrrhizin (heavy intake) corresponds to approximately 250 g of licorice per week. In Finland, packages of licorice confectionery now commonly contain 200 g or even 400 g, a quantity easily consumed by aficionados. Confectionery is the major source of glycyrrhizin in Finland and probably other western societies as well, but other forms of consumption (for example, herbal products) also may be common in some parts of the world. Their possible role in preterm births might warrant further exploration.
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NOTES |
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REFERENCES |
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