Abstract
Background:
Esomeprazole is the S-isomer of omeprazole and is used to treat stomach acid-related diseases. Most data regarding the safety of esomeprazole during pregnancy are derived from studies on omeprazole, and the data characterizing esomeprazole transfer across the placenta and excretion into breast milk are limited. In this report, we discuss the safety of esomeprazole with reference to drug concentrations in maternal and neonatal blood and breast milk.
Materials and Methods:
After the patient provided informed consent, esomeprazole concentrations in maternal serum, breast milk, cord blood, and infant's serum were measured after 10 mg of maternal oral esomeprazole administration.
Case Report:
A 34-year-old female diagnosed with rheumatoid arthritis received esomeprazole before and during pregnancy and lactation. The esomeprazole concentration in cord blood was 40% of the level in maternal serum. At 12 hours after delivery (23.2 hours after dose), omeprazole was not detected in the infant's serum. In breast milk, esomeprazole concentrations at 0.7, 4.0, and 8.2 hours after the last dose were 10.5, 19.6, and 3.0 ng/mL, respectively, and esomeprazole was not detected at 10 hours after maternal administration. The calculated daily infant dose of esomeprazole through breast milk was 0.003 mg/[kg·day]. The infant demonstrated normal developmental progress and no detectable drug-related adverse effects.
Discussion and Conclusions:
Exposure to esomeprazole through placenta and breast milk was not clinically relevant in the infant. Further studies are needed to evaluate any harmful effects after exposure to esomeprazole in utero or during breastfeeding after esomeprazole treatment.
Introduction
Gastroesophageal reflux disease is estimated to occur in 30–50% of pregnancies, with the frequency approaching 80% in some populations. 1 Most patients begin to note their troublesome symptoms occurring late during the first trimester or during the second trimester of pregnancy, with heartburn becoming more frequent and severe in the later months of gestation, 2 and the progressive increase in severity of gastroesophageal reflux disease during pregnancy. 3 Esomeprazole is the S-isomer of omeprazole and is used to treat acid-related diseases. 4 Like omeprazole, esomeprazole demonstrates highly effective inhibition of gastric acid secretion. 5 Most of the data regarding the safety of esomeprazole during pregnancy are derived from the studies on omeprazole. Multiple cohort studies in pregnant women with omeprazole use during the first trimester do not show an increased risk of congenital anomalies or adverse pregnancy outcomes.7–9 Esomeprazole is identical to one isomer of omeprazole, however, health care professionals such as physicians, pharmacists, and nursing staff are cautioned with regard to extrapolation of data from omeprazole to esomeprazole as there are no major well-controlled studies to confirm this assumption. For the safety of esomeprazole for nursing women, well-controlled prospective data reviewing proton pump inhibitors excretion in breast milk or infant safety with breastfeeding are not available. The excretion of omeprazole into breast milk was confirmed in one case study 10 and maximum omeprazole level in breast milk (20.0 ng/mL, 3 hours after treatment) was <7% of those in maternal serum. Although omeprazole is not contraindicated during breastfeeding, clinical risks and benefits of omeprasole treatment for lactating women and breastfed infants should be considered. 11 In this case report, we discuss the safety of esomeprazole with reference to drug concentrations in maternal and neonatal blood and breast milk.
Materials and Methods
Esomeprazole detection
Esomeprazole in serum and breast milk samples was determined by a modified version of a previously validated method using liquid chromatography tandem-mass spectrometry (LC/MS/MS). 12 In brief, chromatography was performed on a 3000 Ultimate nano-LC system interfaced with a TSQ Vantage mass spectrometer (Thermo Fisher Scientific, Tokyo, Japan). The compounds were eluted from a Unison UK-C18 (3 μm reversed phase, 3.0 mm i.d. × 50 mm; Imtakt, Kyoto, Japan). Omeprazole and lansoprazole (internal standards for omeprazole) were obtained from Toronto Research Chemicals (Toronto, Canada). LC-MS–grade acetonitrile, ammonium formate, methyl tert-butyl ether, ethyl acetate, and formic acid were obtained from Thermo Fisher Scientific (Tokyo, Japan). Water was purified by the Milli Q system (Millipore Waters, Tokyo, Japan). The developed method has good precision and accuracy over the concentration ranges between 0.5 and 2,000 ng/mL, and the lower limit of detection for esomeprazole in both breast milk and serum was 0.1 ng/mL.
Sample collection and preparation
Maternal serum samples were collected after 10 mg of oral esomeprazole administration. Umbilical cord blood was collected after delivery and serum was immediately separated by ultracentrifugation. Infant serum samples were collected after birth. Breast milk samples were collected in several times after administration, and stored below −80°C until analysis. The time of sample collection after esomeprazole administration is presented in Table 1.
Esomeprazole Concentrations in Serum and Breast Milk Samples After 10 mg of Oral Esomeprazole Administration
ESO, esomeprazole.
Ethical approval
This study was approved by the ethics committee of the National Center for Child Health and Development, and the participant provided written informed consent.
