Breast milk concentrations of acetaminophen and diclofenac - unexpectedly high mammary transfer of the general-purpose drug acetaminophen.

BACKGROUND: Breastfeeding is considered to be the most effective way of ensuring the health and survival of newborns. However, mammary transfer of drugs administered to mothers to breastfeeding infants remains a pressing concern. Acetaminophen and diclofenac sodium are widely prescribed analgesics for postpartum pain relief, but there have been few recent reports on the mammary transfer of these drugs, despite advances in analytic techniques. METHODS: We conducted a study on 20 postpartum mothers from August 2019-March 2020. Blood and milk samples from participants were analyzed using liquid chromatography-electrospray ionization tandem mass spectrometry within 24 hours after oral administration of acetaminophen and diclofenac sodium. The area under the concentration-time curve (AUC) was calculated from the concentration curve obtained by a naive pooled-data approach. RESULTS: For acetaminophen, AUC was 36,053 ng/mL.h and 37,768 ng/mL.h in plasma and breast milk, respectively, with a milk-to-plasma drug concentration ratio of 1.048. For diclofenac, the AUC was 0.227 ng/mL.h and 0.021 ng/mL.h, in plasma and breast milk, respectively, with a milk-to-plasma drug concentration ratio of 0.093. CONCLUSIONS: While diclofenac sodium showed low mammary transfer, acetaminophen showed a relatively high milk-to-plasma drug concentration ratio. Given recent studies suggesting potential connections between acetaminophen use during pregnancy and risks to developmental prognosis in children, we believe that adequate information regarding the fact that acetaminophen is easily transferred to breast milk should be provided to mothers.

A lower ratio of reduced to total albumin in serum is associated with protein nutritional status of pregnant women in Japan.

Protein-energy undernutrition is potentially prevalent among Japanese pregnant women, and biomarkers that objectively indicate the protein nutritional status during pregnancy may help in implementing appropriate protein supplementation to these women. We hypothesized that a serum parameter of pregnant women, the ratio of reduced to total albumin (reduced ALB ratio), would be associated with protein intake during pregnancy. The serum reduced ALB ratio of pregnant women was compared with protein intake and with gestation outcomes (gestation length and infant birth weight) in an observational study of 115 Japanese pregnant women. The serum reduced ALB ratio in the third trimester tended to be positively correlated with gestation length (P = .07). Infant birth weights tended to be different between protein intake tertiles (P = .09); the mean infant birth weight was higher in the third tertile compared with the first and second tertiles. The protein intake of pregnant women was significantly and positively correlated with the serum reduced ALB ratio in the second trimester. The serum reduced ALB ratio reflects protein nutritional status during pregnancy and may contribute to healthier gestation outcomes.

Association between Edinburgh Postnatal Depression Scale and Serum Levels of Ketone Bodies and Vitamin D, Thyroid Function, and Iron Metabolism.

Suicide due to postpartum depression is the most common perinatal-related death and is a social concern in Japan. Nutritional deficiencies during pregnancy may contribute to postpartum depression; therefore, we investigated the relationship between postpartum depression and nutritional status during pregnancy and postpartum. We focused specifically on ketone bodies because they are known to protect brain cells. The relationship between the Edinburgh Postnatal Depression Scale (EPDS) scores and the serum levels of ketone bodies and vitamin D, thyroid function, and iron metabolism was examined. Overall, 126 pregnant women were identified for the study, and 99 were eventually included in the analysis. We defined an EPDS score of ≥9 as being positive for postpartum depression, and serum ketone levels were found to be higher in the group with an EPDS score of ≥9 during the second trimester; however, there were no other significant findings. We may be able to predict postpartum depression from a pregnant woman's serum ketone levels in the second trimester. There was a positive correlation between the EPDS scores at 3 days and 1 month postpartum (r = 0.534, p < 0.001). EPDS scores assessed in the early postpartum period may be useful for the timely detection of postpartum depression.

Changes in Serum Levels of Ketone Bodies and Human Chorionic Gonadotropin during Pregnancy in Relation to the Neonatal Body Shape: A Retrospective Analysis.

