Real-time monitoring of enzyme-catalyzed phosphoribosylation of anti-influenza prodrug favipiravir by time-lapse nuclear magnetic resonance spectroscopy.

Favipiravir (brand name Avigan), a widely known anti-influenza prodrug, is metabolized by endogenous enzymes of host cells to generate the active form, which exerts inhibition of viral RNA-dependent RNA polymerase activity; first, favipiravir is converted to its phosphoribosylated form, favipiravir-ribofuranosyl-5'-monophosphate (favipiravir-RMP), by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Because this phosphoribosylation reaction is the rate-determining step in the generation of the active metabolite, quantitative and real-time monitoring of the HGPRT-catalyzed reaction is essential to understanding the pharmacokinetics of favipiravir. However, assay methods enabling such monitoring have not been established. 19 F- or 31 P-based nuclear magnetic resonance (NMR) are powerful techniques for observation of intermolecular interactions, chemical reactions, and metabolism of molecules of interest, given that NMR signals of the heteronuclei sensitively reflect changes in the chemical environment of these moieties. Here, we demonstrated direct, sensitive, target-selective, nondestructive, and real-time observation of HGPRT-catalyzed conversion of favipiravir to favipiravir-RMP by performing time-lapse 19 F-NMR monitoring of the fluorine atom of favipiravir. In addition, we showed that 31 P-NMR can be used for real-time observation of the identical reaction by monitoring phosphorus atoms of the phosphoribosyl group of favipiravir-RMP and of the pyrophosphate product of that reaction. Furthermore, we demonstrated that NMR approaches permit the determination of general parameters of enzymatic activity such as Vmax and Km . This method not only can be widely employed in enzyme assays, but also may be of use in the screening and development of new favipiravir-analog antiviral prodrugs that can be phosphoribosylated more efficiently by HGPRT, which would increase the intracellular concentration of the drug's active form. The techniques demonstrated in this study would allow more detailed investigation of the pharmacokinetics of fluorinated drugs, and might significantly contribute to opening new avenues for widespread pharmaceutical studies.

Voltammetric and In Situ Spectroscopic Investigations on the Redox Processes of Trioxotriangulene Neutral Radicals on Graphite Electrodes.

To investigate the microscopic electrochemical dynamics of a stable trioxotriangulene (TOT) organic neutral π-radical on a graphite electrode surface, voltammetric and in situ infrared (IR) spectroelectrochemical studies were conducted using electrolyte solutions containing TOT monoanions. Upright columnar crystals (face-on alignment) of the TOT neutral radical were preferentially formed and dissolved in a rather reversible manner in the electrolyte with a low concentration of TOT monoanion under electrochemical conditions; however, more flat-lying columnar crystals (edge-on alignment) were formed in a higher concentration electrolyte. The flat-lying crystals remained on the graphite surface even at a fully reduced potential, owing to the lack of direct π-π interactions between the molecules and the graphite electrode. In situ IR attenuated total reflectance spectroscopy analyses successfully characterized the alignment of the columnar crystals of the TOT neutral radicals and their electrochemical behaviors, including the possible origins of the irreversible redox reaction of TOT on the graphite electrode.

Maternal magnesium intake and childhood wheezing in offspring at 3 years of age: the Japan Environment and Children's Study.

This study evaluated the association between maternal magnesium intake (MMI) and childhood wheezing incidence in 3-year-old offspring. We hypothesised that higher MMI imparts anti-inflammatory and antioxidant effects that decrease childhood wheezing incidence in offspring. Data of 79 907 women (singleton pregnancy, ≥ 22 weeks) from the Japan Environment and Children's Study (enrolled between 2011 and 2014) were analysed. Participants were categorised into quintiles of MMI (< 148·00, 148·00-187·99, 188·00-228·99, 229·00-289·99 and ≥ 290·00 mg/d), quintiles of adjusted MMI for daily energy intake (aMMI) (< 0·107, 0·107-0·119, 0·120-0·132, 0·133-0·149 and ≥ 0·150 mg/kcal) and MMI levels either below or above the ideal value (< 310·00 or ≥ 310·00 mg/d). Multivariable logistic regression analysis was performed to calculate OR for the incidence of childhood wheezing in offspring among participants in each MMI category, with the lowest MMI group considered the reference group. Maternal demographic, socio-economic, medical and other nutrient intake backgrounds were considered potential confounding factors. The adjusted OR (aOR) for childhood wheezing in the offspring of women with the highest MMI was 1·09 (95 % CI, 1·00, 1·20), whereas that calculated based on aMMI categories and offspring of women with above-ideal MMI levels remained unchanged. The highest MMI was associated with slightly increased childhood wheezing incidence in the offspring. MMI during pregnancy had an insignificant clinical impact on this incidence; moreover, modifying MMI would not significantly improve childhood wheezing incidence in offspring. Therefore, further studies should clarify the association between other prenatal factors and childhood wheezing incidence in offspring.