Results
Case
A 34-year-old woman (60 kg body weight) with rheumatoid arthritis positive for rheumatoid factor and anticitrullinated peptide antibody was pregnant with her first child. She received oral esomeprazole at a dose of 10 mg (0.17 mg/kg) once daily during pregnancy and lactation. She was concurrently treated daily with 2.5 mg of prednisolone and 1 g of sulfasalazine. She also received biweekly subcutaneous certolizumab pegol injections at a dose of 200 mg (3.3 mg/kg) during pregnancy. Before switching to certolizumab pegol treatment, she was treated with 50 mg of weekly etanercept and 4–6 mg of weekly methotrexate. Only methotrexate was discontinued before conception and esomeprazole, certolizumab pegol, prednisolone, and sulfasalazine were continued during pregnancy and lactation. At 40 weeks' gestational age, a healthy female infant was born by cesarean section delivery with a birth weight of 2,750 g. During 6 months of lactation period, the infant was partially breastfed (>50% of nutrition was derived from breastfeeding). The infant in this case demonstrated normal developmental progress and no detectable drug-related adverse effects at 1, 3, and 6 months postpartum health checkup assessed by the primary care physician.
Esomeprazole concentrations in maternal serum, umbilical cord blood, and infant's serum
Esomeprazole concentrations in maternal serum were 35.8 ng/mL at 24 hours before delivery (12.2 hours after the last esomeprazole dose) and 0.56 ng/mL at 9 hours after delivery (21.5 hours after dose). The esomeprazole concentration in cord blood that was collected immediately after delivery (12.5 hours after dose) was 14.8 ng/mL, which was 40% of the level in maternal serum. At 12 hours after delivery (23.2 hours after dose), esomeprazole was not detected in the infant's serum.
Esomeprazole concentrations in breast milk
To assess the degrees of esomeprazole transfer to breast milk after esomeprazole administration, the concentrations of esomeprazole in breast milk were measured several times after childbirth. In breast milk, esomeprazole concentrations at 0.7, 4.0, and 8.2 hours after the last dose were 10.5, 19.6, and 3.0 ng/mL, respectively (Table 1), and esomeprazole was not detected in breast milk at 10 hours after maternal administration. The calculated daily infant dose of esomeprazole through breast milk, which was calculated from the maximum detected esomeprazole concentration (19.6 ng/mL) in breast milk and the standard milk intake (150 mL/[kg·day]), was 0.003 mg/[kg·day].
Discussion
Information on drug disposition in lactating women is important for enabling adequate and safe treatment decisions for both mothers and their infants. Here we report a case of maintenance therapy for gastritis with esomeprazole during pregnancy and lactation. Even though the esomeprazole concentrations in the umbilical cord blood was 40% of those in maternal serum at ∼12 hours after administration, esomeprazole was rapidly eliminated from the infant's body. According to the pharmacokinetic analysis of esomeprazole, the plasma elimination half-life ranged from 0.94 to 1.43 hours after repeated once-daily 10 mg of esomeprazole dosing, and it is completely eliminated between doses with no tendency for accumulation during once-daily administration. 13 In fact, esomeprazole was rapidly eliminated from the maternal serum and breast milk, and esomeprazole could not be detected from the breast milk at 10 hours after oral esomeprazole administration.
The calculated daily infant dose of esomeprazole through breast milk was 0.003 mg/[kg·day]; this was extremely low compared with the therapeutic dosage of esomeprazole for children aged between 1 month and 1 year (2.5 mg once daily), 13 suggesting that exposure to esomeprazole through breast milk is not clinically relevant in infants. The infant in this case demonstrated no detectable drug-related adverse effects. Further studies of safety in breastfed infants are needed because esomeprazole has several acid inhibition unrelated adverse events (i.e., allergic reaction, collagenous colitis, and acute interstitial nephritis), and acid inhibiton related adverse events (i.e., pneumonia, gastrointestinal infection, iron deficiency, bone fracture, and hypomagnesemia). 14 Although drug exposure through breast milk was small and that may be a subtherapeutic drug level, 15 decreased drug metabolism and clearance in infants may cause unexpected drug exposure after breastfeeding.
Discussions and Conclusions
In our case, esomeprazole transferred from the maternal blood to the infant was rapidly eliminated, and breast milk concentrations of esomeprazole were quite low. These results suggested that the infant's exposure to esomeprazole through placenta and breast milk was not clinically relevant. Further studies are needed to evaluate potential harmful effects after exposure to esomeprazole in utero and during breastfeeding.
Footnotes
Acknowledgments
We thank Ms. Mariko Takagai for her expert research assistance. We are also grateful to the lactating mother for donating her precious breast milk.
Authors' Contributions
J.S., N.Y., and A.M. contributed to concept and design, data collection, article drafting, and final approval of the article. N.S. and H.K. were involved in data collection, data interpretation, article drafting, and final approval. K.K., T.S., and A.Y. drafted and approved the final article. H.S. were involved in design and concept, critical revision, and final approval of the article.
Ethical Approval
This study was approved by the ethics committee of the National Center for Child Health and Development, and the participant provided written informed consent.
Disclosure Statement
A.M. has received research grants from Astellas Pharma, Inc., and Chugai Pharmaceutical Co., Ltd., and has received lecture fees from Astellas Pharma, Inc., Chugai Pharmaceutical Co., Ltd., and Bristol-Myers KK. All other authors declare no conflicts of interest.
Funding Information
No funding was received for this article.