Variation of Milk Intake over Time: Clinical and Pharmacokinetic Implications

Abstract

An important method of determining the safety of maternal drug use during breastfeeding is the use of information from pharmacokinetic studies in which concentrations of drugs in breastmilk are measured. An estimated infant dosage is calculated using the formula below: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}\begin{align*}{\rm Infant \ drug \ dosage} \ ({\rm mg} / {\rm kg} / {\rm day}) = {\rm average \ drug}\\ \quad {\rm concentration \ in \ milk} \ ({\rm mg} / {\rm mL}) \\ \quad \times \ {\rm milk \ volume} \ ({\rm mL} / {\rm kg} / {\rm day})\end{align*}\end{document}

For many years, the value of 150 mL/kg/day has been used as the standard breastmilk volume in these calculations.^1–3 The origin of this value appears to have been an article by Wilson⁴ in which the milk intake from a 1978 review article by Jelliffe and Jelliffe⁵ on milk output in poorly nourished mothers in the developing world was used. Wilson⁴ derived the value of 150 mL/kg/day by selecting the low end of the range of breastmilk output of 600–840 mL/day and dividing it by an infant body weight of 4 kg. The article by Jelliffe and Jelliffe,⁵ which reviewed articles mostly from the 1960s, stated that several different collection methods were used in the original articles, so that the results reported cannot be directly compared with each other.

We examined newer data on milk intake over an extended time period to provide a better estimate of milk intake. Recent articles from developed countries are available that used more reproducible methods of breastmilk volume determination. It is important that some studies have followed milk production over time in groups of exclusively or predominantly nursing mothers.^6–11 The study by Neville et al.⁷ followed a small group of mothers and infants over a period of 1 year. Data from exclusively and nonexclusively breastfed infants were separated at later times when some mothers supplemented their infants.⁷ Data from Table 1 of this article⁷ were used to calculate the milk volume per infant body weight among exclusively breastfeeding mothers. The milk intake in grams per day was converted into milliliters per day by dividing the values by the specific gravity of human milk of 1.03. When calculated in this way, the value on the first day of life is equal to the 13 mL/kg that was reported previously,⁶ although it is somewhat larger than the values of 5–9 mL/kg/day found in other articles.^8–10 Values for milk yield in milliliters from Table 1 in Neville et al.⁷ lead to a higher initial value of 19 mL/kg/day, so these values were not used. At 1 month of age, values are similar, but slightly less, than those reported in a recent study by Kent et al.¹¹ that measured milk production from 1 to 6 months of age. A value of 748 mL at around 28 days was reported by Neville et al.,⁷ compared with 782 mL/day at 4 weeks of age reported by Kent et al.¹¹

For the average weight of infants over time, the World Health Organization growth charts were used.¹² The average of 50^th percentile weights of boys and girls was used as the denominator in the calculations. The average World Health Organization birth weight of 3,250 g is similar to the weighted (by number of boys and girls) average birth weight of infants in the study of Neville et al.⁷ (3,273 g).

The values calculated for daily infant milk intake per kilogram over the first 90 days using data from the study of Neville et al.⁷ are shown in Figure 1. The most noteworthy finding is that the daily milk intake per kilogram of body weight varies considerably with the age of the infant. Milk production is quite low for the first 2–3 days before lactogenesis II. By Day 4, the average value is 141 mL/kg/day, and then it increases to values greater than the standard 150 mL/kg/day. By Day 7, average milk intake is 163 mL/kg/day. The maximum value of 176 mL/kg/day occurred at 28 days of age. By 56 days of age, the value has decreased to 130 mL/kg/day, which represents a 24% drop in milk intake from the maximum value. At 90 days of age, the value is 117 mL/kg/day, which is a 32% decrease from the maximum value. At 6 months of age, the value for exclusively breastfeeding mothers is 108 mL/kg/day.

FIG. 1.

Graph of breastfeeding infants' daily milk intake from Neville et al.⁷ over time prepared using the R Graphics Package smoothing function (The R Foundation for Statistical Computing; www.rgraph.net).

