Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

Efficacy of a prospective community-based intervention to prevent preterm birth.

OBJECTIVES: To evaluate a community-based intervention trial for the prevention of preterm birth. METHODS: This trial was conducted on pregnant women in the Amakusa area, and in the Hitoyoshi-Kuma area, both in Japan. Prophylactic oral antibiotics were recommended for pregnant women with high-risk on preterm birth. The subjects were also encouraged to undergo a periodontal examination. An explanation of proper tooth brushing was given and full mouth scaling was allowed if deemed necessary. RESULTS: Of 720 consented subjects in the Amakusa area and of 373 in the Hitoyoshi-Kuma area, bacterial vaginosis was found in 100 (13.9%) Amakusa residents and 71 (19.0%) Hitoyoshi-Kuma residents. Prophylactic antibiotics were prescribed for 93 Amakusa residents and 39 Hitoyoshi-Kuma residents. Among subjects who underwent a periodontal examination, periodontal disease was found in 47.7% of Amakusa residents and 59.7% of Hitoyoshi-Kuma residents. Periodontal health was improved among these women by a nonsurgical intervention during their pregnancy. Comparing the incidences of very low birth weight (VLBW) with the averages during the preceding 6 years in each area, the incidences of VLBW was 46.4% lower in Amakusa and 69.7% Hitoyoshi-Kuma during the study year. CONCLUSIONS: A community-based multifaceted intervention might reduce the incidence of VLBW infants.

[Oral health status of pregnant women in Kumamoto Prefecture].

OBJECTIVES: As part of Kumamoto RAINBOW Project, which is a multifaceted implementation for the prevention of premature labor, we investigated pregnant women's oral health status and assessed the effects of dental care and oral hygiene instruction. METHODS: We examined the oral health status of pregnant women both in the first and the second half of pregnancy in Kumamoto Prefecture from 2012 to 2014. The Community Periodontal Index (CPI) was used to assess the periodontal condition, and women having periodontal pockets with a depth ≥4 mm were defined as suffering from periodontitis. This project covered the cost of dental checkups. RESULTS: Of the 20,702 pregnant women enrolled in this project, 9,527 (46.0%) received dental checkups during the first half of pregnancy. The response rate of dental examinations in Kumamoto City (63.3%), the capital city of Kumamoto Prefecture, was significantly higher than that of the other local areas (32.0%). In Kumamoto City, 4,890 women (83.4%) had dental examinations at the city office when they received a maternal handbook. Three thousand forty-five women (32.0%) had periodontitis. Among 1,605 women who received oral examinations twice at dental clinics, 698 received nonsurgical interventions. Dental interventions significantly decreased the prevalence of periodontitis in pregnant women (55.1% to 45.1%). Dental examinations without interventions also significantly decreased the prevalence of periodontitis (44.6% to 39.9%). CONCLUSIONS: Pregnant women living in Kumamoto City had higher rate of visits to dental clinics for checkups than those in other areas. Periodontitis was found in one-third of pregnant women. Not only dental interventions, but also dental examinations improve pregnant women's oral health status.

Clinical features of early-stage nonhydropic mole for diagnosis of persistent trophoblastic disease.

OBJECTIVES: To characterize the clinical features of "nonhydropic" hydatidiform mole and to investigate regression of serum human chorionic gonadotropin (hCG) as an aid in detecting persistent trophoblastic disease after nonhydropic hydatidiform mole. METHODS: Our study included women with histologically diagnosed nonhydropic molar pregnancies. Women did not exhibit macroscopic or characteristic ultrasonographic appearances specific to hydatidiform mole. Regression of serum hCG levels was compared with abortions of nonmolar pregnancies, which were histologically confirmed. RESULTS: Among 34 nonhydropic molar pregnancies, 32 complete hydatidiform moles were analyzed, excluding two partial hydatidiform moles. Compared with nonmolar aborted pregnancies, pre-evacuation hCG levels were significantly higher in the 32 complete hydatidiform moles. The 32 molar pregnancies progressed to 24 cases of spontaneous remission and eight cases of persistent trophoblastic disease. Among patients with spontaneous remission, the time at which serum hCG levels became undetectable and the onset of first postabortion menstruation were similar to those in patients who had nonmolar abortions. In all patients who experienced regression, serum hCG was undetectable after the third postabortion menstruation. In all patients with persistent trophoblastic disease, serum hCG levels exceeded 25 milli-international units/mL 4 weeks after evacuation. CONCLUSION: Without histological confirmation, it is difficult to diagnose nonhydropic molar pregnancy based solely on clinical presentation. Follow-up studies of serum hCG levels 4 weeks after abortion and after the third postabortion menstruation may aid in detecting impending persistent trophoblastic disease. LEVEL OF EVIDENCE: II.

Hypertriglyceridemic acute pancreatitis during pregnancy: prevention with diet therapy and omega-3 fatty acids in the following pregnancy.

Acute pancreatitis complicating pregnancy is rare and has previously been associated with high mortality rates. We report a case of repeated hypertriglyceridemia during pregnancy. During the patient's first pregnancy, acute pancreatitis was elicited in the third trimester by pregnancy-induced hypertriglyceridemia. The patient was treated successfully with a conservative treatment course. The hypertriglyceridemia recurred during her second pregnancy. She carried the pregnancy to term without incident while maintaining a diet low in fat diet and high in omega-3 fatty acids. Early diagnosis and intensive treatment can help to preserve the lives of the patient and the fetus. Prophylactic diet therapy and omega-3 fatty acids may prevent recurrent hypertriglyceridemia during pregnancy.