Among the physiological changes occurring during pregnancy, the benefits of morning sickness, which is likely mediated by human chorionic gonadotropin (HCG) and induces serum ketone production, are unclear. We investigated the relationship between serum levels of ketone bodies and HCG in the first, second, and third trimesters and neonatal body shape (i.e., birth weight, length, head circumference, and chest circumference) in 245 pregnant women. Serum levels of 3-hydroxybutyric acid peaked in late-stage compared with early stage pregnancy (27.8 [5.0−821] vs. 42.2 [5.0−1420] µmol/L, median [range], p < 0.001). However, serum levels of ketone bodies and HCG did not correlate with neonatal body shape. When weight loss during pregnancy was used as an index of morning sickness, a higher pre-pregnancy body mass index was associated with greater weight loss. This study is the first to show that serum ketone body levels are maximal in the third trimester of pregnancy. As the elevation of serum ketone bodies in the third trimester is a physiological change, high serum levels of ketone bodies may be beneficial for mothers and children. One of the possible biological benefits of morning sickness is the prevention of diseases that have an increased incidence due to weight gain during pregnancy.

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys.

Development of the adrenal cortex, a vital endocrine organ, originates in the adrenogonadal primordium, a common progenitor for both the adrenocortical and gonadal lineages in rodents. In contrast, we find that in humans and cynomolgus monkeys, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to-mesenchymal transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages provides a molecular framework for understanding human adrenal and gonadal disorders.

C-reactive protein level predicts need for medical intervention in pregnant women with SARS-CoV2 infection: A retrospective study.

AIM: To make effective use of the limited available hospital space during the Coronavirus disease 2019 (COVID-19) pandemic, we conducted this study to investigate the laboratory indices that identify pregnant women with SARS-CoV2 infection who require medical intervention. METHODS: We carried out a retrospective analysis of pregnant women positive for COVID-19 who were admitted to Hokkaido University Hospital from September 2020 to June 2021. Medical interventions included oxygen supplementation, systemic corticosteroids, or supplemental liquids to treat infection-related symptoms. RESULTS: Forty-two infected pregnant patients were admitted to the hospital, half of whom required medical intervention (n = 21). Fever, C-reactive protein (CRP), and platelet count are all associated with need for medical intervention. Of the 32 patients with a fever of ≥37.5°C on days 0-3 after onset of syndromes, 22 (69%) continued to have a fever on days 4-6, of which 19 (86.4%) required medical intervention. CRP level on days 4-6 predicted the presence or absence of medical intervention (area under the receiver operating characteristic curve = 0.913), with a sensitivity of 81% and specificity of 100% at a CRP cutoff of 1.28 mg/dL. CONCLUSIONS: The need for medical intervention in pregnant patients can be predicted with high accuracy using a CRP cutoff of 1.28 mg/dL on days 4-6 after onset of syndromes. The presence of fever also may be an easy marker for selecting subjects who need or will need therapeutic intervention. These could be an effective triage method to determine appropriate indications for the hospitalization of pregnant women in future outbreaks.

Hemoglobin Concentration during Early Pregnancy as an Accurate Predictor of Anemia during Late Pregnancy.

It is undetermined which blood variables related to iron storage during the first trimester of pregnancy could efficiently predict anemia occurring during the third trimester. Red blood cell count (RBC), hemoglobin concentration, hematocrit, ferritin, iron, and total iron binding capacity (TIBC) were assessed longitudinally during the first, second, and third trimesters of 231 healthy Japanese women. None of the patients had anemia in the first trimester and none used iron supplementation before the second trimester blood test. Anemia was defined as hemoglobin (Hb) < 11 g/dL for the first trimester and Hb < 10.0 g/dL for the third trimester. Forty-seven (20%) women developed anemia in the third trimester. The first trimester RBC, Hb, hematocrit, and ferritin levels were significantly lower in women with third-trimester anemia than those without anemia. The first trimester hemoglobin level exhibited a greater area under the curve of the receiver operating characteristic curve for prediction of the third trimester anemia than other blood variables; the optimal cut-off (12.6 g/dL) of hemoglobin yielded a sensitivity of 83% (39/47). First trimester hemoglobin levels were significantly better predictors of anemia during the third trimester than the indices of iron storage, including serum iron, ferritin, and TIBC levels.

Association between pre-pregnancy body mass index and gestational weight gain and perinatal outcomes in pregnant women diagnosed with gestational diabetes mellitus: The Japan Environment and Children's Study.

