Measures of Secretory Activation for Research and Practice: An Integrative Review

Abstract

Background:

Maternal concern about inadequate milk volume commonly emerges in the first 2 weeks postpartum, a critical lactation period that includes secretory activation. This review summarizes the biology of secretory activation and evaluates the accuracy and feasibility of published measures of secretory activation.

Materials and Methods:

A systematic search of measures of secretory activation for mothers of healthy term and preterm infants yielded 62 abstracts. Following additional screening, 15 publications qualified for quantitative synthesis review and were evaluated with respect to accuracy (validated with another measure of secretory activation in the same mother) and feasibility (accessibility, cost, and ease of use).

Results:

Maternal perception of milk coming in (MP) is the most feasible measure, but its accuracy has not been established. Patterns of increase in maternal milk volume have been validated with maternal milk-borne biomarkers in breastfeeding, and breast pump-dependent mothers and normal values have been published. Accuracy of serial maternal urinary lactose concentrations has not been established for secretory activation and lacks feasibility. Maternal milk biomarkers are the accurate standard to which other measures are compared but currently lack feasibility for routine use.

Conclusions:

Use of secretory activation measures can personalize lactation care by matching maternal risk with appropriate diagnostics. Priorities for research and practice include validation of MP as a population-based screening tool, implementation of techniques that measure patterns of increase in milk volume for moderate risk populations, and the development of milk biomarker science for point-of-care use in the most complicated lactation scenarios.

Introduction

Maternal concern about inadequate milk volume is the most frequently reported reason for the cessation of exclusive or partial breastfeeding in healthy mother-infant dyads.^1–7 Breast pump-dependent mothers of preterm infants cared for in the neonatal intensive care unit (NICU) also stop providing milk and fail to meet their own self-stated goals for continued feeding of their milk after NICU discharge due to inadequate pumped milk volume.^8,9 In both populations, concerns about inadequate milk volume commonly emerge in the first 2 weeks postpartum, a critical period in the establishment of lactation and the development of an adequate milk volume that includes secretory activation or lactogenesis II defined as the onset of copious milk secretion.¹⁰ Milk volume concerns during this period predict suboptimal long-term lactation outcomes, including poor infant weight gain, lack of exclusive breastfeeding, supplementation with formula or donor human milk, early unplanned weaning, and mothers' inability to meet their personal feeding goals.^8,11–14

Achievement of secretory activation is so critical for adequate milk volume that nearly two decades ago, Chapman et al. called for targeted lactation care during the early postpartum period as a public health priority.³ Since Chapman's prescient article, multiple risk factors for delayed or impaired secretory activation have been reported, including acute or chronic maternal health conditions such as diabetes, pregnancy-induced hypertension, and prepregnancy overweight (body–mass index; BMI ≥25) or obesity (BMI ≥30). In addition, delivery factors such as preterm birth, breast pump-dependency, cesarean birth, and excessive blood loss have been linked to delayed or impaired secretory activation.^10,15–17 Although these risk factors affect a sizeable proportion of the childbearing population, lactation care has not evolved to address these challenges. Typically, studies recommend providing additional lactation “support” during this period, but “support” has not been translated into evidence-based, personalized interventions that target underlying risk factors. Furthermore, simply providing “additional support” is not always effective in helping at-risk women achieve adequate milk volumes.^8,18–21

Thus, there is a need to prioritize, reconceptualize, and personalize lactation care during this critical period. Central to the design, implementation, and evaluation of evidence-based lactation interventions is the integration of objective, accurate, and feasible measures of secretory activation. These measures should be used in both research and practice to guide the assessment, diagnosis, and management of delayed or impaired secretory activation, especially in high-risk populations. The purpose of this review is to summarize the biology of secretory activation and to evaluate the measures of secretory activation with respect to accuracy and feasibility (accessibility, cost, and ease of use) for use in research and clinical practice. These measures, as reported in the research literature, include MP, patterns of increase in milk volume, serial maternal urinary lactose concentration, and serial maternal milk-borne biomarkers.

