Neonatal metabolic alkalosis and mild diuresis resulting from torasemide self-medication by the mother: a case report

Neonatal metabolic alkalosis and mild diuresis resulting from torasemide self-medication by the mother: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Neonatal metabolic alkalosis and mild diuresis resulting from torasemide self-medication by the mother: a case report Yumi Kitahiro, Mari Hashimoto, Yukako Sonda, Miki Yagi, Kotaro Itohara, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6013457/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Apr, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Abstract Background Torasemide, a loop diuretic, is rarely used for pregnant women because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume. We experienced a case of a newborn with metabolic alkalosis and mild polyuria. The mother was suspected of self-medicating as we detected torasemide in the neonatal serum by LC-MS/MS method. Case presentation: A Japanese pregnant woman in her 20s with mental illness, symptoms of panic and eating disorders, and a history of overdosing on over-the-counter medications, was referred to our hospital for birth control. She presented with vomiting following bulimia nervosa and hypokalemia. Her baby was delivered vaginally at 36 weeks and 4 days of gestation. The baby’s blood gas analysis on day 0 revealed metabolic alkalosis (pH > 7.42, HCO 3 - > 28 mmHg). Up to 16 h after birth, mild polyuria and a urine output of 3.3 mL/kg/h were observed without the administration of diuretics. We suspected diuretic intake by the mother before delivery, because she had a history of taking torasemide before being referred to the hospital. As expected, torasemide was detected in the baby’s serum. The serum concentration on the first day after delivery (4.80 ng/mL) gradually decreased to 0.45 ng/mL on day 5, whereas torasemide was not detected in the maternal serum. Neonatal metabolic alkalosis improved by day 3 following birth. Conclusions This case suggests close counseling and monitoring of pregnant women regarding their past and present use of drugs, particularly in those with mental illness. Metabolic alkalosis Newborn Pregnancy Torasemide Loop diuretic Figures Figure 1 Figure 2 Background Pregnant women with severe mental disorders are at higher risk for prematurity and impaired fetal development [ 1 ]. Eating disorders in women of childbearing age are not only the highest out of all age categories, but are on an increasing trajectory [ 2 ]. A previous report suggests that patients with anorexia nervosa experience hypertension, miscarriage, difficult labor, and premature delivery [ 3 ]. Kuobaa et al. [ 4 ] listed several complications associated with eating disorders in pregnancy, including low birth weight and increased risk of microcephaly. Therefore, pregnant women with mental illness must be carefully managed during pregnancy. As a mental illness that has recently attracted attention, some females and/or young people tend to engage in self-harm using over-the-counter (OTC) medications [ 5 ]. Moreover, the Internet facilitates the availability and acquisition of OTC medications. During pregnancy, substance abuse disorder is one of the most common risk factors for pregnancy-associated suicide [ 6 ]. A significant number of pregnant women with such disorders have one or more psychiatric diagnoses, which can exacerbate the problem of substance abuse disorder [ 7 , 8 ]. Acetaminophen is the most common drug associated with overdose [ 9 ]. Therefore, pregnant women with mental illness should be carefully counseled and monitored. Diuretics are not generally used during pregnancy because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume [ 10 ]. The loop diuretic furosemide has been reported to reduce the intravascular volume during the postpartum period and assist with blood pressure control and readmission rates [ 11 ]. During pregnancy, furosemide is a relatively safe drug, if used sparingly and administered effectively for the symptoms of volume overload or volume control during heart failure [ 12 , 13 ]. In contrast, torasemide, another loop diuretic, has rarely been used for pregnancy because it has approximately 10-fold more potent diuretic effects compared with furosemide [ 14 ]. We experienced a case, involving a mother with panic and eating disorders as well as a history of substance abuse of OTC medications. Her baby presented with metabolic alkalosis and a mild polyuria immediately after birth. Here, we report the possibility of a torasemide self-mediating mother and confirm the presence of torasemide in her neonate’s serum using a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Case presentation The pregnant Japanese woman was in her 20s and became pregnant with her third child. The patient experienced panic disorder, an eating disorder (bulimia nervosa), and a history of abusing OTC medications. She was referred to the Kobe University Hospital for birth control at the gestational age of 25 weeks. After medical interviews, it was determined that the patient had self-medicated with torasemide due to edema during