Establishment of a measurement system to evaluate breast milk transfer of biological agents using dry filter paper: A multi-institutional study.

AIMS: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. METHODS: To generate dried filter paper (DFP) samples, approximately 30 µL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme-linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2-8°C or -20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland-Altman analysis. RESULTS: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within-run and between-run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%-110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (-12.1 to +16.6 ng/mL). CONCLUSIONS: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women.

Preconception underweight impact on postnatal osteoporotic fracture: a retrospective cohort study using Japanese claims data.

BACKGROUND: Undernutrition and underweight are osteoporosis risk factors. Therefore, improving the health of underweight young women in Japan is an important medical issue. However, few studies have evaluated the association between being preconception underweight and postnatal osteoporotic fractures in young women. METHODS: This retrospective cohort study used a Japanese nationwide claims database (JMDC Inc.) to evaluate the effect of preconception underweight on the incidence of osteoporotic fracture within two years after delivery. Data from 16,684 mothers who delivered their first singleton babies between January 2006 and December 2020 were analysed. The combination of disease codes of fractures at sites associated with osteoporosis and medical procedures for fractures was defined as the incidence of osteoporotic fractures, whereas the body mass index (BMI) recorded 12-36 months before delivery was used as the exposure. We estimated the incidence of osteoporotic fractures by BMI category using a Kaplan-Meier curve and examined the fracture risk using Cox hazard regression analyses. RESULTS: Fifty-one women (0.31%) were affected by osteoporotic fractures within two years of delivery. More than 80% of these were rib fractures, and approximately 65% of fractures occurred after the first year postpartum. Preconception underweight (BMI < 18.5 kg/m2) was significantly associated with the incidence of postpartum osteoporotic fractures. There was no significant association between low BMI and postnatal fractures, as analysed via multiple categorical logistic regression analysis. CONCLUSION: Appropriate control of preconception weight might be critical to improving the postpartum quality of life, subsequent bone health, and neonatal care environment.

Pre-pregnancy body mass index and low birthweight: Secondary data analysis using health insurance claims data in Japan.

AIM: For women, being underweight increases their susceptibility to osteoporosis, anemia, and other conditions and affects the weight of their infants and the well-being of future generations. This study examined the association between low pre-pregnancy body mass index (BMI) and low birthweight using health insurance claims data and health checkup data, including weight measurements. METHODS: We used health insurance claims data and health checkup data (JMDC, Tokyo, Japan) of women and their newborns in Japan between 2006 and 2020. We used checkup data, which included more accurate weight measurements and blood test-based diagnoses of anemia and hyperlipidemia compared to self-reported data. Maternal pre-pregnancy BMI was compared across three groups: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), and overweight (BMI ≥25.0 kg/m2). The primary outcome was low birthweight (<2500 g), and secondary outcome was preterm childbirth. Logistic regression analyses were conducted to compare outcomes in the three groups by BMI. The underweight BMI group was considered as the reference group. A subgroup analysis was performed by maternal age. RESULTS: In total, 16 363 mothers (underweight, 3418 [21%], normal weight, 11 493 [70%], and overweight, 1452 [8.9%]) were included. The risk of primary outcome (low birthweight) was significantly lower in the normal weight group than in the underweight group (4.6% vs. 5.7%; adjusted odds ratio 0.78 [95% confidence interval: 0.65-0.96]). In the subgroup analyses, no significant differences were noted in the incidences of low birthweight and preterm childbirth between maternal age groups. CONCLUSIONS: Pre-pregnancy BMI was associated with an increased risk of delivering low-birthweight infant. Awareness about the importance of women's pre-pregnancy health and appropriate BMI may reduce the incidence of low birthweight.

Pregnancy-related issues from the perspective of patients with inflammatory rheumatic diseases - Results from a survey of the members of the National Association for Inflammatory Rheumatic Diseases.

