HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Briggs, G. G. Articles by Wan, S. Search for Related Content PubMed PubMed Citation Articles by Briggs, G. G. Articles by Wan, S. Related Collections Diabetes General obstetrics

Excretion of Metformin Into Breast Milk and the Effect on Nursing Infants

Gerald G. Briggs, BPharm^*, Peter J. Ambrose, PharmD, Michael P. Nageotte, MD, Guadalupe Padilla, MD and Stephanie Wan, PharmD^*

From the *Women's Pavilion, Miller Children's Hospital, Long Beach; Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, California.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: To determine whether metformin is excreted into breast milk and whether this exposure adversely affects the blood glucose of nursing infants.

METHODS: Seven women were started on metformin 500 mg twice daily on the first day after cesarean delivery. Breastfeeding was started at the same time. Two women were excluded. Two other women stopped breastfeeding for personal reasons unrelated to the drug therapy, but did provide serum and milk samples, because they regularly pumped their breasts to maintain lactation. Peak and trough serum and milk samples were drawn between postoperative days 4 and 17. In 3 infants, blood was drawn for glucose determination at the same time as the maternal samples.

RESULTS: The trough milk concentration in 1 subject was below the assay detection limit. Excluding this subject, the mean peak and trough serum metformin concentrations were 1.06 µg/mL (range 0.68–1.90 µg/mL) and 0.42 µg/mL (range 0.26–0.51 µg/mL), respectively, whereas the mean peak and trough metformin concentrations in breast milk were 0.42 µg/mL (range 0.38–0.46 µg/mL) and 0.39 µg/mL (range 0.31–0.52 µg/mL), respectively. The mean milk:serum ratio was 0.63 (range 0.36–1.00) and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65% (range 0.43–1.08%). In 3 infants, the blood glucose concentrations 4 hours after a feeding were within the normal limit, ranging from 47–77 mg/dL.

CONCLUSION: Metformin is excreted into breast milk, but the amounts seem to be clinically insignificant. No adverse effects on the blood glucose of the 3 nursing infants were measured.

LEVEL OF EVIDENCE: III

Metformin, an oral antihyperglycemic agent, is commonly used in the treatment of non–insulin-dependent diabetes mellitus. It decreases hepatic glucose production and intestinal absorption of glucose and increases peripheral glucose uptake and use (product information, Glucophage, Bristol-Myers Squibb, 1995). We conducted a study to determine the amount of metformin that was present in breast milk and whether this exposure would adversely affect a nursing infant's blood glucose. The purpose of this report is to describe the excretion of metformin into the breast milk of 5 women. Neither hypoglycemia nor other adverse effects were detected in the 3 infants that were nursing.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
We prospectively enrolled 5 women with non–insulin-dependent diabetes mellitus who had delivered term infants by cesarean and chose to breastfeed their infants. We included 2 additional women, also delivered at term by cesarean, who had serum and milk metformin concentrations determined before the current study. The seven women were treated with insulin during pregnancy but were started on metformin on postoperative day 1. Metformin was prescribed independently of the study by the women's personal physicians and not for study purposes. All subjects continued the metformin after completion of the study. Subjects were eligible for this study if they were immediately postpartum, had non–insulin-dependent diabetes mellitus that could not be controlled by diet alone, had already been prescribed metformin immediate release 500 mg tablets (every 12 hours), and had a pediatrician assigned to their newborn infants. Subjects were excluded from enrollment if the gestational age at delivery was less than 37 weeks; the infant had intrauterine growth restriction (weight less than the tenth percentile for gestational age); the infant developed hypoglycemia (blood glucose less than 40 mg/dL) within 24 hours of birth, or any other condition, such as sepsis, polycythemia, severe hyperbilirubinemia, or failure to thrive; the infant had a major birth defect; or the infant did not have a physician assigned for routine follow-up care. Subjects who agreed to participate in the study were provided a supply of medication, dispensed by the hospital's outpatient pharmacy.