Tobacco Exposure During Pregnancy and Infections in Infants up to 1 Year of Age: The Japan Environment and Children's Study.

BACKGROUND: Tobacco exposure during pregnancy is associated with several adverse outcomes in infants. We investigated the association between tobacco exposure during pregnancy (both active and second-hand) and various infections in infants up to 1 year. METHODS: This prospective cohort study used a fixed dataset (jecs-an-20180131) from the Japan Environment and Children's Study of registered births in Japan during 2011-2014 that included 104,065 fetal records from enrolled pregnant women. Based on the participants' responses to the questionnaire on smoking status, mothers were first divided into "never smoked," "quit smoking," and "current smoker" groups and then into "no second-hand smoking (SHS)" and "SHS" groups. Infectious diseases included central nervous system infection, otitis media (OM), upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI), gastroenteritis (GI), and urinary tract infection. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis and adjusted for maternal, socioeconomic, and postnatal confounding factors. RESULTS: Among the 73,205 newborns enrolled, multivariable analysis revealed that the aOR of LRTI and GI was 1.20 (95% CI, 1.07-1.33) and 1.18 (95% CI, 1.04-1.35), respectively, for the "current smoker with/without SHS" group compared with the "never smoked without SHS" group. "Quit smoking without SHS" was not associated with the risk of LRTI. SHS was associated with an increased risk of OM, URTI, LRTI, and GI, especially with LRTI and GI. CONCLUSION: Exposure to tobacco smoke during pregnancy was associated with an increased risk of OM, URTI, LRTI, and GI in infants during their first year of life.

Cord blood triglyceride and total cholesterol in preterm and term neonates: reference values and associated factors from the Japan Environment and Children's Study.

This study aimed to investigate the associations between cord serum total cholesterol (TC) and triglyceride (TG)levels and perinatal factors and determine the reference levels of cord blood TC and TG in Japanese neonates. This was a prospective birth cohort study using data from the Japan Environment and Children's Study, which included data on births from 2011 to 2014 in Japan. TC and TG levels were determined in cord blood samples. A total of 70,535 pairs of neonates (male: 36,001, female: 34,524) and mothers were included. The mean cord blood TC and TG levels were 72.2 mg/dL and 24.4 mg/dL, respectively. Multiple regression analyses revealed that gestational age and birth weight were significantly associated with cord blood TC (coefficient -2.35, 95% confidence interval [CI] -2.40 - -2.22 and coefficient 0.002, 95% CI 0.002-0.003, respectively) and TG (coefficient 3.09, 95% CI 3.01-3.17 and coefficient - 0.009, 95% CI - 0.009-0.008, respectively) levels. Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term. Furthermore, the mean cord blood TC and TG levels decreased over the entire range of birth weight categories.    Conclusion: Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term. Furthermore, the mean cord blood TC and TG levels decreased over the entire range of birth weight categories in Japanese newborns. Maternal complications such as maternal parity, HDP, PROM, maternal obesity and income level were associated with cord TC and TG levels. What is Known: • No studies have ascertained the reference levels of cord blood lipid levels in Japan. What is New: • Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term.

Association of Maternal Asthma and Total Serum Immunoglobulin E levels with Obstetric Complications: The Japan Environment and Children's Study.