AIMS/INTRODUCTION: We investigated the association between gestational diabetes mellitus (GDM) and perinatal outcomes stratified by pre-pregnancy body mass index (BMI) and/or gestational weight gain (GWG). MATERIALS AND METHODS: Data from the national birth cohort in the Japan Environment and Children's Study from 2011 to 2014 (n = 85,228) were used. Japan uses the GDM guidelines of the International Association of Diabetes and Pregnancy Study Groups. The odds ratios (ORs) of perinatal outcomes were compared between women with and those without GDM. RESULTS: The OR (95% confidence interval) of having a small for gestational age infant in the GDM group with a pre-pregnancy BMI of ≥25.0 kg/m2 and insufficient GWG (<2.75 kg) was 1.78 (1.02-3.12). The OR of having a large for gestational age infant of the same BMI group with excessive GWG (>7.25 kg) was 2.04 (1.56-2.67). The OR of hypertensive disorders of pregnancy was higher in women with a BMI ≥18.5 kg/m2 in the GDM group than in the non-GDM group. CONCLUSIONS: Large for gestational age and hypertensive disorders of pregnancy were associated with pre-pregnancy BMI and GWG in either normal weight or overweight/obese women, and the relationship was strengthened when GDM was present. Women with GDM and a BMI of ≥25.0 kg/m2 are at risk of having small for gestational age and large for gestational age infants depending on GWG.

Excessive gestational weight gain during the week prior to delivery as a predictor of maternal life-threatening complications in preeclamptic women.

AIM: To investigate the relationship between excessive gestational weight gain during the week prior to delivery (GWG) and severe morbidity and pregnancy termination among pregnant women with preeclampsia (hypertension with proteinuria). METHODS: We compared GWG, laboratory data, and complication(s) between 94 preeclamptic women (preeclampsia group) with singleton pregnancies who delivered at ≥22 gestational weeks and 188 healthy women (control group) with singleton pregnancies undergoing elective cesarean deliveries. The gestational weeks at delivery were matched in the preeclampsia and control groups. RESULTS: Among 282 total participants, median of GWG was significantly higher in the preeclampsia group than in the control group (1.6 kg vs. 0.5 kg, p < 0.0001). Furthermore, the GWG cutoff value for the preeclampsia group was 1.6 kg. The odds ratio for morbidity of preeclampsia among the women with GWG ≥1.6 kg at delivery was 12.5 (95% confidence interval, 6.31-24.5). In the preeclampsia group, 47 women with GWG ≥1.6 kg had significantly higher risks of hypoproteinemia, proteinuria, and renal dysfunction than those of 47 women with GWG < 1.6 kg. While, multivariate analysis showed 1.5 kg was a GWG cutoff value for predicting maternal morbidity (p < 0.0001); preeclamptic women with GWG ≥1.5 kg had a significantly higher risk of pulmonary edema than preeclamptic women with GWG < 1.5 kg (odds ratio, 7.77; 95% confidence interval, 1.64-36.7). CONCLUSION: Excessive GWG in women with preeclampsia might be a predictor for severe maternal life-threatening complications requiring pregnancy termination.

Maternal Serum Albumin Redox State Is Associated with Infant Birth Weight in Japanese Pregnant Women.

BACKGROUND: Plasma albumin (ALB) reflects protein nutritional status in rats, but it is not clear whether it is associated with dietary protein insufficiency in pregnant women and/or their risk of low birth weight delivery. This study aimed to investigate whether maternal serum ALB redox state reflects maternal protein nutritional status and/or is associated with infant birth weights. METHODS: The relationship between the serum reduced ALB ratio and infant birth weight was examined in an observational study of 229 Japanese pregnant women. A rat model simulating fetal growth restriction, induced by protein-energy restriction, was used to elucidate the relationship between maternal nutritional status, maternal serum ALB redox state, and birth weight of the offspring. RESULTS: In the human study, serum reduced ALB ratio in the third trimester was significantly and positively correlated with infant birth weight. In the rat study, serum reduced ALB ratio and birth weight in the litter decreased as the degree of protein-energy restriction intensified, and a significant and positive correlation was observed between them in late pregnancy. CONCLUSIONS: Maternal serum reduced ALB ratio in the third trimester is positively associated with infant birth weight in Japanese pregnant women, which would be mediated by maternal protein nutritional status.

Earlier onset of proteinuria or hypertension is a predictor of progression from gestational hypertension or gestational proteinuria to preeclampsia.

