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.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Diazoxide during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum: a case report.

Safety information on diazoxide for pregnant and lactating women with hypoglycemia is limited. In this case report, we assessed diazoxide concentrations in maternal and infant blood, cord blood, and breast milk. We described a 30-year-old pregnant woman diagnosed with hypoglycemia due to nesidioblastosis at 4 months of age. Before becoming pregnant, she was treated with oral diazoxide (75-375 mg). All medications were discontinued after she was discovered to be pregnant. During gestational week 25, diazoxide treatment was resumed at 150-175 mg daily for repeated hypoglycemic episodes. Diazoxide administration was continued in combination with diet treatment until delivery. Glucose levels were well controlled. During gestational week 40, a male infant weighing 3069 g was delivered via spontaneous vaginal delivery with no pregnancy or neonatal complications. Diazoxide concentrations detected in maternal serum at 2.5-11.6 h after oral treatment ranged from 12.4 to 32.7 µg/mL. In cord blood, the diazoxide concentration was 18.5 µg/mL at 7.2 h after the last dose. During lactation, no hypoglycemia or hyperglycemia was observed. The approximate calculated ratio of diazoxide in breast milk and maternal serum was 0.09. The calculated daily infant dose was 0.47 mg/kg/day. The relative infant dose via breast milk ranged from 3.1% to 5.9%. Diazoxide transferred from maternal blood to the fetus across the placenta. It also transferred into breast milk, but there were no harmful effects on the infant.

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.

Investigation on the accumulation of background and pregnancy outcome information on cases consulted by the Japan Drug Information Institute in Pregnancy.

Since pregnant women are excluded from clinical trials, it is essential to accumulate post-marketing information to evaluate the effects on the fetus of medication use during pregnancy. The Japan Drug Information Institute in Pregnancy (JDIIP) was established at the National Center for Child Health and Development as a Ministry of Health, Labour, and Welfare project to provide patients with information and conduct follow-up surveys. In this study, we investigated the status of the accumulation of JDIIP consultation cases to identify issues for enhancing clinical information appropriate for use during pregnancy and to examine how information should be collected and provided. In addition, the status of descriptions of Japanese package inserts, which are representative of those used by healthcare professionals as a source of information, was confirmed for medications used by JDIIP consultation cases. The characteristics of the JDIIP consultation cases information were that the contents that needed to be adjusted when evaluating the effects on the fetus of medication use during pregnancy were obtained. In addition, the follow-up rate was 83.1%. However, although the number of consultation facilities has increased, the number of consultations has not, indicating the need to further increase the number. It was found that there is limited information on epidemiological studies of clinical use in Japanese package inserts. To improve clinical information on the appropriate use of medications during pregnancy, it is necessary to accumulate more information in the future, and it is considered necessary to consider new approaches utilizing the JDIIP system.

Pregnancy outcomes after first-trimester exposure to fluoroquinolones: Findings based on an integrated database from two Japanese institutions.

Given the paucity of safety data on fluoroquinolone antibiotics in pregnancy, a prospective observational cohort study was conducted in pregnant women who sought help and advice on drug use at two teratology information institutes in Japan. The primary endpoint of the study was the incidence of major congenital anomalies. The study population included pregnant women exposed to (i) fluoroquinolones (fluoroquinolone group), (ii) ß-lactams (infectious control group), or (iii) other agents considered to be nonteratogenic in humans (nonteratogenic control group) during the first trimester. The frequency of major congenital anomalies was compared across groups using a logistic regression model that adjusted for maternal age, smoking status, drinking status, facility consulted, and time of consultation. The fluoroquinolone group consisted of 411 women who had 383 children born alive. The infectious control and nonteratogenic control groups consisted of 1416 and 1482 women who had 1322 and 1401 children born alive, respectively. The incidence of major congenital anomalies was 1.5%, 2.0%, and 1.6% in the fluoroquinolone group, infectious control, and nonteratogenic control groups, respectively. Logistic regression showed that fluoroquinolone exposure is not a significant risk factor for major congenital anomalies. In conclusion, first-trimester exposure to fluoroquinolone antibiotics was not associated with increased maternal or fetal risks.

Risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol: A multicenter prospective cohort study using counseling data for drug safety during pregnancy.

