Assessing Safety of Medications During Pregnancy and Breastfeeding with LC–MS/MS

The assessment of drug exposure levels and associated factors during and post-pregnancy, as well as the toxicological impacts, is critical for the estimation of potential risks to the fetus or infant. Ayako Furugen of Keio University (Tokyo, Japan) and Hokkaido University (Sapporo, Japan) recently conducted a study on medications for psychological and neurological disorders, investigating their effects during pregnancy and breastfeeding through quantitative and toxicological analyses, many of which were established using liquid chromatography-tandem mass spectrometry (LC–MS/MS). A paper written by Furugen based on her research was published in the Biological and Pharmaceutical Bulletin (1).

The journal Pharmacy reports that 78.4% of pregnant women in Japan use drugs or supplements before pregnancy, with 57.1% continuing during the first 12 weeks of pregnancy, and 68.8% continuing after the first 12 weeks (2). Furthermore, a questionnaire survey conducted in Japan revealed that many women have used prescription drugs while their children are in infancy (3).

Breastfeeding offers substantial benefits to both the mother (lowering the likelihood of developing breast and ovarian cancer) and infants (enhancement of the immune function and reduction of infection risk) (4). Despite its benefits, breastfeeding is often avoided when the mother is on medication due to limited data on drug transfer into breast milk and its effects on nursing infants (5). The evaluation of infant drug exposure is essential for estimating risks during breastfeeding, with the milk/plasma (M/P) ratio and the relative infant dose (RID) commonly used risk assessment metrics for nursing infants; the M/P ratio measures the extent of drug transfer to breast milk, while the RID indicates the drug exposure level in infants (6)

Breast milk is made up of a varied formulary of carbohydrates, proteins, lipids, and essential vitamins (7,8). In addition, breast milk contains phospholipids, which may contribute to ion suppression during its analysis (9). To address this, Furugen states that a consistent and reproducible sample preparation protocol is essential and that the development of robust methods for drug quantification in both plasma and breast milk is critical for generating reliable safety data (1). As LC–MS/MS is a highly sensitive and specific technique for measuring drug concentrations in biological matrices, quantification methods were developed using the technique to investigate concentrations of drugs in breast milk, specifically antiepileptic, antipyretic and analgesic, and antianxiety and hypnotic drugs (10–14).

Furugen’s article presents research on the presence of antianxiety and hypnotic drugs, such as benzodiazepines (BZDs), including alprazolam, bromazepam, brotizolam, clonazepam, clotiazepam, etizolam, flunitrazepam, lorazepam, and CM7116 (a metabolite of ethyl loflazepate), and orexin receptor antagonists (ORAs), such as suvorexant and lemborexant. Previous studies have shown that the concentration-time profiles of alprazolam in breast milk and plasma follow similar patterns (15); Furugen’s study suggests that the plasma and breast milk profiles of other BZDs are similar. While the M/P ratios for all the BZDs suggest that these drugs were not concentrated in breast milk, the M/P ratios were not the same for all the BZDs. Typically, compounds characterized by low ionization, low molecular weight, minimal plasma protein binding, and high lipophilicity exhibit a greater propensity for transfer into breast milk (1).

The M/P ratio was <0.1 for the ORA suvorexant, which indicates minimal transfer of the drug into breast milk. The RIDs for suvorexant and lemborexant were <10% and remained within the clinically accepted threshold. Suvorexant exhibited a lower M/P ratio than lemborexant, highlighting the possible differences in the M/P ratio across ORA drugs (1).

Furugen identifies several limitations within the study in her article. Plasma and breast milk samples were collected at only a few points in time due to patient burden. Furthermore, detailed and long-term effects on breastfed infants and their plasma concentrations have not yet been evaluated. More evidence, therefore, is necessary for the establishment of protocols concerning the safety of these medications during breastfeeding, as well as further studies conducted using approaches aimed at improving the health of women of reproductive age (1).