OBJECTIVES: This study aimed to clarify the issues related to pregnancy in patients with inflammatory rheumatic diseases (RDs) and to provide useful information for developing medical services from patients' perspectives. METHODS: A survey involving approximately 5,000 members of the Patients Association for Collagen Vascular Diseases Japan was conducted using a questionnaire that was sent and returned by mail. The questionnaire items included age at the time of the survey, types of RDs, association of RDs with pregnancy/childbirth outcomes, and pregnancy-related supports and hindrances. RESULTS: We received 491 completed questionnaires. The most common RD was systemic lupus erythematosus (n=309). Approximately 60% of participants had a history of childbirth. Approximately 60% of participants had previously experienced pregnancy-related challenges due to RDs. These included concerns about the influence of drugs on babies, genetic transmission, and active disease. Patients with active disease at the time of conception were more likely to experience disease exacerbation during pregnancy, but this did not correlate with whether the pregnancy was planned. CONCLUSION: This study revealed that many patients with RDs experienced pregnancy-related challenges and needed appropriate support based on appropriate information. The findings here should help rheumatologists, health care providers, and public agencies provide counseling and information.

Intravenous immunoglobulin treatment for obstetric antiphospholipid syndrome refractory to conventional therapy: A single-arm, open-labelled multicentre clinical trial.

OBJECTIVES: The objective of the study was to compare the efficacy of intravenous immunoglobulin (IVIG) therapy for obstetric antiphospholipid syndrome (APS) refractory to conventional treatment. METHODS: We conducted a single-arm, open-label multicentre clinical intervention trial. The enrolled criteria were patients with refractory APS who had a history of still or premature birth before 30 weeks of gestational age, even though they had been treated with conventional treatment, i.e. heparin and low-dose aspirin. After confirming the foetal heartbeats, a single course of IVIG (0.4 g/kg body weight daily for 5 days) was added to conventional treatment. The primary outcome was a live birth ratio of >30 weeks of gestational period, and the secondary outcome included improving pregnancy outcomes compared to previous pregnancy. RESULTS: Twenty-five per cent of patients (2 of 8 cases) achieved a live birth after the 30th week of pregnancy by IVIG-only add-on treatment, which is the same prevalence as the historical control. However, by adding other second-line therapy to IVIG and conventional treatment, further three patients (37.5%) achieved improvements in pregnancy outcome compared to previous treatments. In total, five patients (62.5%) were able to achieve preferable pregnancy outcomes through combination treatment including IVIG. CONCLUSIONS: This clinical trial could not demonstrate the efficacy of IVIG-only add-on therapy at improving the pregnancy outcomes of patients with obstetric APS refractory to conventional treatment. However, the combination of IVIG with rituximab or statins adding to conventional treatment improved pregnancy outcomes and resulted in more live births. Further studies are needed to investigate the efficacy of multi-targeted therapy to treat obstetric refractory APS.

Physician approval for pregnancy in patients with systemic lupus erythematosus showing only serological activity: A vignette survey study.

OBJECTIVE: The European League Against Rheumatism recommends that the disease activity of systemic lupus erythematosus should be stable before pregnancy because complications and disease flares increase if pregnancy occurs while disease activity is high. However, some patients have ongoing serological activity even after treatment. Herein, we investigated how physicians decide on the acceptability of pregnancy in patients showing only serological activity. METHODS: A questionnaire was administered from December 2020 to January 2021. It included the characteristics of physicians, facilities, and the allowance for pregnancies of patients using vignette scenarios. RESULTS: The questionnaire was distributed to 4946 physicians, and 9.4% responded. The median age of respondents was 46 years, and 85% were rheumatologists. Pregnancy allowance was significantly affected by the duration of the stable period and status of serological activity [duration: proportion difference 11.8 percentage points (p.p.), P < .001; mild activity: proportion difference -25.8 p.p., P < .001; high activity: proportion difference -65.6 p.p., P < .001]. For patients with high-level serological activity, 20.5% of physicians allowed pregnancy if there were no clinical symptoms for 6 months. CONCLUSIONS: Serological activity had a significant effect on the acceptability of pregnancy. However, some physicians allowed patients with serological activity alone to become pregnant. Further observational studies are required to clarify such prognoses.

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

AIM: Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. METHODS: We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. RESULTS: Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. CONCLUSIONS: Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

A pregnant woman with thymoma-associated pure red cell aplasia.