Biology of Secretory Activation

During mid-pregnancy the breast undergoes secretory differentiation, during which the mammary epithelial cells differentiate into lactocytes capable of synthesizing milk components such as lactose.²² Secretory differentiation is catalyzed by systemic hormones that stimulate lactocyte growth and ductal system proliferation, including reproductive (estrogen, progesterone, prolactin, and oxytocin) and metabolic hormones (human growth hormone, glucocorticoids, and insulin).²³ The transition of the mammary gland from secretory differentiation to secretory activation occurs during a short but critical postpartum period that involves dramatic changes in systemic hormones, anatomical changes in the mammary epithelium, and compositional changes in milk.²⁴

Changes in systemic hormones occur with the delivery of the placenta, causing a rapid decline in circulating progesterone, which antenatally inhibits the milk-synthesis capability of prolactin.²⁵ Prolactin, newly released from its progesterone inhibition, catalyzes anatomic changes in the mammary epithelium, specifically the closure of paracellular pathways.²² Paracellular pathway closure is essential to subsequent milk secretion, adequate milk volume, and the maintenance of lactation.²⁶ Impaired paracellular pathway closure disrupts milk synthesis at a critical lactation stage, making later resolution of low milk volumes difficult or impossible.²⁴ Milk composition changes from colostrum to transitional milk due to a combination of activated milk synthesis in the lactocyte and paracellular pathway closure. As a result, lactose, citrate, and fat are retained in the alveolar lumen and available for feeding.²⁷ For healthy mothers with uncomplicated pregnancy and birth scenarios, secretory activation occurs within 72 hours postpartum.¹⁶

However, several maternal risk factors have been associated with delayed and/or impaired secretory activation, including primigravidae, overweight and obesity, preterm birth, and/or perinatal complications such as antenatal bed rest, cesarean delivery, chorioamnionitis, and pregnancy-induced hypertension along with the use of medications to manage these conditions.^{9,11,16,17,28–30} The biologic mechanisms that explain most of these risk factors have not been well-elucidated.

Methods

A systematic search was undertaken to identify and evaluate the different measures of secretory activation for mothers of both healthy term and preterm infants. No time limits were placed on the search strategy since much of this original research was conducted decades ago.³¹ An exhaustive literature search was performed between June 2016 and July 2019 and included PubMed, the Cumulative Index for Nursing and Allied Health (CINAHL), Embase, and the SCOPUS databases. Search terms included secretory activation, lactogenesis, milk production, milk synthesis, milk yield, milk volume, tight junctions, measure, urine, and biomarker. Terms were searched both separately and in various combinations.

Study selection

The selection of articles was performed using titles, abstracts, and full texts. A minimum of two authors reviewed all full-text studies. Inclusion criteria were as follows: (1) human subjects, (2) English language, (3) purpose was measurement of secretory activation or milk coming in, and (4) a second measure of secretory activation was used to establish accuracy of the proposed measurement with the exception of milk-borne biomarkers because this measure is considered the accurate standard. The search process yielded 62 abstracts, which were reviewed for suitability. An additional eight full-text articles were retrieved by text mining. Of these 70 records, 15 met inclusion criteria (Fig. 1). Agreement among authors was obtained through discussion, yielding a total of 15 publications for quantitative synthesis review.

FIG. 1.

PRISMA flowchart for selection of studies.

Measures of Secretory Activation

The origins and underlying physiology for each of the four measures of secretory activation are described in this section. Table 1 summarizes each measure with respect to its accuracy, defined for this review as the concurrent validation with another measure of secretory activation. This review will also examine the feasibility of each measure, defined for this review as accessibility, cost, ease of use, and interference with normal breastfeeding behaviors or breast pump use.

Table 1.