If values from the study by Kent et al.¹¹ are used at 4 and 13 weeks, average milk intake would be higher than those using data from the study of Neville et al.⁷: 184 and 132 mL/kg/day, respectively. However, the trend of decreasing milk intake by weight over time would be the same because total daily milk intake in this study was relatively constant between 1 and 6 months.¹¹

Our results are similar to those reported previously using different datasets for both milk intake and infant weight.¹³ These authors found a peak milk intake value of about 175 mL/kg/day with decreasing values after 1 month of age.

One implication of these results is that the commonly used value of 150 mL/kg might underestimate the daily dosage of drugs received by breastfed infants during most of the first month postpartum. Maximum average volumes in the range of 170–184 mg/kg/day were observed, with the highest values between Day 4 and Day 35. The time period of maximum milk intake (in milliliters per kilogram) corresponds to the time period when about two-thirds of adverse reactions are reported in breastfed infants whose mothers are taking medications.^14,15 In addition to receiving the highest drug dosage in breastmilk during this time, it is the period of lowest neonatal metabolic and excretory capacity. The reported rate of adverse reactions decreases dramatically in the second month (11–15% of reports) and even further thereafter, corresponding to lower drug dosages in breastmilk and increased metabolic and excretory capacity in the infants. Knowing that drug intake by breastfed infants decreases after the first month provides a rationale for not avoiding maternal medications or discontinuing breastfeeding in older infants.

The analysis also indicates that medications started immediately postpartum and used for only 2 or 3 days may present a lower risk to the infant than the same maternal dosage would if the drug were continued beyond this time. Not only is milk production low during this period, but also drug accumulation in the infant would be avoided if a maternal drug is discontinued after 2 or 3 days of therapy.

Milk production varies widely at any time point, with a coefficient of variation of 22% reported in the study of Kent et al.¹¹ Individual mothers might produce considerably more or less than these average values of breastmilk. The volume of breastmilk usually would be lower than calculated values in mothers who are not exclusively breastfeeding. Clinicians should always monitor neonates or advise their mothers to monitor for side effects during the most critical time period when milk intake on a milliliter per kilogram basis is greatest and infant drug elimination is lowest.

The question arises of whether a value higher than 150 mL/kg/day should continue to be used in pharmacokinetic studies. Changing to a different value would not necessarily be helpful because much useful literature has been generated using this value. However, extrapolations of the calculated values should be tempered by the knowledge of the variability in milliliters per kilogram milk production both between individual mothers and by the same mother over time.

A weight-adjusted percentage of maternal dosage or relative infant dosage (RID) value under 10% is often used to indicate that a drug is safe to use in nursing mothers. The RID is calculated using this formula: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}\begin{align*}{\rm RID} \ (\%) = \frac {{\rm Infant \ dosage} \ ({\rm mg} / {\rm kg} / {\rm day})} {{\rm Maternal \ dosage} \ ({\rm mg} / {\rm kg} / {\rm day})} \times 100\end{align*}\end{document}

Some drugs with a calculated RID of 9% would exceed the 10% level if a value of 175 mL/kg/day were used rather than 150 mL/kg/day. However, the 10% RID value for drug safety was chosen arbitrarily with little empirical support.¹ Other factors such as the age of the infant, drug pharmacokinetics, drug dosage, and inherent drug toxicity are equally, if not more, important.

Use of the 150 mL/kg/day value is most useful in calculating the RID of drugs within a specific drug class. Using a higher value for milk volume and the resulting infant dosage would increase the value for RID but would not change the rank order of drugs within a drug class. Because these values have been calculated for many drugs, they can continue to be used as benchmarks to identify drugs with the lowest relative RID in breastmilk within a class.

Lactation professionals should be aware of the age variations in milk intake in order to appropriately assess the risks to the infant of medications in breastmilk.

Footnotes

Acknowledgments

The authors acknowledge the assistance of Edmund Capparelli, PharmD, in preparing .

Disclosure Statement

No competing financial interests exist.

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