Although gestational hypertension (GH) is a well-known disorder, gestational proteinuria (GP) has been far less emphasized. According to international criteria, hypertensive disorders of pregnancy include GH but not GP. Previous studies have not revealed the predictors of progression from GP to preeclampsia or those of progression from GH to preeclampsia. We aimed to determine both sets of predictors. A retrospective cohort study was conducted with singleton pregnant women who delivered at 22 gestational weeks or later. Preeclampsia was divided into three types: new onset of hypertension/proteinuria at 20 gestational weeks or later and additional new onset of other symptoms at < 7 days or at ≥ 7 days later. Of 94 women with preeclampsia, 20 exhibited proteinuria before preeclampsia, 14 experienced hypertension before preeclampsia, and 60 exhibited simultaneous new onset of both hypertension and proteinuria before preeclampsia; the outcomes of all types were similar. Of 34 women with presumptive GP, 58.8% developed preeclampsia; this proportion was significantly higher than that of 89 women with presumptive GH who developed preeclampsia (15.7%). According to multivariate logistic regression models, earlier onset of hypertension/proteinuria (before or at 34.7/33.9 gestational weeks) was a predicator for progression from presumptive GH/GP to preeclampsia (odds ratios: 1.21/1.21, P value: 0.0044/0.0477, respectively).

Survey of attitudes of individuals who underwent remote prenatal check-ups and consultations in response to the COVID-19 pandemic.

AIM: Perinatal telemedicine efforts have commenced worldwide in response to the COVID-19 pandemic. As there have been no prior studies on the acceptance of telemedicine by pregnant women, we conducted this survey to investigate the same. METHODS: We conducted an anonymous questionnaire survey of pregnant women who underwent telemedicine check-ups from March 4 to June 30, 2020, using a mobile fetal heart rate monitor and video call system through the Hokkaido University Hospital. RESULTS: Out of the 77 individuals who received prenatal telemedicine check-ups, 54 individuals (70%) had complications, and 64 individuals (83%) consented for the questionnaire survey. In the video call system, 18 individuals (28%) were found to be unwell and 17 individuals (27%) experienced difficulty using the mobile fetal heart rate monitoring device. Assuming scores for face-to-face consultations were five out of 10, the mean score for satisfaction was 4.2, but 19 (30%) women felt equal or greater satisfaction with face-to-face consultations. If not for the threat of COVID-19, only four individuals (6%) proactively expressed a desire for telemedicine, with a significantly less demand observed among primiparous women than multiparous women. The permissible additional financial burden enabling telemedicine was $10 or less for 80% of subjects. CONCLUSION: In this small preliminary study, 30% of the pregnant women felt equal or greater satisfaction with telemedicine than face-to-face consultations. A stronger demand for telemedicine was exhibited by multiparous women than primiparous women. Thus, a system that would be advantages by limiting subjects and enabling low-cost examinations is required for making perinatal telemedicine more popular.

Attenuation imaging as a new ultrasonographic application for identifying placental haematoma.

We present a case in which attenuation imaging (ATI), a recently developed ultrasonographic application, facilitated the diagnosis of preplacental and postplacental haematoma. Placental abruption is a serious condition that affects the prognosis of infants and is difficult to diagnose. Ultrasonography is the primary imaging modality that complements the clinical findings in the diagnosis; however, its sensitivity is low, and improved diagnostic accuracy is desired. Here, we found that placental haematomas on the placental fetal surface observed at 19 weeks of gestation were indistinct from placental parenchyma in B-mode ultrasonographic imaging. In ATI, the placental parenchyma was colour-mapped, but the haematoma portion was not, which helped identify the haematoma. ATI, which also colour-maps uniform tissues, did not colour-map vessels within the placenta. ATI has a breakthrough potential for improving the diagnosis of placental abruption.

Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose.

Objective: Benzodiazepines are common therapies for mental illness and insomnia, and are used during pregnancy and lactation. Although benzodiazepines have been shown to be transferred into breast milk, the amount transferred is small and compatible with breastfeeding. However, information is not available for all drugs. Therefore, we aimed to determine the milk to plasma (M/P) ratio and relative infant dose (RID), which are used as indicators of drug transfer to breast milk, to determine the safety of such drugs for lactating women and breastfeeding infants. Methods: The study comprised of 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital (approval number: 017-0131) and Tenshi Hospital (approval number: 103) for childbirth. The samples were analyzed using liquid chromatography-tandem mass spectrometry, and the M/P ratio and RID were calculated. The condition of the mother and baby at 1 month after delivery was determined from the clinical information. The target benzodiazepines were alprazolam, brotizolam, clonazepam, clotiazepam, etizolam, ethyl loflazepate, flunitrazepam, and lorazepam. Results: For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were <10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly >10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications. Conclusions: The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible.