pregnancy. There was a possibility that the mother obtained torasemide by herself on the internet; however, the details of the brand and its dosage were not determined. Torasemide was substituted with a Japanese herbal medicine Saireito (KB-114, Kracie, Tokyo, Japan, 8.10 g/d) at approximately 34 and 35 weeks of gestation. Another drug, zolpidem, was concomitantly administered to treat insomnia. The patient presented with vomiting following bulimia nervosa and hypokalemia, and a laboratory test value just before delivery was 2.9 mmol/L. A baby weighing 2,566 g was delivered vaginally at 36 weeks and 4 days of gestation. The Apgar score for the baby was 8 and 9 points (cyanosis) at 1 and 5 minutes, respectively, and the blood gas analysis showed metabolic alkalosis (pH > 7.42, HCO 3 - > 28 mmHg) (Fig. 1 ). The partial pressure of arterial carbon dioxide seemed to be increased as a compensatory reaction to metabolic alkalosis, but not measured. The baby was controlled by respiratory management in incubator and high-flow nasal cannula. During the first hour after birth, pulses on all extremities and the heart rhythm were normal; however, the baby presented with polycythemia, and fluid replacement was administered. Up to 16 h after delivery, mild polyuria with a urine output of 3.3 mL/kg/h was observed without the administration of diuretics; although amniotic fluid volume of the patient during pregnancy had been normal. Thus, there was a suspicion that the mother was using a diuretic before delivery, because she had a history of using torasemide before consulting our hospital. Neonatal metabolic alkalosis improved within day 3 following birth. The patient provided verbal informed consent for the study, including measurement and publication of drug concentrations in her serum as well as that of her baby by routine laboratory tests. The concentration of torasemide was determined by LC-MS/MS (LCMS-8030, Shimadzu, Kyoto, Japan). Acetonitrile (90 µL) and 10 ng/mL torasemide-d7 (Internal standard) were added to 30 µL of serum sample. After centrifugation at 24,981×g for 5 min, 6 µL of the supernatant was injected into the system. The chromatographic separation was performed on a Mastro C18 analytical column (50 × 2.1 mm, i.d.; 3 µm, Shimadzu) with mobile phase A consisting of 0.1% formic acid in water and mobile phase B consisting of 0.1% formic acid in acetonitrile. A mobile phase gradient was used with varying percentages of solvent B within A and other conditions as follows; 0 min, B 40%; 0.70 min, B 40%; 1.0 min, B 80%; 2.5 min, B 98%; 4.0 min, B 98%; 4.01 min, B 40% and hold for 1 min. The column temperature was maintained at 40°C with a flow rate of 0.2 mL/min. The analytes were detected as follows: Positive mode: torasemide 348.75 > 263.90 and torasemide-d7 355.75 > 264.00. The serum calibration curve showed linearity with a coefficient of determination (R 2 ) > 0.999 and the lowest limit of detection for torasemide at 0.15 ng/mL. The validation was performed using the quality control samples of torasemide (0.3, 1.25, and 5 ng/mL, in triplicate) with a precision ≤ 20% and intraday accuracy within 80–120% of the nominal concentration. As expected, torasemide was detected in the neonatal serum (Fig. 2 ). The serum concentration on day 0 (4.80 ng/mL) gradually decreased to 2.77, 1.97, 1.36, 0.77, and 0.45 ng/mL on days 1 to 5, respectively. However, torasemide was not detected in the maternal serum on day 1. In addition, we attempted to detect furosemide considering the possibility that other diuretics were taken, because the pharmacist in our hospital obtained the information from the mother that she had taken furosemide before. However, furosemide was not observed in the maternal or neonatal serum. Discussion and conclusions Metabolic alkalosis is characterized by an increase in serum bicarbonate and arterial pH [ 15 ]. Vomiting or eating disorders tend to cause metabolic alkalosis in pregnant women, whereas an electrolyte/acid-base disturbance in the mother is transferred to the child [ 16 ]. Pseudo-Bartter’s syndrome is a disorder, in which patients present with Bartter’s syndrome-like symptoms, such as vomiting, diarrhea, and neurogenic emaciation because of secondary factors, such as prolonged use of diuretics and laxatives. When the mother presents with hypokalemia and metabolic alkalosis, the newborn may show similar abnormalities and require neonatal resuscitation to compensate for respiratory depression [ 17 , 18 ]. In the present case, the mother ingested a diet during pregnancy, and no urinary ketones were observed in laboratory tests. However, the mother had an eating disorder of bulimia nervosa and presented with vomiting, which may have affected her baby’s metabolic alkalosis. In the present case, increased urine output in the baby and metabolic alkalosis was an uncommon finding. The mother had taken torasemide frequently using her own judgment. Concerned with edema during pregnancy, the Japanese herbal medicine Saireito (KB-114) was administered at 8.10 g/d at approximately 34 and 35 weeks of gestation by her physician. However, she took 24.3 g/d of Saireito on her