Subjects eligible for the study were identified while they were in the hospital after delivery, and written informed consent was obtained. A Home Health Care nurse visited the subject's home to collect the blood and milk specimens.

The infant's blood glucose concentration was determined before discharge of the mother and infant from the hospital. To be continued in the study, the infant's blood glucose concentration was required to be 40 mg/dL or higher. Hypoglycemia was defined as less than 40 mg/dL.³ Only maternal samples were obtained if the infant remained in the hospital after the mother was discharged and if the mother was regularly pumping her breasts at home to maintain lactation.

Four to 17 days after delivery (ie, metformin concentration was at steady state), a trough blood sample was obtained from the mother immediately before a scheduled morning dose of metformin. A trough milk sample was also collected at the same time. Using an electric breast pump (Medela Lactina Select Breast Pump, Medela, Inc, McHenry, IL), both breasts were emptied, the milk pooled, and a 10-mL aliquot of milk was taken. On the day of sampling, if the baby was home, the mother was instructed not to feed the baby within 4 hours of the sampling appointment, and a blood sample (< 1 mL) for glucose determination was obtained by heel prick, after which the remaining milk was bottle-fed to the infant. Any changes in the nursing infant's behavior reported by the mother were recorded. After obtaining the trough blood and milk samples, the nurse observed the mother taking the next prescribed dose of metformin. Peak blood and milk samples were obtained from the mother approximately 2 hours later. Samples were transported to the laboratory on ice.

Maternal blood specimens were centrifuged, and 2 mL of serum was separated into specimen transport vials. Both maternal serum and breast milk samples were refrigerated and sent by overnight delivery to National Medical Services, Inc. (Willow Grove, PA) for quantitative measurement of metformin concentrations. Serum samples were analyzed by high-performance liquid chromatography with ultraviolet detection, after derivatization of metformin and an internal standard using p-nitrobenzoyl chloride. The detection limit was 0.05 µg/mL, and the coefficient of variation was 5.62% and 6.19% at 1.0 µg/mL and 2.5 µg/mL, respectively. The concentration of metformin in breast milk was also determined by this high-performance liquid chromatography procedure, using serum-based calibrators. This was validated by a matrix matching study analyzing drug-free breast milk with and without analyte fortification. The detection limit was also 0.05 µg/mL, and the coefficient of variation was 4.26% and 3.06% at 0.50 µg/mL and 4.0 µg/mL, respectively. There are no known interferences with these assay procedures. Plasma glucose determinations on the infant were determined by an enzymatic procedure (Gluco-quant, Roche Diagnostics, Mannheim, Germany) at Miller Children's Hospital.

For each subject, the average serum metformin concentration was estimated by calculating the mathematical mean of the peak and trough serum metformin concentrations. Similarly, the average metformin concentration in milk was estimated using the peak and trough milk concentrations. Milk:serum ratios were calculated by dividing the average milk metformin concentration by the average serum concentration.

The mother's weight-adjusted dose was expressed as mg/kg/d using the subject's actual body weight. The daily intake of breast milk was estimated to be 150 mL/kg/d.⁴ The estimated infant weight-adjusted dose (mg/kg/d) was calculated by multiplying 150 mL/kg/d by the average milk concentration (in mg/mL determined by multiplying the average milk concentration in µg/mL by 1 mg/1,000 µg). The resulting estimated infant weight-adjusted dose was then divided by the mother's weight-adjusted dose and multiplied by 100 to obtain the percentage of the mother's dose.