To assess the risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol during pregnancy, we conducted a prospective cohort study using counseling data for drug use during pregnancy provided by the Japan Drug Information Institute in Pregnancy and Toranomon Hospital. Counseling information, including drug usage and participants' demographic information, was collected between April 1988 and December 2017. Pregnancy outcome data, including major birth defects, were obtained using a questionnaire administered 1 month after delivery. The risks of major birth defects after first-trimester exposure to carbocisteine (n = 588) and ambroxol (n = 341) were compared with those of nonteratogenic drug use during the first trimester (n = 1525). The adjusted odds ratio (aORs) for major birth defects was calculated using a multiple logistic regression analysis adjusted for confounders. The incidence of major birth defects was 1.2% (7/588) and 2.1% (7/341) in the carbocisteine and ambroxol groups, respectively, which was comparable to the control group (26/1525, 1.7%). Results of multiple logistic regression demonstrated similar nonsignificant risks for both carbocisteine (aOR: 0.66, 95% confidence interval [CI]: 0.40-1.1, p = 0.11) and ambroxol (aOR: 1.1, 95% CI: 0.18-7.2, p = 0.88). No specific major birth defects were reported in the carbocisteine or ambroxol groups. This study demonstrated that carbocisteine and ambroxol exposure during the first trimester was not associated with an increased risk of major birth defects. These results could help in counseling for the use of these drugs during pregnancy and further alleviate anxiety in patients.

Pregnancy Outcomes With Exposure to Second-Generation Antipsychotics During the First Trimester.

Objective: To investigate the risk of major congenital malformations associated with exposure to second-generation antipsychotics (SGAs) in the first trimester.Methods: Pregnant women who received consultation on drug exposure from the Japan Drug Information Institute in Pregnancy from October 2005 to December 2016 were asked to complete a questionnaire at 1 month after the expected delivery date. The questionnaire included items on pregnancy outcome, date of delivery, gestational age at delivery, malformations in the infant that were confirmed by the pediatrician's report, and the following parameters at birth: height, weight, head circumference, and chest circumference. Odds ratios (ORs) for major congenital malformations among live-born children of pregnant women with SGA exposure during the first trimester (SGA group) relative to children of women not exposed to SGAs and medications known to be teratogenic (comparison group) were estimated using an inverse probability of treatment weighting approach.Results: Of 404 women with SGA exposure during the first trimester, there were 351 live births, 3 stillbirths, 34 spontaneous abortions, and 16 elective abortions. The rate of major congenital malformations among live-born children was 0.9% (3/351) in the SGA group and 1.8% (70/3,899) in the comparison group. No statistically significant differences were observed in the adjusted OR for major congenital malformations (adjusted OR = 0.44; 95% CI, 0.12-1.48; P = .179).Conclusions: SGA exposure during the first trimester is not associated with an increased risk of major congenital malformations. These findings might be reassuring for pregnant women who require SGAs.

Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum.

BACKGROUND: Patients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum. CASE PRESENTATION: A 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum. The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant's body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study. CONCLUSION: The placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.

Transfer of brotizolam, periciazine, and sulpiride in cord blood and breast milk, and alprazolam in breast milk: a case report.

BACKGROUND: A high prevalence of mental disorders including depression, anxiety, somatoform, and dissociative disorder is reported during pregnancy, however, information on the transfer of antipsychotics across the placenta and into breast milk is limited. We evaluated brotizolam, periciazine and sulpiride in cord blood, maternal serum, and breast milk, and alprazolam in breast milk. CASE PRESENTATION: A 38-year-old woman with dissociative disorder was treated with brotizolam, propericiazine, and sulpiride during pregnancy and lactation, and alprazolam during lactation. The drug concentration ratios for both cord blood and maternal serum were 33.3 and 61.5% for brotizolam and sulpiride, respectively, and periciazine (metabolite of propericiazine) was not detected in the cord blood. In breast milk, alprazolam (0.9 ng/mL), sulpiride (445.8 ng/mL), and periciazine (0.3 ng/mL) concentrations were noted at 7.5 h after the last dose on postpartum, whereas brotizolam was not detected. The relative infant doses via breast milk were 1.4, 2.7 and 0.02% of the maternal daily dose, respectively. The neonate had no congenital anomalies and did not experience any severe withdrawal symptoms after birth. CONCLUSION: Use of brotizolam, propericiazine, and sulpiride during pregnancy and lactation, and use of alprazolam during lactation were acceptable in this case.

The safety of pranlukast and montelukast during the first trimester of pregnancy: A prospective, two-centered cohort study in Japan.

For leukotriene receptor antagonists (LTRAs), especially pranlukast, safety data during pregnancy is limited. Therefore, we conducted a prospective, two-centered cohort study using data from teratogen information services in Japan to clarify the effects of LTRA exposure during pregnancy on maternal and fetal outcomes. Pregnant women who being counseled on drug use during pregnancy at two facilities were enrolled. The primary outcome of this study was major congenital anomalies. The incidence of major congenital anomalies in women exposed to montelukast or pranlukast during the first trimester of pregnancy was compared with that of controls. Logistic regression analysis was performed to analyze the effects of maternal LTRA use during the first trimester of pregnancy on major congenital anomalies. The outcomes of 231 pregnant women exposed to LTRAs (montelukast n = 122; pranlukast n = 106; both n = 3) and 212 live births were compared with those of controls. The rate of major congenital anomalies in the LTRA group was 1.9%. Multivariable logistic regression analysis revealed that LTRA exposure was not a risk factor for major congenital anomalies (adjusted odds ratio, 0.78; 95% confidence interval, 0.23-2.05; p = 0.653). In addition, no significant difference was detected in stillbirth, spontaneous abortion, preterm birth, and low birth weight between the two groups. The present study revealed that montelukast and pranlukast were not associated with the risk of major congenital anomalies. Our findings suggest that LTRAs could be safely employed for asthma therapy during pregnancy.