own as she was concerned about heavy edema. MacGregor et al. [ 19 ] reported a transient edema following discontinuation of loop diuretics, which may be a reason why the mother complained about edema. We also considered the possibility of pseudo-hyperaldosteronism. Saireito is prescribed to alleviate various types of water retention and edema [ 20 ]. Glycyrrhizic acid, which is the main component of licorice (Glycyrrhizae Radix) in Saireito , causes pseudo-hyperaldosteronism, a clinical condition characterized by hypertension, hypokalemia, and suppression of plasma renin and aldosterone levels [ 21 ]. However, the patient did not show hypertension and her serum sodium levels were normal (the laboratory test just before delivery was 139 mmol/L), which may not have contributed to the metabolic alkalosis. The baby’s serum anion gap (AG) on day 0, calculated as [Na + ] – ([HCO 3 − ] + [Cl − ]), supports the diagnosis by classifying the disorders as a normal (hyperchloremic) anion gap or elevated anion gap [ 22 ]. The present neonate’s AG and corrected HCO 3 - on day 0 was 6.3 (normal AG value ranges between 12 ± 2) and 31 (calculated as [HCO 3 - ] + ΔAG and normal corrected HCO 3 - value ranges between 24–26 mmol/L), respectively, showing renal tubular alkalosis [ 15 ]. Therefore, the baby’s metabolic alkalosis was caused not only by vomiting of the mother, but also other causes, and the suspicion of diuretic use before delivery was suspected following the patient’s medical history. Torasemide is primarily metabolized by the hepatic cytochrome P450 (CYP) 2C9 enzyme [ 23 , 24 ], with a half-life (t 1/2 ) of 2.0 ± 0.8 hours after repeated administration [ 25 ]. In addition, the excretion of metabolites and torasemide in urine is 50–80% [ 25 ]. In the present case, the neonatal serum concentration on day 0 gradually decreased. The expression levels and activity of CYP2C9 in neonates are higher compared with those of other CYP species [ 26 ]. The rapid decrease in the serum concentrations of torasemide in the baby suggests that CYP2C9 may contribute to the metabolism of torasemide. Whereas, torasemide was not detected in the maternal serum despite its detection in the neonate serum. The concentration of torasemide in the neonatal plasma was reported to be one-fifteenth of that in the maternal plasma in a rat model [ 27 ]. In the present case, the last intake time and dose of torasemide were not provided by the mother. On one hand, there is an increase in the activity of CYP2C9 and CYP3A4, hepatic blood flow, renal blood flow, and circulating blood volume during pregnancy [ 28 , 29 ]. In addition, because torasemide has a short t 1/2 , it may be eliminated rapidly and below the lower detection limit in the mother. This case study had some limitations. First, precise medication information was not obtained from the mother. There was a possibility that the mother obtained torasemide by herself on the internet; however, the details of the brand and its dosage were not determined. Second, the maternal serum sample represented only one point and we did not know the time course of torasemide concentration. This study included only one maternal case and her baby, thus further information on torasemide in perinatal women is needed. Substance abuse through self-administration can result in significant toxicity in pregnant women and neonates [ 30 ]. Because of the multiple clinical and psychosocial challenges of preventing pregnancy-related overdose, care for women at risk requires a multipronged approach. Therefore, close counseling and monitoring of pregnant women concerning the past and present use of drugs should be performed, particularly in mothers with mental illness. Abbreviations AG anion gap CYP hepatic cytochrome P450 OTC over-the-counter t 1/2 half-life Declarations Ethics approval and consent to participate Because this is a case report, ethical approval was deemed unnecessary by the Kobe University Clinical Research Ethical Committee. Informed consent was obtained from the patient. Consent for publication Consent for the publication was obtained from the patient. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions All authors participated in the design of the study and review of the results. YK analyzed the serum samples and drafted the manuscript. MH, YS, MY, TK, KF, and HI cared for the patient in the clinical settings. All authors helped revise the manuscript and approved the final manuscript. Acknowledgments We want to thank Enago for conducting the English-language review. References Cantwell R. Mental disorder in pregnancy and the early postpartum. Anaesthesia. 2021;76(Suppl 4):76–83. https://doi.org/10.1111/anae.15424 . Arnold C, Johnson H, Mahon C, et al. The effects of eating disorders in pregnancy on mother and baby: a review. Psychiatr Danub. 2019;31(Suppl 3):615–8. Dinas K, Daniilidis A, Sikou K, et al. Anorexia nervosa in pregnancy: a case report and review of the literature. Obstet Med. 2008;1(2):97–8. https://doi.org/10.1258/om.2008.080026 . Koubaa S, Hällström T, Lindholm C, et al. Pregnancy and neonatal outcomes in women with eating disorders. Obstet Gynecol. 