Measures of Secretory Activation: Methodologies, Subjects, and Accuracy

Measure	Investigator	Definition of measure	Subjects	Accuracy
Measure	Investigator	Definition of measure	Subjects	Measure of secretory activation comparison	Procedure for measuring MP	Findings
Maternal Perception of Milk Coming In (MP)
	Kulski et al.³²	Sudden sensation of breast distentionMilk leakage	Mothers of term infantsMean gestational age: 39.7 weeks107 vaginal57 cesarean	No comparison measure	MP:Mothers recorded time they first noted milk coming in	MP:Mean interval between birth and MP = 60 hours (range: 12–138)Vaginal vs. cesarean = 59 ± 16.3 hours vs. 63.6 ± 24.2 hours (M, SD)Conclusion:Investigators did not report the accuracy of MP by comparing with biomarkers or increases in milk volume in individual mothers
	Arthur et al.³⁹	Feeling of overfullness in breasts	Mothers of 44 mostly term infants38 healthy mothers6 mothers withType I diabetesMean gestational age: 39.5 weeks43 vaginal (term)1 34-week infant1 cesarean with set of twins	No comparison measure	MP:Mothers recorded time they first noted milk coming in	MP:Mean interval between birth and MP = 59 ± 13 hours (range: 38–98)Mean interval longer for diabetic mothers (72 ± 24 hours)Conclusion:MP is not valid indicator of secretory activationImpreciseHighly variableInvestigators did not report the accuracy of MP by comparing changes in biomarkers or patterns in increases in milk volume in individual mothers
	Chen et al.³⁴	Sudden feeling of fullness in the breasts	Mothers of 40 term infants24 primiparous19 vaginal5 cesarean16 multiparous16 vaginalMean gestational age: 40.3 weeks	No comparison measure	MP:Mothers recorded time they first noted milk coming in	MP:Mean interval between birth and MPPrimiparous mothersvaginal vs. cesarean = 89 ± 10 hours vs. 68 ± 10 hoursMultiparous mothers = 54 ± 22 hoursConclusion:Investigators did not report the accuracy of MP by comparing changes in biomarkers or pattern increases in milk volume in individual mothers
	Hildebrant³⁵	Sudden surge in milk production, using indicators:Prickly feelingBreast tinglingMilk dripping from opposite nipple	Mothers of 127 term infants46 primiparous81 multiparousMean gestational age: 38 ± 1 weeks	No comparison measure	MP:Mothers noted the time milk production surged, using indicators in the MP definitionMaternal report collected in person during maternity hospitalization:Maternal report collected by phone when discharge occurred before MP	MP:Mean interval between birthand MP = 50 ± 15 hours(range: 24–96)Primiparous vs. Multiparous mothers 59 ± 14 hours (range: 31–96) vs. 45 ± 12 hours (range: 24–80)Vaginal vs. cesarean birth49 ± 15 hours vs. 56 ± 13 hoursConclusion:Earlier MP was related to parity and birth modeLater MP was related to Increase use of medication during laborMP is less exact as a research tool but may be useful in clinical practiceInvestigators did not report the accuracy of MP by comparing changes in biomarkers or pattern increases in milk volume in individual mothers
	Chapman et al.³⁶	Maternal perceptionof the onset of lactation	Mothers of 188 term infantsMean gestational age: 39.4 weeksSubset of mothers performed test weights24 primiparous33 multiparous	No comparison measure	MP:Mothers reported timing of milk coming in beginning at 24 hours postpartumMeasures collected at 3 daily time pointsResearchers asked: Has your milkcome in yet?If subjects were dischargedbefore MP, data collected by phoneData grouped by:Early onset <72 hours postpartumLate onset ≥72 hours postpartum	MP:98% of mothers (N = 188)reported MPMean and median intervals between birth and MP = 66.9 hours and 64.0 hours, respectively (range: 1–148)Conclusion:MP and increases in milk volume independently predicted delayed secretory activationInvestigators did not report accuracy of MP by comparing changes in patterns of increases in milk volume in individual mothers