OBJECTIVE: To evaluate the association between maternal asthma (MA) and obstetric complications, while considering subdivided total serum immunoglobulin E (IgE) levels. METHODS: Data of the participants enrolled in the Japan Environment and Children's Study between 2011 and 2014 were analyzed. In total, 77,131 women with singleton live births at and after 22 weeks of gestation were included. MA was defined based on a self-administered questionnaire. Women with MA were stratified based on the quartile of total serum IgE levels during pregnancy as follows: low IgE levels (< 52.40 IU/mL), moderate IgE levels (52.40-331.00 IU/mL), and high IgE levels (> 331.00 IU/mL). The adjusted odds ratios (aORs) for preterm births (PTB), small for gestational age (SGA) infants, gestational diabetes mellitus, and hypertensive disorders of pregnancy (HDP) were calculated using multivariable logistic regression, while considering women without MA as reference and maternal socioeconomic factors as confounders. RESULTS: The aORs for SGA infants and HDP in women with MA and high total serum IgE levels were 1.26 (95% confidence interval [CI], 1.05-1.50) and 1.33 (95% CI, 1.06-1.66), respectively. The aOR for SGA infants among women with MA and moderate total serum IgE levels was 0.85 (95% CI, 0.73-0.99). The aOR for PTB among women with MA and low total serum IgE levels was 1.26 (95% CI, 1.04-1.52). CONCLUSIONS FOR PRACTICE: MA with subdivided total serum IgE levels was associated with obstetric complications. Total serum IgE level may be a potential prognostic marker to predict obstetric complications in pregnancies with MA.

What is Already Known on this Subject? Maternal asthma (MA) is associated with several obstetric complications, including preterm births (PTB), small for gestational age (SGA) infants, and hypertensive disorders of pregnancy (HDP). Few studies with data from nationwide cohorts have elucidated the association between MA and obstetric complications comprehensively while accounting for the subdivided objective biomarkers of MA.What this Study Adds? MA with subdivided total serum IgE levels was associated with various obstetric complications. Total serum IgE level may be a potential prognostic marker for pregnant women with MA to predict the potential risk of PTB, SGA infants, and HDP.

Influence of preconception carbohydrate intake on hypertensive disorders of pregnancy: The Japan Environment and Children's Study.

AIM: Hypertensive disorders of pregnancy (HDP) are a crucial cause of morbidity and mortality. We aimed to examine whether preconception carbohydrate intake is associated with new-onset HDP and small for gestational age (SGA) births. METHODS: We identified 93 265 normotensive (primiparous, 37 387; multiparous, 55 878) participants from the Japan Environmental Children's Study database who delivered between 2011 and 2014. After excluding participants with multiple gestations, preconception hypertension, and insufficient data, primiparous and multiparous participants were categorized into five groups according to their preconception carbohydrate-intake quintiles (Q1 and Q5 were the lowest and highest groups, respectively). Multiple logistic regression analysis was performed to identify the effect of preconception carbohydrate intake on early (<34 weeks) and late-onset (≥34 weeks) HDP and the incidence of SGA births. RESULTS: With the middle carbohydrate intake group (Q3) as a reference, the risk for late-onset HDP among multiparous women was higher in the Q5 group (adjusted odds ratio [aOR] 1.31, 95% confidence interval [CI] 1.02-1.69). The incidence of SGA births was higher in the Q1 group among both primiparous (aOR 1.16, 95% CI 1.01-1.33) and multiparous women (aOR 1.16, 95% CI 1.02-1.32). CONCLUSIONS: Excessive carbohydrate intake increases the incidence of HDP in multiparous women, while low-carbohydrate intake increases the incidence of SGA births. New recommendations for preconception carbohydrate intake are required to prevent major HDP-related complications.

Tocolytic treatment and maternal characteristics, obstetric outcomes, and offspring childhood outcomes among births at and after 37 weeks of gestation: the Japan environment and children's study.

PURPOSE: To evaluate differences in maternal characteristics and obstetric and offspring childhood outcomes between births at and after 37 weeks of gestation (referred to as term and post-term births) according to the use of tocolytic treatment. METHODS: Data for 63,409 women with singleton births at and after 37 weeks of gestation were analyzed using data from the Japan Environment and Children's Study (JECS). We compared maternal characteristics, obstetric outcomes, and offspring childhood outcomes between term and post-term births exposed and not exposed to tocolytic treatment. Additionally, multivariable logistic regression models were used to calculate adjusted odds ratios for offspring childhood outcomes with significant between-group differences in the univariable analysis, with term and post-term births without tocolytic agents as the reference group. RESULTS: We observed differences in maternal characteristics and obstetric outcomes between term and post-term births exposed and not exposed to tocolytic treatment. The incidence of offspring childhood developmental disorders showed no significant between-group differences. However, participants exposed to tocolytic agents had higher incidence of offspring childhood allergic disorders. The adjusted odds ratio for any of the offspring childhood allergic disorders in term and post-term births with tocolytic agents was 1.08 (95% confidence interval, 1.03-1.13). CONCLUSION: This study found no significant difference in the incidence of offspring developmental disorders between term and post-term births exposed and not exposed to tocolytic treatment. However, tocolytic treatment was associated with differences in maternal characteristics and obstetric outcomes, along with a marginal increase in the incidence of childhood allergic disorders in offspring.