2005;105(2):255–60. https://doi.org/10.1097/01.AOG.0000148265.90984.c3 . Shoib S, Patel V, Khan S, et al. Over-the-counter drug use in suicidal/self-harm behavior: Scoping review. Health Sci Rep. 2022;5(3):e662. https://doi.org/10.1002/hsr2.662 . Mangla K, Hoffman MC, Trumpff C, et al. Maternal self-harm deaths: an unrecognized and preventable outcome. Am J Obstet Gynecol. 2019;221(4):295–303. https://doi.org/10.1016/j.ajog.2019.02.056 . Fitzsimons HE, Tuten M, Vaidya V, et al. Mood disorders affect drug treatment success of drug-dependent pregnant women. J Subst Abuse Treat. 2007;32(1):19–25. https://doi.org/10.1016/j.jsat.2006.06.015 . Wouldes TA, LaGasse LL, Derauf C, et al. 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Pharmacokinetic Studies of Torasemide, a New Diuretic (2): Distribution in Rats. Jpn Pharmacol Ther. 1994;22(Suppl5):1203–16. (in Japanese). Tasnif Y, Morado J, Hebert MF. Pregnancy-related pharmacokinetic changes. Clin Pharmacol Ther. 2016;100(1):53–62. https://doi.org/10.1002/cpt.382 . Tracy TS, Venkataramanan R, Glover DD, et al. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005;192(2):633–9. https://doi.org/10.1016/j.ajog.2004.08.030 . Wheeler SF. Substance abuse during pregnancy. Prim Care. 1993;20(1):191–207. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6013457","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":432623533,"identity":"56d3a7e6-23da-4ec8-bce5-c88cea3f7244","order_by":0,"name":"Yumi 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04:54:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":197089,"visible":true,"origin":"","legend":"\u003cp\u003eTime course of torasemide concentrations in the neonatal serum after birth.\u003c/p\u003e","description":"","filename":"torasemidefig250210cleanfig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6013457/v1/066af97392e507247e231b72.jpg"},{"id":80558643,"identity":"e38f964d-b31c-4495-8033-d388bd2cc588","added_by":"auto","created_at":"2025-04-14 16:15:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1307328,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6013457/v1/c5a528df-1886-4f09-8ddd-d311c7fd85f1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neonatal metabolic alkalosis and mild diuresis resulting from torasemide self-medication by the mother: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003ePregnant women with severe mental disorders are at higher risk for prematurity and impaired fetal development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Eating disorders in women of childbearing age are not only the highest out of all age categories, but are on an increasing trajectory [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A previous report suggests that patients with anorexia nervosa experience hypertension, miscarriage, difficult labor, and premature delivery [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Kuobaa et al. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] listed several complications associated with eating disorders in pregnancy, including low birth weight and increased risk of microcephaly. Therefore, pregnant women with mental illness must be carefully managed during pregnancy.\u003c/p\u003e \u003cp\u003eAs a mental illness that has recently attracted attention, some females and/or young people tend to engage in self-harm using over-the-counter (OTC) medications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, the Internet facilitates the availability and acquisition of OTC medications. During pregnancy, substance abuse disorder is one of the most common risk factors for pregnancy-associated suicide [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A significant number of pregnant women with such disorders have one or more psychiatric diagnoses, which can exacerbate the problem of substance abuse disorder [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Acetaminophen is the most common drug associated with overdose [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, pregnant women with mental illness should be carefully counseled and monitored.\u003c/p\u003e \u003cp\u003eDiuretics are not generally used during pregnancy because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The loop diuretic furosemide has been reported to reduce the intravascular volume during the postpartum period and assist with blood pressure control and readmission rates [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. During pregnancy, furosemide is a relatively safe drug, if used sparingly and administered effectively for the symptoms of volume overload or volume control during heart failure [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In contrast, torasemide, another loop diuretic, has rarely been used for pregnancy because it has approximately 10-fold more potent diuretic effects compared with furosemide [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe experienced a case, involving a mother with panic and eating disorders as well as a history of substance abuse of OTC medications. Her baby presented with metabolic alkalosis and a mild polyuria immediately after birth. Here, we