	Parker et al.³⁷	Maternal report of sudden feeling of breast fullness	Mothers of 40 preterm infants11 vaginal29 cesareanMean gestational age = 27.4 weeksMean birth weight = 959.2 grams	No comparison measure	MP:Beginning 24 hours postpartum, mothers were asked: Did you notice a sudden feeling of fullness in your breasts? When?Time recorded in 12-hour increments: 8a-8p or 8p-8a	MP:Median interval between birth and MP = 97.1 hours (range: 69–137)No difference between early vs. late pumping groupsConclusion:Researchers unable to confirm MP as validindicator for individualmothers of preterm infantsInvestigators did not report accuracy of MP by comparing patterns of increases in milk volume in individual mothers
	Baka et al.³⁸	Maternal perceptionof onset of lactation by breast fullness	Mothers of 66 term infants born by cesarean19 primiparous47 multiparousMean gestational age: 39.5 weeks	No comparison measure	MP:Mothers' report of onset of lactation beginning 48 hours postpartumData collected by interview on days 3 and 4 postpartum33 mothers each received Paracetamol and Nefopam for the cesarean birthMothers reporting MP >72 hours postpartum were identified as delayed secretory activation	MP:Majority of mothers (65%) (N = 44), reported MP between days 2 and 3 postpartumNo difference in report of delayed MP between mothers in the Paracetamol group (N = 10) vs. the Nefopam group (N = 12)35% of mothers (N = 22) reported a delay in MP >72 hoursConclusion:Investigators did not report accuracy of MP using prolactin data for individual mothers
Patterns of increases in milk volume
Infant milk intake	Neville et al.⁴⁴	Measured infant intake using test weights	Mothers of 13 term infants13 multiparous13 vaginalMean gestational age: 39.6 weeks	Milk biomarkers:LactoseSodiumPotassiumLipidsTotal protein	Increases in milk volume:24-hour test weights performed by mothers or research nurses beginning 12 hours postpartum through postpartum day 14Complete test-weight data for 9 infants; partially complete data for 3 infants	Increases in milk volume:Mean increase in infant intake was gradual the first 36 hours postpartum, then increased abruptly between 49 and 96 hours postpartumBeyond 97 hours infant milk intake increased at slower rateMilk biomarkers:Rapid changes in biomarkers between birth and achieving ≥300 mL of milk per day
					Milk biomarkers:3–5 mL samples collected mid-feed from each breast once or twice daily for days 1–7, on day 14, and weekly until 8 weeks postpartumMean biomarker concentration values were determined by pooling across individuals	LactoseRapid increase after birth, reaching plateau by 60 hours postpartumIncrease in lactose corresponded to decreases in sodiumSodiumSignificant decrease immediately postpartum preceded marked increase in milk volumePotassiumRapid increase immediately postpartum, stabilizing ≤96 hours postpartumLipidsIncreased immediately postpartum from 2% to 3.5% and continued to increase through day 7 postpartumTotal proteinDecreased by day 1 postpartumConcentration reached a plateau = 1.5% by day 4 postpartumConclusion:Patterns of increases in milk volume appear to be established by the end of the first monthBiomarker changes are consistent with increases in milk volumeBiomarkers stabilize as milk volume reaches 500 mL
Infant milk intake	Saint et. al.⁴⁵	Infant intake using test weights	Mothers of 9 term infants who gave birth vaginally7 multiparous2 primiparousMean gestational age not reported	Milk biomarkers:LactoseTotal proteinFat	Increases in milk volume:Data collected from birth to day 5 postpartumMilk volume determined by test weights at each breastfeeding session, performed primarily by mothers3 of the 9 mothers withdrew from study: 2 on day 3 and 1 on day 5 postpartum	Increases in milk volume:Mean infant milk intake ≤1 hour postpartum = 2.2 g (range: 0–5 g)Mean infant intake during the first 24-hours postpartum = 37.1 g(range: 7–122.5 g)Day 3 postpartum, mean daily infant milk intake = 408 g (range: 98.3–775 g)Day 5 postpartum mean daily infant milk intake = 705.4 (range: 452.5–876)
					6 mothers performed test weights on day 14 and day 28 postpartumMilk biomarkers:0.1–0.5 mL milk samples were collected by manual expression from birth to day 5 postpartum5 mothers collected samples at varied time points4 mothers did not collect any milk samples	Milk biomarkers:Mean (SD) daily changes in biomarker concentration:LactoseDay 1 39.5 (14.4) g/LDay 3 62.7 (14.6) g/LDay 5 67.9 (9.4) g/LTotal proteinDay 1 65.6 (27) g/LDay 3 24.6 (7) g/LDay 5 23.5 (8) g/LFatDay 1 17.7 (5.2) g/LDay 3 20.3 (13.4) g/LDay 5 24.4 (5.2) g/LConclusionIncreases in milk volume correlated with increase in lactose, a decrease in protein, and no correlation with fatRelationship between increases in milk volume and lactose concentration may estimate secretory activationIncreases in milk volume are consistent with biomarker changes in individual mothers