BACKGROUND: Pure red cell aplasia (PRCA) is a hematological disorder characterized by anemia with severe reticulocytopenia caused by a marked reduction in erythroid precursors in the bone marrow. PRCA is known to be associated with pregnancy, but thymoma-associated PRCA during pregnancy is very rare, and its successful management has not been reported. CASE PRESENTATION: A 37-year-old primiparous woman with severe anemia was referred to our center at 27 weeks' gestation. She was diagnosed with PRCA based on bone aspiration findings at 33 weeks' gestation. Magnetic resonance imaging (MRI) revealed an anterior mediastinal mass 4 cm in size suspected of being thymoma. She was therefore diagnosed with thymoma-associated PRCA during pregnancy. Surgery for thymoma was planned after delivery, since the imaging findings were suggestive of early-stage thymoma (Masaoka stage I or II). With transfusion of a total 3,360 ml of red blood cells (RBCs) during pregnancy, the patient gave birth to a baby girl weighing 2,548 g at 40 weeks' gestation. The baby showed transient congenital cutaneous candidiasis. The placental pathology revealed subamniotic inflammation with a fungal structure. Treatment with topical anti-fungal cream immediately ameliorated the baby's skin lesion. Maternal anemia did not improve after delivery; however, the thymoma did not increase in size. At five months after delivery, the mother underwent thymectomy with oral cyclosporine A. A pathological examination revealed Masaoka stage II-a thymoma. She completely had recovered from anemia at six months after surgery. Cyclosporine A treatment was discontinued three years after surgery. Remission has been sustained for four years since surgery. CONCLUSIONS: A very rare case of thymoma-associated PRCA during pregnancy was diagnosed without any subjective symptoms and was expectantly managed, resulting in a good prognosis. Although bone marrow aspiration during pregnancy is an invasive test, it is important to confirm the diagnosis. Conservative management with blood transfusion was possible for early-stage thymoma-associated PRCA during pregnancy. Active surveys, including MRI, for PRCA during pregnancy led to the detection of thymoma at an early stage and the achievement of a preferable pregnancy outcome.

Pravastatin concentrations in maternal serum, umbilical cord serum, breast milk and neonatal serum during pregnancy and lactation: A case study.

WHAT IS KNOWN AND OBJECTIVE: Statins are associated with improved pregnancy outcomes in patients with preeclamptic antiphospholipid syndrome (APS) and intrauterine foetal death. Several studies showed that statins are not teratogenic. However, data characterizing placental transfer and excretion of pravastatin into breast milk are limited. CASE SUMMARY: We experienced two patients diagnosed with APS received 10 mg of pravastatin from the first trimester until delivery to prevent pre-eclampsia. Pravastatin concentrations in maternal serum, infant serum and cord blood were evaluated. The estimated maternal-foetal transfer ratios of pravastatin in the two patients were 25.5% and 23.8% respectively. Pravastatin was eliminated from neonatal serum within 2 days. Both infants developed normally with no drug-related adverse effects. Pravastatin was not detected in either patient's breast milk at 3 days after the last dose. WHAT IS NEW AND CONCLUSION: The infants delivered from the mothers who were treated with pravastatin during pregnancy had no apparent adverse effects.

The effect of parity, history of preeclampsia, and pregnancy care on the incidence of subsequent preeclampsia in multiparous women with SLE.

OBJECTIVES: To clarify the correlation between preeclampsia and parity and to identify protective factors against preeclampsia in multiparous women with systemic lupus erythematosus (SLE). METHODS: We conducted a single-center, retrospective chart review study of 85 pregnant women. We used multiple logistic regression analysis to assess the association between parity and preeclampsia in women with SLE, and described the detailed clinical courses and management of four women with a history of severe preeclampsia and of a woman who experienced preeclampsia during her latest pregnancy. RESULTS: Multiparity was significantly associated with a low risk of preeclampsia (adjusted odds ratio: 0.08; 95% confidence interval: 0.01-0.95). One multiparous woman without a history of preeclampsia developed preeclampsia during her latest pregnancy; she had critical risk factors for preeclampsia, including chronic kidney disease and hypertension, and was not administered aspirin. In contrast, four multiparous women with a history of severe preeclampsia received adequate medications; they did not develop recurrent preeclampsia and delivered live newborns. CONCLUSIONS: Multiparity and maintenance therapy for SLE before and during pregnancy and preventive treatment for preeclampsia may improve outcomes in subsequent pregnancies.

Clinical feature and anti-phospholipid antibody profiles of pregnancy failure in young women with antiphospholipid antibody syndrome treated with conventional therapy.