Predictors of recurrent gestational diabetes mellitus: A Japanese multicenter cohort study and literature review.

AIM: To clarify whether maternal characteristics or laboratory parameters could help predict the onset of recurrent gestational diabetes mellitus (GDM). METHODS: We enrolled 615 women with consecutive singleton deliveries at or after 28 GW from two perinatal medical centers between 2011 and 2019 and divided them into four groups according to whether they had GDM in the first and second pregnancies. The outcome of this study was to clarify the incidence and the predictors of recurrent GDM. RESULTS: We found that among 72 women (11.7%) who had GDM during their first pregnancy, the rate of recurrent GDM was 47.2%. The 34 women (5.5%) with recurrent GDM gained significantly less weight in the first and second pregnancies and lost less weight between the first delivery and the second conception compared with those women without GDM in both pregnancies. Of women with GDM during the first pregnancy, 21 scored 2 or 3 (multiple) positive points on a 75-g oral glucose tolerance test (OGTT) during their first pregnancies; the GDM recurrence rate among these women (66.7%) was significantly higher than that among the 51 women who scored 1 positive point (39.2%; p = 0.0411). During the first pregnancy, insulin administration therapy was significantly more frequent in women with recurrent GDM than in women without recurrent GDM (23.5% vs. 5.3%, p = 0.0396, respectively). CONCLUSION: A predictor of recurrent GDM onset was a score of 2 or 3 positive points on the OGTT during the first pregnancy.

Mild thrombocytopenia indicating maternal organ damage in pre-eclampsia: a cross-sectional study.

BACKGROUND: Currently, there is a disagreement between guidelines regarding platelet count cut-off values as a sign of maternal organ damage in pre-eclampsia; the American College of Obstetricians and Gynecologists guidelines state a cut-off value of < 100 × 109/L; however, the International Society for the Study of Hypertension in Pregnancy guidelines specify a cut-off of < 150 × 109/L. We evaluated the effect of mild thrombocytopenia: platelet count < 150 × 109/L and ≥ 100 × 109/L on clinical features of pre-eclampsia to examine whether mild thrombocytopenia reflects maternal organ damage in pre-eclampsia. METHODS: A total of 264 women were enrolled in this study. Participants were divided into three groups based on platelet count levels at delivery: normal, ≥ 150 × 109/L; mild thrombocytopenia, < 150 × 109/L and ≥ 100 × 109/L; and severe thrombocytopenia, < 100 × 109/L. Risk of severe hypertension, utero-placental dysfunction, maternal organ damage, preterm delivery, and neonatal intensive care unit admission were analyzed based on platelet count levels. Estimated relative risk was calculated with a Poisson regression analysis with a robust error. RESULTS: Platelet counts indicated normal levels in 189 patients, mild thrombocytopenia in 51 patients, and severe thrombocytopenia in 24 patients. The estimated relative risks of severe thrombocytopenia were 4.46 [95 % confidence interval, 2.59-7.68] for maternal organ damage except for thrombocytopenia, 1.61 [1.06-2.45] for preterm delivery < 34 gestational weeks, and 1.35 [1.06-1.73] for neonatal intensive care unit admission. On the other hand, the estimated relative risks of mild thrombocytopenia were 0.97 [0.41-2.26] for maternal organ damage except for thrombocytopenia, 0.91 [0.62-1.35] for preterm delivery < 34 gestational weeks, and 0.97 [0.76-1.24] for neonatal intensive care unit admission. CONCLUSIONS: Mild thrombocytopenia was not associated with severe features of pre-eclampsia and would not be suitable as a sign of maternal organ damage.

Human papillomavirus type 16 sequence variation in concurrent vulvar and penile carcinoma in a married couple.

We encountered an elderly married couple with concurrent vulvar and penile carcinoma with an Asian variant of human papillomavirus type 16. Asian variants might have an elevated risk of concurrent external genital carcinomas of a male and a female, and analysis of human papillomavirus variants might be important to understand the mechanism of carcinogenesis.