	Arthur et al.³³	Infant intake using test weights	Mothers of 13 mostly term infants delivered vaginallyMean gestational age: 39.5 weeks1 of the 13 mothers delivered preterm (34 weeks) and had Type 1 diabetes	Milk biomarkers:LactoseCitrateGlucose	Increases in milk volume:Data collected 24–144 hours postpartumMothers performed test weights for individual breastfeeding sessionsInfant intake calculated for consecutive 24-hour periodsMilk biomarkers:0.1–2.0 mL milk samples collected by manual expression before breastfeeding on variable days between days 2–10 postpartum	Increases in milk volume:Average daily infant intake increased from 82 to 556 mL between 24 and 144 hours postpartum24-hour infant intake significantly less for diabetic mother with preterm birthMilk biomarkers:Healthy mothers vs. diabetic mother:Biomarkers revealed delayed secretory activation in mothers with diabetesLactoseIncrease began shortly after birth for all mothersSignificant increase between days 1 and 2 postpartum for healthy mothers and between days 2 and 3 for diabetic mothers
					Samples collected and analyzed for each breast separately.Concentration of each biomarker was compared with increases in milk volume	Stabilized at 53 ± 12 hours vs. 72 ± 13 for healthy and diabetic mothers, respectivelyCitrateSignificant increases began at 32 + 9 hours vs. 39 + 7 hours postpartum for healthy and diabetic mothers, respectivelyIncreases stabilized at 77 ± 10 vs. 89 ± 14 hours for healthy and diabetic mothers, respectivelyGlucoseSignificant increase noted between days 2 and 3 postpartum for both healthy and diabetic mothersMarked variability limited exact timingRelationship between milk volume and biomarkers:Significant relationship between Increases in milk volume and biomarker changesAverage 24-hour infant intake during first 48 hours postpartum significantly related to biomarkersLactose (r = 0.52)Citrate (r = 0.52)Glucose (r = 0.69)Conclusion:Changes in biomarker concentrations for lactose, citrate, and glucose were related to increases in milk volume in individual mothers
Urinary Lactose
	Yoon et al.⁶⁵	Urinary lactose concentration	13 healthy mothers of term infantsGestational age not reported10 primiparous3 multiparous	No comparison measure during secretory activation	Urinary lactose concentration:24H urine samples collected by participants in their homesSamples collected between 7 and 9 weeks postpartum in lactating mothersSamples collected in 11 nonlactating mothers1 mother collected sample in 1st trimester1 mother collected sample during weaningSamples were separated into aliquots and stored at −20 degrees	Urinary lactose concentration:Total urinary lactose concentrations were significantly higher during lactation vs. nonlactationConclusion:10-fold increase in urinary lactose concentration during lactationHigh correlation between urinary lactose concentration and total milk volume suggests a valid biomarker for lactation performanceUrinary lactose concentration not measured during secretory activation
	Murtaugh et al.⁶³	Relationship between urinary lactose excretion and expressed milk volume	12 mothers of term (4) and preterm (8) infants4 vaginal8 cesareanInfant gestational age range: 25–42 weeks	No comparison measure during secretory activation	Urinary lactose concentration:One 24-hour sample collected between 4 and 35 weeks postpartumPumped milk volume:Mothers used electric breast to pump milk during entire 24-hour period that urine samples were collected.Mothers recorded pumped milk volume	Urinary lactose concentration:24-hour urinary lactose concentrations were 25 times higher than for nonpregnant, nonlactating womenNo significant difference between term and preterm mothersPumped milk volume:Urinary lactose excretion directly correlated 24-hourpumped milk volumeConclusion:First report of a positive relationship between urinary lactose concentrations and pumped milk volume, suggesting that urinary lactose may be developed into a meaningful clinical indicator of lactation performanceUrinary lactose concentration was not measured during secretory activation