A Redox-Active Microporous Organosiloxane Containing a Stable Neutral Radical, Trioxotriangulene.

A new silyl-substituted trioxotriangulene (TOT) neutral radical and corresponding porous organosiloxanes (POSs) were synthesized. The neutral radical exhibited a peculiarly high stability and formed a diamagnetic π-dimer characteristic to TOT neutral radicals stabilized by the strong multiple SOMO-SOMO interaction in both solution and solid states. POSs including TOT units within the organosiloxane-wall were prepared by polycondensation of the silyl groups and formed microporous structures with ∼1 nm-size diameters. Redox ability of TOT units in the POS was demonstrated by the treatment of oxidant/reductant in heterogeneous suspension condition, where the TOT units were reversibly converted between reduced and neutral radical species. Furthermore, the solid-state electrochemical measurements of the POS revealed the reversible multi-stage redox ability of TOT units involving polyanionic species within the organosiloxane-wall.

Double-σ-Bonded Close-Shell Dimers and Peroxy-Linked Open-Shell Dimer Derived from a C3 Symmetric Trioxophenalenyl Neutral Diradical.

A novel neutral diradical of π-extended phenalenyl derivative having three oxo-groups, tri-tert-butyl-1,4,7-trioxophenalenyl, and two types of the corresponding σ-dimers were investigated. Quantum chemical calculations showed that the neutral diradical is in triplet ground state having doubly degenerate singly occupied molecular orbitals. The neutral diradical undergoes a σ-dimerization, generating two types of σ-dimers immediately after the preparation. One of the σ-dimers, which was selectively generated in the crystalline state, was a close-shell dimer linked through double-σ-bonds on the phenalenyl skeleton with a long C-C bond length of 1.66 Å. The other σ-dimer, which existed only in the solution state, was a peroxy-linked open-shell dimer in which one σ-bond was formed between two oxygen atoms. Furthermore, the temperature-dependent 1 H NMR and ESR spectra revealed that these σ-dimers are in equilibrium in the solution state by the reversible σ-bond formation/cleavage via the neutral diradical as a key intermediate.

Maternal folic acid supplement use/dietary folate intake from preconception to early pregnancy and neurodevelopment in 2-year-old offspring: the Japan Environment and Children's Study.

We evaluated the association between maternal prenatal folic acid supplementation/dietary folate intake and motor and cognitive development in 2-year-old offspring using data from the Japan Environment and Children's Study database. Neurodevelopment of 2-year-old offspring were evaluated using the Kyoto Scale of Psychological Development 2001. In total, data of 3839 offspring were analysed. For folic acid supplementation, a multiple regression analysis showed that offspring of mothers who started using folic acid supplements before conception had a significantly lower developmental quotient (DQ) in the postural-motor DQ area than offspring of mothers who did not use them at any time throughout their pregnancy (partial regression coefficient (B) -2·596, 95 % CI -4·738, -0·455). Regarding daily dietary folate intake from preconception to early pregnancy, a multiple regression analysis showed that the group with ≥ 200 µg had a significantly higher DQ in the language-social area than the group with <200 µg. The DQ was higher in the ≥ 400 µg group (B 2·532, 95 % CI 0·201, 4·863) than the 200 to <400 µg group (B 1·437, 95 % CI 0·215, 2·660). In conclusion, our study showed that maternal adequate dietary folate intake from preconception to early pregnancy has a beneficial association with verbal cognition development in 2-year-old offspring. On the other hand, mothers who started using folic acid supplements before conception had an inverse association with motor development in 2-year-old offspring. There were no details on the amount of folic acid in the supplements used and frequency of use. Therefore, further studies are required.

Effects of External Radiation Exposure on Perinatal Outcomes in Pregnant Women After the Fukushima Daiichi Nuclear Power Plant Accident: the Fukushima Health Management Survey.