OBJECTIVE: To elucidate clinical feature and anti-phospholipid antibody (aPL) profiles, including lupus anticoagulant (LA), anti-cardiolipin (CL) antibodies and anti-phosphatidylserine/prothrombin (PS/PT) antibodies, of pregnancy failure in patients with antiphospholipid antibody syndrome (APS) already treated with conventional therapy. MATERIALS AND METHODS: Thirty-four women with a history of pregnancy who were diagnosed with APS between 2008 and 2016 were included in the study. We defined the successful pregnancy group as women who gave birth to a healthy baby over 1500 g after 34 weeks of pregnancy under conventional treatment (heparin and/or low-dose aspirin). The unsuccessful pregnancy group was defined as women whose pregnancy outcomes did not meet the aforementioned criteria despite the conventional therapy. The clinical features and aPL profiles were compared between the two groups. RESULTS: Fifteen women were classified into the unsuccessful pregnancy group; seven women were in the successful pregnancy group. Having history of both thrombosis and pregnancy morbidity and LA positivity were significantly more prevalent in the unsuccessful pregnancy group than in the successful pregnancy group (p <.05, respectively). In contrast, single positivity of anti-CL antibody was negatively associated with APS-associated pregnancy morbidity under the conventional treatment (p <.01). The proportion of anti-PS/PT IgG-positive patients was significantly higher in the unsuccessful pregnancy group (p = .02, OR 18.7, 95% CI 1.50, 232.29) with high concordance rate with LA (97% consistence). CONCLUSION: History of both thrombosis and pregnancy morbidity and the positivity of LA and/or anti-PS/PT-IgG, not but anti-CL-antibodies were correlated with APS-associated pregnancy morbidity refractory to conventional treatment. Clinical feature and aPL profiles might help us to make risk assessment for adverse pregnancy outcomes in patients with APS.

Tocilizumab and pregnancy: Four cases of pregnancy in young women with rheumatoid arthritis refractory to anti-TNF biologics with exposure to tocilizumab.

OBJECTIVES: To investigate the use of tocilizumab (TCZ) in pregnant patients with active rheumatoid arthritis (RA) refractory to anti-tumour necrosis factor (TNF) agents. METHODS: We retrospectively analysed the medical records of pregnant women with active RA treated between July 2008 and January 2015 by the Division of Maternal Medicine at our hospital. Inclusion criteria for this case series included active RA refractory to anti-TNF agents and exposure to TCZ at the time of conception. RESULTS: Our review of 28 patient hospital records identified four patients who met the inclusion criteria. All four patients had active synovitis before starting treatment with TCZ. Successful TCZ therapy allowed them to plan to become pregnant. When pregnancy was confirmed, TCZ was terminated as soon as possible in all patients. Three patients delivered full-term infants without any adverse outcomes. One patient had a partial molar pregnancy and miscarried during gestational week 11. Two patients remained in clinical remission with low-dose prednisolone (PSL) or no treatment for RA during pregnancy. CONCLUSIONS: TCZ may be a good alternative therapy for RA patients with symptoms that are hard to control with TNF blockers who desire to bear children.

Comparison of physical activity energy expenditure in Japanese adolescents assessed by EW4800P triaxial accelerometry and the doubly labelled water method.

The present study compared the accuracy of triaxial accelerometry and the doubly labelled water (DLW) method for measuring physical activity (PA) in Japanese adolescents. A total of sixty adolescents aged 12-15 years were analysed. The total energy expenditure (TEE) was measured over 7 d by the DLW method and with an EW4800P triaxial accelerometer (Panasonic Corporation). The measured (RMR)(m) and predicted RMR (RMR(p)) were 5·7 (SD 0·9) and 6·0 (SD 1·0) MJ/d, respectively. TEE measured by the DLW method and accelerometry using RMR(m) or RMR(p) were 11·0 (SD 2·6), 10·3 (SD 1·9), and 10·7 (SD 2·1) MJ/d, respectively. The PA levels (PAL) measured by the DLW method using RMR(m) or RMR(p) were 1·97 (SD 0·31) and 1·94 (SD 0·31) in subjects who exercised, and 1·85 (SD 0·27) and 1·74 (SD 0·29) in subjects who did not exercise. The percentage of body fat correlated significantly with the percentage difference between RMR(m) v. RMR(p), TEE, PA energy expenditure (PAEE) and PAL using RMR(p), and PAL using RMR(m) assessed by the DLW method and accelerometry. The present data showed that while accelerometry estimated TEE accurately, it did not provide the precise measurement of PAEE and PAL. The error in accelerometry was attributed to the prediction error of RMR and assessment in exercise.

Initiation of hydroxychloroquine therapy during pregnancy can cause adverse effects and alter pregnancy outcomes: A case of acute generalised exanthematous pustulosis induced by hydroxychloroquine in a patient with systemic lupus erythematosus.