The study protocol was approved by the Memorial Health Services Research Council (institutional review board), Long Beach, California, and by the Committee on Human Research at the University of California, San Francisco.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Five women, aged 24–35 years, had serum and milk samples analyzed for metformin. Their weights ranged from 76.4 kg to 152.7 kg. Two women were excluded because their infants remained in the hospital after the mothers were discharged, but they did not maintain lactation by regularly pumping their breasts at home. No subject was dropped from the study due to an infant's low plasma glucose concentration at time of discharge. The demographics and results are displayed in Tables 1 and 2, respectively. As expected, the peak and trough metformin concentrations in milk varied little during the 12-hour dosing interval. The trough milk concentration, at the end of the dosing interval, was higher for subject 1 than the peak concentration.

The estimated absolute daily dose for the five infants ranged from less than 0.014 to 0.070 mg/kg/d, and their weight-adjusted daily dose relative to their mothers’ dose ranged from less than 0.18% to 1.08%. Excluding subject 3, the mean estimated infant's dose relative to the mother's dose was 0.65%. Of note is that the infant of subject 1, whose trough milk metformin concentration was reported to be greater than the peak sample, had approximately twice the relative estimated daily dose (1.08%) as the other infants. Three infants had plasma glucose concentrations measured at the time of maternal sampling, and all were within normal limits (more than 40 mg/dL). The mothers reported no adverse effects in the nursing infants. In the 2 prestudy cases, infant plasma glucose concentrations were not determined because the mothers stopped breastfeeding for personal reasons unrelated to the drug therapy, but did regularly pump their breasts to maintain lactation.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The study was conducted during a 2-year period. At our institution, the treatment of choice for control of non–insulin-dependent diabetes mellitus in a nursing mother is insulin. In some cases, however, oral antidiabetic agents are used, either alone or in combination. Although metformin monotherapy is not common, it is used occasionally. All diabetic women prescribed metformin as monotherapy in the postpartum period, and who met the study criteria, were enrolled in the study.

The volume of milk excreted by the mother and ingested by the nursing infant can vary widely, especially in the first week after delivery. In general, however, an accepted estimation of the volume of milk ingested by a nursing infant is 150 mL/kg/d.⁴ Because the infant therapeutic dose of most drugs (including metformin) is unknown, a clinically insignificant dose, if there are no data suggesting otherwise, is considered to be no more than 10% of the mother's weight-adjusted dose (mg/kg/d).⁴ Therefore, in the absence of conflicting data, we considered percentages of 10% or less to be clinically insignificant.

Peak plasma concentrations of metformin, usually less than 1 µg/mL, occur at about 2 hours with an elimination half-life of about 6.2 hours after a single 500-mg dose. However, the blood elimination half-life is approximately 3 times (17.6 hours) longer, suggesting that metformin is distributed into erythrocytes (product information, Glucophage, Bristol-Myers Squibb, 1995). This may help to explain the relatively flat concentration profile of metformin in milk.

Metformin was detected in the breast milk of all 5 women. Except for 1 subject, the peak serum concentrations were less than 1 µg/mL. Trough concentrations were about 40% of the peak concentrations. In contrast, the milk peak and trough concentrations were nearly similar (in 1 case, the trough concentration exceeded the peak level) suggesting that the milk concentration varied little over the 12-hour interval. The mean milk:serum ratio in 4 subjects with measurable concentrations was 0.63. Thus, a strategy to limit exposure of the nursing infant by avoiding nursing around the time of peak serum concentrations would not be successful. However, regardless of the nearly constant milk concentrations, the estimated dose ingested by the nursing infant is about 1% or less of the mother's weight-adjusted dose. No adverse effects were observed on the blood glucose concentrations of the nursing infants. Based on the estimated infant dose, none should be expected.