BACKGROUND: This study aimed to investigate the effects of maternal exposure to external radiation on perinatal outcomes among women who experienced the Fukushima Daiichi Nuclear Disaster (FDND) using the Fukushima Health Management Survey (FHMS). METHODS: Data from the Pregnancy and Birth Survey and Basic Survey in the FHMS were combined to analyze external maternal radiation exposure following the FDND, and the relationship between radiation dose and perinatal outcomes was analyzed using binomial logistic regression analysis. Missing dose data were supplemented using multiple imputation. RESULTS: A total of 6,875 individuals responded to the survey. Congenital anomalies occurred in 2.9% of patients, low birth weight (LBW) in 7.6%, small for gestation age (SGA; <10th percentile) in 8.9%, and preterm birth in 4.1%. The median maternal external radiation dose was 0.5 mSv (maximum, 5.2 mSv). Doses were classified as follows: <1 mSv (reference), 1 to <2 mSv, and ≥2 mSv. For congenital anomalies, the crude odds ratio for 1 to <2 mSv was 0.81 (95% confidence interval [CI], 0.56-1.17) (no participants with congenital anomaly were exposed to ≥2 mSv). At 1 to <2 mSv and ≥2 mSv, the respective adjusted odds ratios were 0.91 (95% CI, 0.71-1.18) and 1.21 (95% CI, 0.53-2.79) for LBW, 1.14 (95% CI, 0.92-1.42) and 0.84 (95% CI, 0.30-2.37) for SGA, and 0.91 (95% CI, 0.65-1.29) and 1.05 (95% CI, 0.22-4.87) for preterm birth. CONCLUSION: External radiation dose due to the FDND was not associated with congenital anomalies, LBW, SGA, or preterm birth.

The Effects of the Great East Japan Earthquake on Perinatal Outcomes: Results of the Pregnancy and Birth Survey in the Fukushima Health Management Survey.

There are limited studies on the long-term effects of natural/environmental disasters, especially nuclear disasters, on obstetric outcomes. This study aimed to review the results of perinatal outcomes immediately after the Great East Japan Earthquake (GEJE) and the Fukushima Daiichi Nuclear Power Plant accident, as well as their long-term trends over 8 years, in the Fukushima Health Management Survey. The annual population-based Pregnancy and Birth Survey is conducted as part of the Fukushima Health Management Survey. The Fukushima Prefecture government launched it to assess the health conditions of pregnant women and their neonates after the GEJE. The self-reported questionnaire was sent to 115,976 pregnant women by mail from January 2012, with 58,344 women responding to the questionnaire (50.3% response rate). Pregnancy complications, such as gestational hypertension, respiratory diseases, and mental disorders, increased in some women who were pregnant at the time of the earthquake and immediately after the earthquake. However, the direct effects on newborns, such as preterm birth, low birth weight, and congenital anomalies, were not immediately clear after the earthquake. Although there were significant differences in the occurrence of preterm birth and low birth weight among the districts, there was no change in the occurrences of preterm birth, low birth weight, or anomalies in newborns in Fukushima Prefecture from the fiscal year 2011 to the fiscal year 2018. Therefore, the long-term effects of the post-disaster radiation accident on perinatal outcomes are considered to be very small.

Meconium-stained amniotic fluid during labor may be a protective factor for the offspring's childhood wheezing up to 3 years of age: the Japan Environment and Children's Study.