report the possibility of a torasemide self-mediating mother and confirm the presence of torasemide in her neonate\u0026rsquo;s serum using a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe pregnant Japanese woman was in her 20s and became pregnant with her third child. The patient experienced panic disorder, an eating disorder (bulimia nervosa), and a history of abusing OTC medications. She was referred to the Kobe University Hospital for birth control at the gestational age of 25 weeks. After medical interviews, it was determined that the patient had self-medicated with torasemide due to edema during pregnancy. There was a possibility that the mother obtained torasemide by herself on the internet; however, the details of the brand and its dosage were not determined. Torasemide was substituted with a Japanese herbal medicine \u003cem\u003eSaireito\u003c/em\u003e (KB-114, Kracie, Tokyo, Japan, 8.10 g/d) at approximately 34 and 35 weeks of gestation. Another drug, zolpidem, was concomitantly administered to treat insomnia. The patient presented with vomiting following bulimia nervosa and hypokalemia, and a laboratory test value just before delivery was 2.9 mmol/L. A baby weighing 2,566 g was delivered vaginally at 36 weeks and 4 days of gestation.\u003c/p\u003e \u003cp\u003eThe Apgar score for the baby was 8 and 9 points (cyanosis) at 1 and 5 minutes, respectively, and the blood gas analysis showed metabolic alkalosis (pH \u0026gt; 7.42, HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e \u0026gt; 28 mmHg) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The partial pressure of arterial carbon dioxide seemed to be increased as a compensatory reaction to metabolic alkalosis, but not measured. The baby was controlled by respiratory management in incubator and high-flow nasal cannula. During the first hour after birth, pulses on all extremities and the heart rhythm were normal; however, the baby presented with polycythemia, and fluid replacement was administered. Up to 16 h after delivery, mild polyuria with a urine output of 3.3 mL/kg/h was observed without the administration of diuretics; although amniotic fluid volume of the patient during pregnancy had been normal. Thus, there was a suspicion that the mother was using a diuretic before delivery, because she had a history of using torasemide before consulting our hospital. Neonatal metabolic alkalosis improved within day 3 following birth. The patient provided verbal informed consent for the study, including measurement and publication of drug concentrations in her serum as well as that of her baby by routine laboratory tests.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe concentration of torasemide was determined by LC-MS/MS (LCMS-8030, Shimadzu, Kyoto, Japan). Acetonitrile (90 µL) and 10 ng/mL torasemide-d7 (Internal standard) were added to 30 µL of serum sample. After centrifugation at 24,981×g for 5 min, 6 µL of the supernatant was injected into the system. The chromatographic separation was performed on a Mastro C18 analytical column (50 × 2.1 mm, i.d.; 3 µm, Shimadzu) with mobile phase A consisting of 0.1% formic acid in water and mobile phase B consisting of 0.1% formic acid in acetonitrile. A mobile phase gradient was used with varying percentages of solvent B within A and other conditions as follows; 0 min, B 40%; 0.70 min, B 40%; 1.0 min, B 80%; 2.5 min, B 98%; 4.0 min, B 98%; 4.01 min, B 40% and hold for 1 min. The column temperature was maintained at 40°C with a flow rate of 0.2 mL/min. The analytes were detected as follows: Positive mode: torasemide 348.75 \u0026gt; 263.90 and torasemide-d7 355.75 \u0026gt; 264.00. The serum calibration curve showed linearity with a coefficient of determination (R\u003csup\u003e2\u003c/sup\u003e) \u0026gt; 0.999 and the lowest limit of detection for torasemide at 0.15 ng/mL. The validation was performed using the quality control samples of torasemide (0.3, 1.25, and 5 ng/mL, in triplicate) with a precision ≤ 20% and intraday accuracy within 80–120% of the nominal concentration.\u003c/p\u003e \u003cp\u003eAs expected, torasemide was detected in the neonatal serum (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The serum concentration on day 0 (4.80 ng/mL) gradually decreased to 2.77, 1.97, 1.36, 0.77, and 0.45 ng/mL on days 1 to 5, respectively. However, torasemide was not detected in the maternal serum on day 1. In addition, we attempted to detect furosemide considering the possibility that other diuretics were taken, because the pharmacist in our hospital obtained the information from the mother that she had taken furosemide before. However, furosemide was not observed in the maternal or neonatal serum.