Presence of Hypnotics in the Cord Blood and Breast Milk, with No Adverse Effects in the Infant: A Case Report.

Background: Hypnotics are frequently used for insomnia in pregnant and lactating women. This case study assessed zolpidem concentrations in the cord blood and breast milk and ramelteon concentrations in the breast milk of a woman who was treated with zolpidem and ramelteon for insomnia. Materials and Methods: Zolpidem concentrations were measured in maternal serum, breast milk, and cord blood. Concentrations of ramelteon and M-II, an active ramelteon metabolite, were measured in maternal serum and breast milk. Case Report: A 46-year-old female patient diagnosed with insomnia received 5-10 mg/day zolpidem during pregnancy and lactation and 8 mg/day ramelteon during lactation. A male infant weighing 3,329 g was born at 38 weeks' gestation, with no congenital abnormalities found during pregnancy or at birth. The infant was normal at the 1-month postpartum checkup. The maternal/placental ratio of zolpidem concentrations was 0.1 at 7.4 hours after maternal dosing, similar to that reported in previous studies. The calculated relative infant dose through breast milk based on the maximum drug concentration in breast milk at 2.2 hours after maternal dosing was 2.7% for zolpidem and 0.2% for ramelteon. Ramelteon and its metabolite (M-II) concentrations in the breast milk were equivalent to those in the maternal serum, although the infant exposure of these drugs was low for an oral dose. Conclusions: In the current case, zolpidem transferred into the placenta and breast milk, and ramelteon transferred into the breast milk. Further studies should assess the safety of zolpidem and ramelteon in fetus and breastfed infants.

Transfer of Zolpidem to Cord Blood and Breast Milk: A Case Series Evaluating Zolpidem Serum Levels and Outcomes in Birth and Suckling Infants.

Background: Zolpidem is used for insomnia in pregnant and lactating women. Although zolpidem has been shown to cross the placenta and to be secreted into breast milk, it would not be expected to cause any adverse effects in newborn and breastfed infants. However, there is no relevant information on serum zolpidem levels in the newborn and breastfed infant from zolpidem-treated mother. This study aimed to present the outcomes of zolpidem exposure into infant who was delivered or breastfed by a zolpidem-treated mother. Methods: In this case series, zolpidem-treated pregnant women were recruited between September 2019 and April 2022, and maternal serum, cord blood, breast milk, and infants' serum were collected, and the zolpidem concentration in each sample was evaluated. Childbirth outcomes, including 1-month health care checkup, were also evaluated. Results: Three cases were recruited during investigation period. No spontaneous abortion or preterm live deliveries occurred. Oxygen intervention was required in one term infant, but the findings resolved on postpartum day 1. No medical intervention was required in other three infants. Zolpidem was not detected in infants' serum even after breastfeeding. There are no abnormal developmental findings in any of the infants in their 1-month health checkups. Conclusions: Zolpidem transferred into fetal circulation in utero and breast milk, however no harmful findings existed in infants during pregnancy and lactation. Exposure doses through breastfeeding is small, which may be a cause of rare detection from the infants' serum. Due to the limited number of cases, larger studies and integrated review are needed.

The advances in dealing with the safety of medicated drugs in pregnancy.

The Japan Drug Information Institute in Pregnancy (JDIIP) was established with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. A network consisting of Core hospitals in 47 prefectures plays an important role in providing information for women living anywhere in Japan. Because cases of exposure to drugs whose safety we want to analyze are usually rare, networks of domestic and foreign teratology information services are necessary in order to produce high-quality evidence. JDIIP has been contributing to the education of pharmacists and doctors and to the creation of clinical practice guidelines in various medical societies by using keywords such as "pregnancy" and "medication". Future issues include creating an environment that is easily accessible for those seeking consultation, building a mechanism that makes it easy to create a basis for safety, and aiming for the continuing development of the organization.

Tocilizumab drug levels during pregnancy and lactation: A woman who discontinued tocilizumab therapy until the end of the first trimester and resumed it after birth.

The demand for tocilizumab is increasing in women who wish to bear children and who have active rheumatoid arthritis. Described here is a woman with rheumatoid arthritis who discontinued her tocilizumab therapy at the end of the first trimester and resumed it after delivery and where tocilizumab levels in maternal serum, infant serum, and the breast milk were measured. Tocilizumab was not detected in maternal serum just before delivery, or in umbilical cord blood or infant serum after birth. Tocilizumab levels in colostrum after intravenous injection were 0.57% of those in serum. Tocilizumab treatment in the first trimester was not associated with a significant drug level in the fetus at delivery and no fetal complications were noted .