Portrait of mother and breastfeeding baby. © Анастасія Стягайло- stock.adobe.com

References

1. Furugen, A. Safety Assessment of Medications During Pregnancy and Breastfeeding Based on Quantitative and Toxicological Analyses. Biol. Pharm. Bull.2025,48(4), 337–343. DOI: 10.1248/bpb.b25-00016

2. Nishigori, H.; Obara, T.; Nishigori, T.; et al. Japan Environment & Children’s Study Group. Drug Use Before and During Pregnancy in Japan: The Japan Environment and Children's Study. Pharmacy (Basel) 2017, 5 (2), 21. DOI: 10.3390/pharmacy5020021

3. Fujii, Y.; Hirokawa, K.; Kobuke, Y.; et al. Use of Nonprescription and Prescription Drugs and Drug Information Sources among Breastfeeding Women in Japan: A Cross-Sectional Study. Int. J. Environ. Res. Public Health 2022, 19 (18), 11722. DOI: 10.3390/ijerph191811722

4. Victora, C. G.; Bahl, R.; Barros, A. J.; et al. Breastfeeding in the 21st Century: Epidemiology, Mechanisms, and Lifelong Effect. Lancet 2016, 387 (10017), 475–490. DOI: 10.1016/S0140-6736(15)01024-7

5. Mazer-Amirshahi, M.; Samiee-Zafarghandy, S.; Gray, G.; et al. Trends in Pregnancy Labeling and Data Quality for US-Approved Pharmaceuticals. Am. J. Obstet. Gynecol. 2014, 211 (6), 690.e1-11. DOI: 10.1016/j.ajog.2014.06.013

6. Anderson, P. O.; Sauberan, J. B. Modeling Drug Passage into Human Milk. Clin. Pharmacol. Ther. 2016, 100 (1), 42–52. DOI: 10.1002/cpt.377

7. Ballard, O.; Morrow, A. L. Human Milk Composition: Nutrients and Bioactive Factors. Pediatr. Clin. North Am. 2013, 60 (1), 49–74. DOI: 10.1016/j.pcl.2012.10.002

8. Delplanque, B.; Gibson, R.; Koletzko, B.; et al. Lipid Quality in Infant Nutrition: Current Knowledge and Future Opportunities. J. Pediatr. Gastroenterol Nutr. 2015, 61 (1), 8–17. DOI: 10.1097/MPG.0000000000000818

9. Furey, A.; Moriarty, M.; Bane, V.; et al. Ion Suppression; A Critical Review on Causes, Evaluation, Prevention and Applications. Talanta 2013, 115, 104–122. DOI: 10.1016/j.talanta.2013.03.048

10. Furugen, A.; Nishimura, A.; Kobayashi, M.; et al. Quantification of Eight Benzodiazepines in Human Breastmilk and Plasma by Liquid-Liquid Extraction and Liquid-Chromatography Tandem Mass Spectrometry: Application to Evaluation of Alprazolam Transfer into Breastmilk. J. Pharm. Biomed. Anal. 2019, 168, 83–93. DOI: 10.1016/j.jpba.2019.02.011

11. Nishimura, A.; Furugen, A.; Umazume, T.; et al. Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose. Breastfeed Med. 2021,16 (5), 424–431. DOI: 10.1089/bfm.2020.0259

12. Furugen, A.; Nishimura, A.; Umazume, T.; et al. Simple and Validated Method to Quantify Lacosamide in Human Breast Milk and Plasma Using UPLC/MS/MS and its Application to Estimate Drug Transfer into Breast Milk. J. Pharm. Health Care Sci. 2023, 9 (1), 26.DOI: 10.1186/s40780-023-00295-w

13. Tamaki, R.; Noshiro, K.; Furugen, A.; et al. Breast Milk Concentrations of Acetaminophen and Diclofenac - Unexpectedly High Mammary Transfer of the General-Purpose Drug Acetaminophen. BMC Pregnancy Childbirth 2024, 24 (1), 90. DOI: 10.1186/s12884-024-06287-4

14. Ishikawa, H.; Furugen, A.; Nishimura, A.; et al. Validated UPLC-MS/MS Method for Quantification of Melatonin Receptor Agonists and Dual Orexin Receptor Antagonists in Human Plasma and Breast Milk: Application to Quantify Suvorexant and Lemborexant in Clinical Samples. J. Pharm. Biomed. Anal. 2024, 251, 116432 DOI: 10.1016/j.jpba.2024.116432

15. Oo, C. Y.; Kuhn, R. J.; Desai, N.; et al. Pharmacokinetics in Lactating Women: Prediction of Alprazolam Transfer into Milk. Br. J. Clin. Pharmacol. 1995, 40 (3), 231–236. DOI: 10.1111/j.1365-2125.1995.tb05778.x