\u003c/p\u003e "},{"header":"Discussion and conclusions","content":"\u003cp\u003eMetabolic alkalosis is characterized by an increase in serum bicarbonate and arterial pH [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Vomiting or eating disorders tend to cause metabolic alkalosis in pregnant women, whereas an electrolyte/acid-base disturbance in the mother is transferred to the child [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Pseudo-Bartter’s syndrome is a disorder, in which patients present with Bartter’s syndrome-like symptoms, such as vomiting, diarrhea, and neurogenic emaciation because of secondary factors, such as prolonged use of diuretics and laxatives. When the mother presents with hypokalemia and metabolic alkalosis, the newborn may show similar abnormalities and require neonatal resuscitation to compensate for respiratory depression [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the present case, the mother ingested a diet during pregnancy, and no urinary ketones were observed in laboratory tests. However, the mother had an eating disorder of bulimia nervosa and presented with vomiting, which may have affected her baby’s metabolic alkalosis.\u003c/p\u003e\u003cp\u003eIn the present case, increased urine output in the baby and metabolic alkalosis was an uncommon finding. The mother had taken torasemide frequently using her own judgment. Concerned with edema during pregnancy, the Japanese herbal medicine \u003cem\u003eSaireito\u003c/em\u003e (KB-114) was administered at 8.10 g/d at approximately 34 and 35 weeks of gestation by her physician. However, she took 24.3 g/d of \u003cem\u003eSaireito\u003c/em\u003e on her own as she was concerned about heavy edema. MacGregor et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported a transient edema following discontinuation of loop diuretics, which may be a reason why the mother complained about edema. We also considered the possibility of pseudo-hyperaldosteronism. \u003cem\u003eSaireito\u003c/em\u003e is prescribed to alleviate various types of water retention and edema [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Glycyrrhizic acid, which is the main component of licorice (Glycyrrhizae Radix) in \u003cem\u003eSaireito\u003c/em\u003e, causes pseudo-hyperaldosteronism, a clinical condition characterized by hypertension, hypokalemia, and suppression of plasma renin and aldosterone levels [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, the patient did not show hypertension and her serum sodium levels were normal (the laboratory test just before delivery was 139 mmol/L), which may not have contributed to the metabolic alkalosis.\u003c/p\u003e\u003cp\u003eThe baby’s serum anion gap (AG) on day 0, calculated as [Na\u003csup\u003e+\u003c/sup\u003e] – ([HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e−\u003c/sup\u003e] + [Cl\u003csup\u003e−\u003c/sup\u003e]), supports the diagnosis by classifying the disorders as a normal (hyperchloremic) anion gap or elevated anion gap [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The present neonate’s AG and corrected HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e on day 0 was 6.3 (normal AG value ranges between 12 ± 2) and 31 (calculated as [HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e] + ΔAG and normal corrected HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e value ranges between 24–26 mmol/L), respectively, showing renal tubular alkalosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, the baby’s metabolic alkalosis was caused not only by vomiting of the mother, but also other causes, and the suspicion of diuretic use before delivery was suspected following the patient’s medical history.\u003c/p\u003e\u003cp\u003eTorasemide is primarily metabolized by the hepatic cytochrome P450 (CYP) 2C9 enzyme [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], with a half-life (t\u003csub\u003e1/2\u003c/sub\u003e) of 2.0 ± 0.8 hours after repeated administration [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In addition, the excretion of metabolites and torasemide in urine is 50–80% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In the present case, the neonatal serum concentration on day 0 gradually decreased. The expression levels and activity of CYP2C9 in neonates are higher compared with those of other CYP species [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The rapid decrease in the serum concentrations of torasemide in the baby suggests that CYP2C9 may contribute to the metabolism of torasemide. Whereas, torasemide was not detected in the maternal serum despite its detection in the neonate serum. The concentration of torasemide in the neonatal plasma was reported to be one-fifteenth of that in the maternal plasma in a rat model [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the present case, the last intake time and dose of torasemide were not provided by the mother. On one hand, there is an increase in the activity of CYP2C9 and CYP3A4, hepatic blood flow, renal blood flow, and circulating blood volume during pregnancy [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In addition, because torasemide has a short t\u003csub\u003e1/2\u003c/sub\u003e, it may be eliminated rapidly and below the lower detection limit in the mother.\u003c/p\u003e\u003cp\u003eThis case study had some limitations. First, precise medication information was not obtained from the mother. There was a possibility that the mother obtained torasemide by herself on the internet; however, the details of the brand and its dosage were not determined. Second, the maternal serum sample represented only one point and we did not know the time course of torasemide concentration. This study included only one maternal case and her baby, thus further information on torasemide in perinatal women is needed.