Association Between Interpregnancy Interval and Risk of Preterm Birth and Its Modification by Folate Intake: The Japan Environment and Children's Study.

BACKGROUND: Both short and long interpregnancy intervals (IPIs) have been associated with risk of preterm birth, but the evidence is limited in Asians. It is also uncertain whether the association is modified by dietary folate intake or folic acid supplementation during pregnancy. Thus, we examined associations between IPI and risk of preterm birth and effect modification of those associations by dietary intake of folate and supplementation with folic acid on the basis of a nationwide birth cohort study. METHODS: Among 103,062 pregnancies registered in the Japan Environment and Children's Study, 55,203 singleton live-birth pregnancies were included in the analysis. We calculated IPI using birth date, gestational age at birth of offspring, and birth data of the latest offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) of the risk of preterm birth were estimated according to IPI categories. RESULTS: Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth, compared with an 18-23-month IPI. The multivariable ORs were 1.63 (95% CI, 1.30-2.04) for <6-month and 1.41 (95% CI, 1.11-1.79) for ≥120-month IPIs. These associations were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. Multivariable ORs were 1.76 (95% CI, 1.35-2.29) for <6-month IPI and 1.65 (95% CI, 1.24-2.19) for ≥120-month IPI. CONCLUSION: Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth. These higher risks were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy.

Hypertensive Disorders of Pregnancy in Relation to Coffee and Tea Consumption: The Japan Environment and Children's Study.

BACKGROUND: The association between coffee/tea intake and hypertensive disorders of pregnancy (HDP) remains unclear. This study aimed to investigate the association of caffeine, coffee, and tea intake during pregnancy with the risk of HDP. METHODS: We assessed this association in 85,533 singleton pregnant women with live births in the Japan Environment and Children's Study, a prospective cohort in Japan that included women from early pregnancy onward. Caffeinated and decaffeinated coffee and tea (green, oolong, and black) consumption during pregnancy was assessed using a validated food frequency questionnaire conducted at mid-pregnancy, and caffeine intake was calculated based on coffee and tea consumption. Multivariable logistic regression was used to assess the association with the risk of HDP. RESULTS: HDP developed in 2222 women (2.6%). Caffeine intake was weakly associated with increased risk of HDP; the multivariable odds ratio of HDP for the highest versus the lowest quartile was 1.26 (95% confidence interval: 1.11, 1.43). Coffee drinkers of two or more cups per day showed a decreased risk compared with non-drinkers (multivariable odds ratio 0.79; 0.62, 0.99) even after adjustment for total caffeine intake. Tea consumption was not associated with the risk of HDP. CONCLUSIONS: Our study suggests that higher caffeine intake may increase HDP risk, while coffee drinkers had a lower risk. Further high-quality studies are needed to replicate these findings, and to elucidate if other substances in coffee may be protective against HDP.

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library.

INTRODUCTION: Preeclampsia therapy has not been established, except for the termination of pregnancy. The aim of this study was to identify a potential therapeutic agent from traditional Japanese medicine (Kampo) using the drug repositioning method. MATERIALS AND METHODS: We screened a library of 74 Kampo to identify potential drugs for the treatment of preeclampsia. We investigated the angiogenic effects of these drugs using human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were performed to measure the levels of placental growth factor (PlGF) in conditioned media treated with 100 µg/mL of each drug. We assessed whether the screened drugs affected cell viability. We performed tube formation assays to evaluate the angiogenic effects of PlGF-inducing drugs. PlGF was measured after administering 10, 50, 100, and 200 µg/mL of the candidate drug in the dose correlation experiment, and at 1, 2, 3, 6, 12, and 24 h in the time course experiment. We also performed tube formation assays with the candidate drug and 100 ng/mL of soluble fms-like tyrosine kinase 1 (sFlt1). PlGF production by the candidate drug was measured in trophoblastic cells (BeWo and HTR-8/SVneo). The Mann-Whitney U test or one-way analyses of variance followed by the Newman-Keuls post-hoc test were performed. P-values < 0.05 were considered significant. RESULTS: Of the 7 drugs that induced PlGF, Tokishakuyakusan (TS), Shoseiryuto, and Shofusan did not reduce cell viability. TS significantly facilitated tube formation (P = 0.017). TS administration increased PlGF expression in a dose- and time-dependent manner. TS significantly improved tube formation, which was inhibited by sFlt1 (P = 0.033). TS also increased PlGF production in BeWo (P = 0.001) but not HTR-8/SVneo cells (P = 0.33). CONCLUSIONS: By using the drug repositioning method in the in vitro screening of the Kampo library, we identified that TS may have a therapeutic potential for preeclampsia. Its newly found mechanisms involve the increase in PlGF production, and improvement of the antiangiogenic state.