We aimed to evaluate the association between meconium-stained amniotic fluid during labor and offspring's childhood wheezing. This study analyzed the data of participants enrolled in the Japan Environment and Children's Study, a nationwide prospective birth cohort study, between 2011 and 2014. Data of women with singleton live births between 22 and 40 weeks' gestation were analyzed. Participants were categorized into two groups according to the presence or absence of meconium-stained amniotic fluid. The primary outcome measure was the offspring's childhood wheezing up to 3 years of age. A logistic regression model was used to calculate the adjusted odds ratio for childhood wheezing in children of women with meconium-stained amniotic fluid, considering those without meconium-stained amniotic fluid as a reference, taking into account the potential confounding factors affecting the incidence of wheezing. We analyzed data from 61,991 participants: 1796 (2.9%) participants had meconium-stained amniotic fluid during labor and 18,919 (30.5%) of the offspring had childhood wheezing. The adjusted odds ratios for the offspring's childhood wheezing were 0.89 (95% confidence interval, 0.79-0.99) in total participants, 0.87 (95% confidence interval, 0.78-0.97) in term births, and 2.00 (95% confidence interval, 0.98-4.09) in preterm births. CONCLUSIONS: This study revealed a decreased incidence of childhood wheezing among the children of women with meconium-stained amniotic fluid in term births. By yet unknown mechanisms, meconium-stained amniotic fluid was associated with a decreased incidence of childhood wheezing in the offspring. Further studies are required to clarify the mechanism of one's own meconium in affecting their health condition. WHAT IS KNOWN: • Meconium-stained amniotic fluid during labor is associated with several adverse perinatal outcomes, and meconium aspiration syndrome is associated with offspring's childhood asthma and wheezing. • Meconium-stained amniotic fluid during labor could be an independent protective factor for the offspring's dermatitis and skin rash. WHAT IS NEW: • Whole cases with meconium-stained amniotic fluid during labor were associated with a decreased incidence of offspring's childhood wheezing up to 3 years of age. • This study may shed light on the effects of simple meconium-stained amniotic fluid on offspring's childhood health.

Potential critical risks of pulmonary thromboembolism from an asymptomatic postpartum ovarian vein thrombosis: a case report.

BACKGROUND: Ovarian vein thrombosis (OVT) may cause maternal mortality by inducing pulmonary thromboembolism (PTE). However, the prevalence, etiology, risk factors, prognosis, and optimal treatments for asymptomatic OVT during and after pregnancies are unclear, which therefore requires a high clinical index of suspicion for certain diagnoses due to its vague presentation. We herein present a case of asymptomatic postpartum OVT that extended toward the inferior vena cava (IVC), resulting in a potential risk of PTE. CASE PRESENTATION: A 30-year-old postpartum woman presented with slight dyspnea after an uneventful vaginal delivery at 40 weeks of gestation. We checked her laboratory data to exclude lethal thrombosis; D-dimer levels were 85.6 µg/mL. We performed computed tomography (CT) to search the presence of PTE and deep vein thrombosis (DVT); although no signs of PTE and DVT in her legs were detected, CT and trans-abdominal ultrasonography (TAUS) revealed a right OVT. Heparin was administered, and D-dimer levels decreased; warfarin at a dose of 2 mg/day was subsequently administered to control anti-coagulopathy. However, D-dimer was re-elevated despite adequate anticoagulation treatment, and extension of the right OVT to the IVC was detected by CT and TAUS. With warfarin administration, CT and TAUS showed the disappearance of right OVT. The patient was discharged from the hospital 17 days after delivery. CONCLUSIONS: Even asymptomatic postpartum OVT may lead to PTE. Universal screening guidelines and optimal treatment strategies for asymptomatic OVT in pregnant and postpartum women should be established through future studies.

Gestational weight gain as a risk factor for dystocia during first delivery: a multicenter retrospective cohort study in Japan.

BACKGROUND: Dystocia is a common obstetric complication among nulliparous women, which requires medical intervention and carries the risk of negative maternal and neonatal outcomes. Our aim was to examine the association between body mass index (BMI) and the occurrence of dystocia. We also identified cutoffs of gestational weight gain, based on pre-pregnancy BMI, associated with the risk of dystocia. METHODS: This was a multicenter, retrospective, cohort study conducted in two tertiary Maternal-Fetal medicine units in Fukushima, Japan. The study population included nullipara women who delivered at either of the two units between January 1, 2013, and December 31, 2020. Women (n = 2597) were categorized into six groups (G) based on their pre-pregnancy BMI: G1 (< 18.5 kg/m2), G2 (18.5 to < 20.0 kg/m2), G3 (20.0 to < 23.0 kg/m2), G4 (23.0 to < 25.0 kg/m2), G5 (25.0 to < 30.0 kg/m2), and G6 (≥ 30.0 kg/m2). Using G3 as a reference, multiple logistic regression analyses were performed to estimate the risk of dystocia for each BMI category. Receiver operating characteristic curve analyses were performed to determine the cutoff value of gestational weight gain for the risk of dystocia. RESULTS: The highest BMI category (G6) was an independent risk factor for dystocia (adjusted odds ratio, 3.0; 95% confidence interval, 1.5-5.8). The receiver operating characteristic curve analysis revealed no association between gestational weight gain and the occurrence of dystocia in G5 and G6 (P = 0.446 and P = 0.291, respectively). For G1 to G4, AUC and predictive cutoffs of gestational weight gain for dystocia were as follows: G1, AUC 0.64 and cutoff 11.5 kg (P < 0.05); G2, AUC 0.63 and cutoff 12.3 kg (P < 0.05); G3, AUC 0.67 and cutoff 14.3 kg (P < 0.01); and G4, AUC 0.63 and cutoff 11.5 kg (P < 0.05). CONCLUSION: A pre-pregnancy BMI > 30.0 kg/m2 was an independent risk factor for dystocia. For women with a pre-pregnancy BMI < 25.0 kg/m2, the risk of dystocia increases as a function of gestational weight gain. These findings could inform personalized preconception care for women to optimize maternal and neonatal health.