\u003c/p\u003e\u003cp\u003eSubstance abuse through self-administration can result in significant toxicity in pregnant women and neonates [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Because of the multiple clinical and psychosocial challenges of preventing pregnancy-related overdose, care for women at risk requires a multipronged approach. Therefore, close counseling and monitoring of pregnant women concerning the past and present use of drugs should be performed, particularly in mothers with mental illness.\u003c/p\u003e"},{"header":"Abbreviations","content":" \u003cp\u003eAG anion gap\u003c/p\u003e \u003cp\u003eCYP hepatic cytochrome P450\u003c/p\u003e \u003cp\u003eOTC over-the-counter\u003c/p\u003e \u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e half-life\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBecause this is a case report, ethical approval was deemed unnecessary by the Kobe University Clinical Research Ethical Committee. Informed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for the publication was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors participated in the design of the study and review of the results. YK analyzed the serum samples and drafted the manuscript. MH, YS, MY, TK, KF, and HI cared for the patient in the clinical settings. All authors helped revise the manuscript and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to thank Enago for conducting the English-language review.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCantwell R. Mental disorder in pregnancy and the early postpartum. Anaesthesia. 2021;76(Suppl 4):76\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/anae.15424\u003c/span\u003e\u003cspan address=\"10.1111/anae.15424\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold C, Johnson H, Mahon C, et al. 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Prim Care. 1993;20(1):191\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metabolic alkalosis, Newborn, Pregnancy, Torasemide, Loop diuretic","lastPublishedDoi":"10.21203/rs.3.rs-6013457/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6013457/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTorasemide, a loop diuretic, is rarely used for pregnant women because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume. We experienced a case of a newborn with metabolic alkalosis and mild polyuria. The mother was suspected of self-medicating as we detected torasemide in the neonatal serum by LC-MS/MS method.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase presentation:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA Japanese pregnant woman in her 20s with mental illness, symptoms of panic and eating disorders, and a history of overdosing on over-the-counter medications, was referred to our hospital for birth control. She presented with vomiting following bulimia nervosa and hypokalemia. Her baby was delivered vaginally at 36 weeks and 4 days of gestation. The baby\u0026rsquo;s blood gas analysis on day 0 revealed metabolic alkalosis (pH\u0026thinsp;\u0026gt;\u0026thinsp;7.42, HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e \u0026gt; 28 mmHg). Up to 16 h after birth, mild polyuria and a urine output of 3.3 mL/kg/h were observed without the administration of diuretics. We suspected diuretic intake by the mother before delivery, because she had a history of taking torasemide before being referred to the hospital. As expected, torasemide was detected in the baby\u0026rsquo;s serum. The serum concentration on the first day after delivery (4.80 ng/mL) gradually decreased to 0.45 ng/mL on day 5, whereas torasemide was not detected in the maternal serum. Neonatal metabolic alkalosis improved by day 3 following birth.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case suggests close counseling and monitoring of pregnant women regarding their past and present use of drugs, particularly in those with mental illness.\u003c/p\u003e","manuscriptTitle":"Neonatal metabolic alkalosis and mild diuresis resulting from torasemide self-medication by the mother: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:38:40","doi":"10.21203/rs.3.rs-6013457/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"009b0383-a1ac-4485-bcc1-05b66e2119b9","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-14T16:09:43+00:00","versionOfRecord":{"articleIdentity":"rs-6013457","link":"https://doi.org/10.1186/s40780-025-00436-3","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2025-04-11 16:05:28","publishedOnDateReadable":"April 11th, 2025"},"versionCreatedAt":"2025-03-27 04:38:40","video":"","vorDoi":"10.1186/s40780-025-00436-3","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00436-3","workflowStages":[]},"version":"v1","identity":"rs-6013457","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6013457","identity":"rs-6013457","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}