Hydroxychloroquine (HCQ) is effective for treating a number of autoimmune diseases, including systemic lupus erythematosus. HCQ is generally safe and may be prescribed to pregnant women. Although current guidelines recommend initiating HCQ when considering pregnancy, the drug can cause adverse effects such as acute generalised exanthematous pustulosis (AGEP), which should be carefully evaluated. A 30-year-old pregnant woman with systemic lupus erythematosus at 16 + 5 gestational weeks was referred to National Center for Child Health and Development for persistent proteinuria and alopecia. Tacrolimus was initiated, and the dose of prednisone was increased. At 20 + 3 weeks of gestation, HCQ was administered to allow for a dose reduction of prednisolone. Proteinuria gradually improved as the pregnancy course stabilised. At 27 + 1 weeks of gestation, generalised pustular exanthema developed, presumably due to HCQ. Based on the clinical course and the analysis of the skin lesions, she was diagnosed to have either AGEP or generalised pustular psoriasis. Despite discontinuing HCQ, the skin lesions worsened dramatically, and infliximab therapy was required. After one course of infliximab treatment, exanthema gradually subsided. The final diagnosis was AGEP, based on the clinical course and pathological findings. At 30 weeks, pyothorax developed because of the pyogenic skin lesion and the compromised immune system, and long-term antibiotic therapy was required until 32 + 4 weeks, after which she underwent caesarean section. Although introducing HCQ is occasionally necessary during pregnancy, it is preferable to initiate HCQ in the preconception period and not after pregnancy because of the possible adverse effect, which can alter perinatal prognosis. Rheumatologists should consider the potential risks of HCQ.

Arthritic joint-targeting small interfering RNA-encapsulated liposome: implication for treatment strategy for rheumatoid arthritis.

RNA interference, mediated by small interfering RNA (siRNA), is effective in silencing genes with a high degree of specificity. To explore the therapeutic potential of systemically administered siRNA for rheumatoid arthritis (RA), we tested the complex of siRNA and the recently developed wrapsome (siRNA/WS) containing siRNA-encapsulated liposome in mice with collagen-induced arthritis (CIA). Mice with CIA received an intravenous injection of Cy5-labeled siRNA/WS. Fluorescence stereoscopic microscopy and flow cytometry were used to assess the siRNA/WS tissue distribution. The efficacy of siRNA-targeting tumor necrosis factor (TNF)-α/WS in CIA was evaluated by arthritis score. TNF-α mRNA levels in the joints were measured by real-time reverse transcriptase-polymerase chain reaction. The intensity of Cy5 fluorescence was higher in arthritic joints than in nonarthritic sites in Cy5-siRNA/WS-treated mice and remained higher up to 48 h after injection, compared with that in naked Cy5-siRNA-treated mice. Cy5 fluorescence intensity was higher in synovial cells than in splenocytes, bone marrow cells, and peripheral blood leukocytes. The majority of Cy5-positive synovial cells were CD11b⁺ with only a few CD3⁺ cells. Treatment with TNF-α siRNA/WS resulted in significant decreases in severity of arthritis and TNF-α mRNA level in the joints compared with control siRNA/WS. In conclusion, the use of our WS allowed efficient and targeted delivery of siRNAs to arthritic joints. The siRNA/WS was mainly incorporated into CD11b⁺ cells, including macrophages and neutrophils, in the inflamed synovium, suggesting its potential therapeutic effects in RA by silencing the expression of inflammatory molecules produced by these cells.

Obstetric anti-phospholipid syndrome: from pathogenesis to treatment.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by clinical manifestations such as thrombosis and obstetric complications with documented persistence of antiphospholipid antibodies (aPLs). Recent studies have revealed that the cause of aPL-related obstetric complications is dysfunction of placental trophoblasts and inflammation of the maternal-fetal interface induced by aPLs, not thrombosis. Although aPLs are associated with recurrence of serious complications during pregnancy, appropriate combination therapy with heparin and low-dose aspirin can improve the course of 70-80% of subsequent pregnancies. Preconception counseling and patient-tailored treatment are fundamental to improving maternal and fetal outcomes. Non-anticoagulant treatments such as hydroxychloroquine and statins are being developed for cases refractory to conventional treatment. Risk factors for thrombosis after pregnancy complications were identified based on the analysis of large databases of obstetric APS.