Preconception vitamin D intake and obstetric outcomes in women using assisted reproductive technology: the Japan Environment and Children's Study.

BACKGROUND: In reproductive medicine, vitamin D (VitD) is of particular interest because its deficiency has been linked to various infertility issues. Thus, preconception care, including appropriate VitD supplementation, is essential, especially in women using assisted reproductive technology (ART). Despite the therapeutic benefits of VitD, adverse events due to a high daily intake may influence obstetric outcomes. However, the effects of either low or high preconception VitD intake on obstetric outcomes, including the outcomes in women who used ART, remain unclear. Therefore, the aim of this study was to examine the association between pre-pregnancy daily VitD intake and obstetric outcomes in Japanese women, including those who conceived through ART. METHODS: Data were obtained from the Japan Environment and Children's study database comprising 92,571 women recruited between January 2011 and March 2014 in Japan. Participants were categorized into five quintiles according to pre-pregnancy VitD intake (Q1 and Q5 had the lowest and highest VitD intake, respectively) and stratified according to the use of ART. Multiple logistic regression was performed to identify the effects of pre-pregnancy VitD intake on preterm birth (PTB), low-birth weight infant (LBW), and small for gestational age (SGA). RESULTS: Using Q3 (middle VitD intake) as a reference, our analysis revealed that Q5 (highest VitD intake) showed an increased risk of LBW < 1500 g (adjusted odds ratio [aOR]: 1.09, 95% confidence interval [CI]: 1.00-1.18) and SGA (aOR: 1.26, 95% CI: 1.14-1.39) among women who conceived without ART. Among women who conceived with ART, we found that Q5 (highest VitD intake) showed an increased risk of PTB at < 37 weeks (aOR: 2.05, 95% CI: 1.27-3.31). CONCLUSION: The present study revealed that higher VitD intake before pregnancy may affect perinatal outcomes, particularly in women using ART. Our findings may facilitate personalized preconceptional counseling regarding VitD intake based on the method of conception, especially among women using ART.

Association of preconception dysmenorrhea with obstetric complications: the Japan Environment and Children's Study.

BACKGROUND: The association of maternal preconception dysmenorrhea, especially primary dysmenorrhea, with obstetric complications has not been clearly described. Therefore, we evaluated the association of preconception dysmenorrhea with obstetric complications while accounting for the presence of pelvic pathologies. METHODS: We analyzed the data of women with singleton live births at and after 22 weeks of gestation enrolled in the Japan Environment and Children's Study, a nationwide birth cohort study, between 2011 and 2014. Participants with psychological disorders were excluded. Preconception dysmenorrhea, identified in the medical record transcripts, was categorized into mild dysmenorrhea (MD) and severe dysmenorrhea (SD). Furthermore, excluding those who had pelvic pathologies via self-reported questionnaires (endometriosis, adenomyosis, and uterine myomas) with MD and SD, preconception dysmenorrhea was categorized into mild primary dysmenorrhea (MPD) and severe primary dysmenorrhea (SPD), respectively. Using multiple logistic regression, adjusted odds ratios (aORs) for obstetric complications, including preterm birth (PTB) before 37 weeks and 34 weeks, small-for-gestational-age infants, preterm premature rupture of membrane, and hypertensive disorders of pregnancy, were calculated (considering confounders) in women with (1) MD or SD and (2) MPD or SPD. Women without preconception dysmenorrhea were used as a reference. RESULTS: A total of 80,242 participants were analyzed. In women with SD, the aOR for PTB before 37 weeks was 1.38 (95% confidence interval [CI] 1.10, 1.72). In women with SPD, the aOR for PTB before 37 weeks was 1.32 (95% CI 1.02, 1.71). There was no association between women with MD or MPD and obstetric complications. CONCLUSIONS: SD and SPD are significantly associated with an increased incidence of PTB before 37 weeks. Care providers should provide proper counseling regarding the association between preconception dysmenorrhea and obstetric complications. Optimal management of pregnant women with preconception dysmenorrhea to reduce the incidence of PTB should be elucidated in further studies, with detailed clinical data of pelvic pathologies.