Since the beginning of our study, 2 groups of investigators have reported the excretion of metformin into the breast milk of 15 mothers, 10 of whom had steady-state drug levels.^5,6 In a 2002 study, 6 women took metformin 500 mg 3 times daily and 1 took 500 mg daily of a slow-release formulation.⁵ The women had been n these dosage regimens for at least 3 weeks. The mean milk:plasma ratio, milk drug concentration over the dosing interval, and infant dose as a percentage of the mother's weight-adjusted dose were 0.35, 0.27 µg/mL, and 0.28%, respectively. There were wide ranges in metformin excretion, which is consistent with our findings. Metformin was detected in the plasma of 2 infants (0.08 µg/mL and 0.05 µg/mL), was below the detection limit in 2 (< 0.01 µg/mL), and was not determined in 3 others.⁵ In a 2003, 2-part study, steady-state milk:plasma ratios in 3 breastfeeding women receiving metformin 500 mg twice daily ranged from 0.37–0.71.⁶ Metformin was not detectable in the plasma of 2 infants for whom blood samples were available. In the second part of the study, a single 500-mg dose of metformin was given to 5 women who stopped breastfeeding during and after the study. Milk concentrations of metformin were detected in 2 women (0.13 and 0.27 µg/mL; milk:plasma ratios 0.27 and 0.47, respectively) but not in the other 3.⁶ No adverse effects attributable to metformin were observed in the combined 10 nursing infants, but infant blood glucose concentrations were not determined in either study.

In conclusion, metformin is excreted into breast milk. Our data are consistent with the 2 studies that quantified the amount of metformin in breast milk. In our study, no adverse effects on blood glucose concentrations were observed in 3 nursing infants whose mothers were being treated with metformin, 500 mg twice daily. The estimated daily doses ingested by the infants seem to be clinically insignificant. Although additional data are required, we conclude that metformin is compatible with breastfeeding.

	Footnotes

 
Supported by the Memorial Care Foundation, Long Beach, California.

Address reprint requests to: Gerald G. Briggs, BPharm, Perinatal Support Service, Women's Pavilion, Miller Children's Hospital, 2801 Atlantic Avenue, Long Beach, CA 90806; e-mail: jbriggs{at}memorialcare.org.

Received December 15, 2004. Received in revised form February 21, 2005. Accepted March 3, 2005.

doi:10.1097/01.AOG.0000163249.65810.5b

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
1. Nathan DM. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342–9.[Free Full Text]

2. American College of Obstetricians and Gynecologists. Breastfeeding: maternal and infant aspects. ACOG Educational Bulletin 258; 2000.

3. Sperling MA. Hypoglycemia. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. Philadelphia (PA): WB Saunders; 2000. p. 439–50.

4. Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000;343:118–28.[Free Full Text]

5. Hale TW, Kristensen JH, Hackett LP, Kohan R, Ilett KF. Transfer of metformin into human milk. Diabetologia 2002;45:1509–14.[Medline]

6. Gardiner SJ, Kirkpatrick CMJ, Begg EJ, Zhang M, Moore MP, Saville DJ. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71–7.[Medline]

This article has been cited by other articles:

				D. R. Coustan A 40-Year-Old Woman With Diabetes Contemplating Pregnancy After Gastric Bypass Surgery JAMA, June 4, 2008; 299(21): 2550 - 2557. [Abstract] [Full Text] [PDF]

				D. S Feig, G. G Briggs, and G. Koren Oral Antidiabetic Agents in Pregnancy and Lactation: A Paradigm Shift? Ann. Pharmacother., July 1, 2007; 41(7): 1174 - 1180. [Abstract] [Full Text] [PDF]

				J. L. Kitzmiller, L. Dang-Kilduff, and M. M. Taslimi Gestational Diabetes After Delivery: Short-term management and long-term risks Diabetes Care, July 1, 2007; 30(Supplement_2): S225 - S235. [Full Text] [PDF]

				H. C. Zisser Polycystic Ovary Syndrome and Pregnancy: Is Metformin the Magic Bullet? Diabetes Spectr, April 1, 2007; 20(2): 85 - 89. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Briggs, G. G. Articles by Wan, S. Search for Related Content PubMed PubMed Citation Articles by Briggs, G. G. Articles by Wan, S. Related Collections Diabetes General obstetrics