Effect of gestational weight gain on preeclampsia among underweight women: A single tertiary referral center study in Japanese women.

AIM: To examine the effect of weight gain during pregnancy on preeclampsia among women with a prepregnancy body mass index < 18.5 kg/m2 . METHODS: This retrospective cohort study included 479 Japanese women with singleton pregnancies and a prepregnancy body mass index < 18.5 kg/m2 , who gave birth between 2013 and 2019 at Ohta Nishinouchi Hospital. The study included 22 (18 with preeclampsia and four with gestational hypertension) and 457 patients with and without hypertensive disorders of pregnancy, respectively. RESULTS: The prevalence of hypertensive disorders of pregnancy and preeclampsia was 4.6% and 3.8%, respectively. With weight gain during pregnancy (continuous variable) set as a reference, multiple logistic regression revealed that excessive weight gain during pregnancy increased the risk of preeclampsia (adjusted odds ratio: 1.13, 95% confidence interval: 1.00-1.28, p < 0.05) and hypertensive disorders of pregnancy (adjusted odds ratio: 1.15, 95% confidence interval: 1.03-1.29, p < 0.05). Based on receiver operating characteristic curve analyses (area under the curve 0.65, 95% confidence interval: 0.50-0.80; p < 0.05), we determined the cutoff value of weight gain during pregnancy for the occurrence of preeclampsia among women with body mass index < 18.5 kg/m2 to be 13.0 kg, with sensitivity and specificity of 0.50 and 0.78, respectively. CONCLUSION: This study indicates that excessive weight gain during pregnancy increases preeclampsia risk among underweight women and provides new recommendations for weight gain during pregnancy for such women. Further research regarding the pathogenesis of preeclampsia for underweight women is warranted.

Optimal gestational weight gain to reduce the risk of hypertension disorders of pregnancy among women with obesity: A single tertiary referral center study in Japan.

AIM: To examine the effect of weight gain during pregnancy on hypertension disorders of pregnancy among women with a prepregnancy body mass index ≥30.0 kg/m2 . METHODS: This retrospective cohort study included 257 Japanese women (116 primipara; 141 multipara) with singleton pregnancies with a prepregnancy body mass index ≥ 30.0 kg/m2 , who gave birth during 2013 to 2020 at Ohta Nishinouchi Hospital. Multiple logistic regression analyses were performed to identify the effect of gestational weight gain on early-onset (<34 weeks), late-onset (≥34 weeks), and overall hypertension disorders of pregnancy. RESULTS: The prevalence of hypertension disorders of pregnancy in primiparas and multiparas was 28.4% and 11.3%, respectively. By multiple logistic regression analysis, gestational weight gain during pregnancy increased the risk of early-onset (adjusted odds ratio: 1.20, 95% confidence interval: 1.03-1.39, p < 0.05) and overall hypertension disorders of pregnancy (adjusted odds ratio: 1.12, 95% confidence interval: 1.03-1.22, p < 0.05) among primiparas. Based on receiver operating characteristic curve analyses for early-onset (area under the curve 0.67, 95% confidence interval: 0.56-0.78; p < 0.05) and overall hypertension disorders of pregnancy (area under the curve 0.76, 95% confidence interval: 0.61-0.91; p < 0.05) among primiparas, we determined the cut-off weight gain during pregnancy for early-onset and overall hypertension disorders of pregnancy as 3.85 kg, with sensitivity/specificity of 0.76/0.59 and 0.91/0.53, respectively. CONCLUSION: We recommend that the optimal gestational weight gain for reducing HDP be under 3.85 kg. This information may facilitate personalized pre-conception counseling among women with obesity.