	Kalkwarf et al.⁶⁴	Urinary lactose concentration as predictor of milk output	Study 1:50 breastfeeding mothers49 nonbreastfeeding mothers (control)Study 2:62 healthy breastfeeding mothersInfant gestational:Mean 5.4 months(range: 1.5–12 months)	No comparison measure during secretory activation	Urinary lactose concentration:Study 1Mothers collected 24-hour urine samples 3 times during the study:Breastfeeding mothers collected samples: at 2 weeks (baseline), 3 and 6 months postpartumNonbreastfeeding mothers collected samples at 5, 8, and 11 months postpartumUrinary lactose concentration was expressed as total output in mmol/d and relative to urinary creatine molar ratio	Urinary lactose concentration:Study1Urinary lactose in both breastfeeding and non-breastfeeding mothers was increased at 2 weeks postpartum baselineUrinary lactose decreased from baseline by 30% in breastfeeding mothers vs. an 85% decline for non-breastfeeding mothers at 3 months postpartumUrinary lactose concentration was significantly higher for breastfeeding mothers who began weaning vs. nonbreastfeeding mothers at 5 or 6 months postpartumNo difference in urinary lactose concentration at 11 months postpartum between breastfeeding mothers who had completely weaned and non-breastfeeding mothers
					Study 2Infant milk intakeMajority of data collection was done over 3 consecutive daysMothers were exclusively breastfeeding or partially breastfeedingMothers were breastfeeding or pumping at least twice dailyInfant milk intake determined by test weightsMothers weighed infants before and after each feeding for three 24-hour periodsMothers recorded weight and time of pre- and postfeeding sessionMothers who pumped weighed the container before and after pumpingUrinary lactose concentrationUrine samples were collected on corresponding days when infant milk intake was also measuredUrine samples collected over 24-hour periodsUrine voids were kept separately: first morning, random, and pooled 24-hour urine	Study 2Infant milk intakeMean infant milk intake was 726 ± 232 g/dayUrinary lactose concentration24-hour median urinary lactose concentration = 1.85 mmol/d (range: 0.36–6.30 mmol/d)Low correlation between infant milk intake over the 3-24-hour periods and a 3-day average of lactose concentration (r = 0.30)Low correlation between infant milk intake and 1-day total urinary lactose concentrationConclusion:Urinary lactose concentration does not predict milk volumeUrinary lactose concentration does reflect changes in biologic activity of mammary glandUrinary lactose concentration was not performed during secretory activation
Milk biomarkers
	Kuslki et al.³²	Serial changes in milk biomarkers during the first 7 days postpartumLactoseGlucoseTotal proteinFatSodiumPotassium	Mothers of 19 term infants11 vaginal8 cesareanMean gestational age: 39.7 weeks	Not applicable	Milk biomarkers:0.5–3 mL samples collected by hand expression between 10A-12P daily from birth to day 7 postpartumMilk samples collected and analyzed separately for each breast	Milk biomarkers:Lactose:increased 100% between 0 and 30 hours postpartum, and stabilized by day 5 postpartum in both vaginal and cesarean mothersNo significant differences for vaginal and cesarean mothers at any measured time pointTotal protein:Mean concentration decreased by 28% between days 1 in vaginal and cesarean mothersFat:No significant/consistent change during first 7 days postpartum for vaginal vs. cesarean mothersSodium:Decreased by 36% between days 1 and 5 postpartumPotassium:Increased 150% between days 1 and 5 postpartumNo significant difference between vaginal vs. cesarean mothersGlucose:Increase from 0.3 to 1.33 mM between days 1 and 7No difference between vaginal or cesarean mothersGlucose and lactose significantly correlated (r = 0.78) during first 7 days postpartumConclusion:Initiation of lactation occurs between 32 and 40 hours postpartum in vaginal and cesarean birth based on milk biomarker changes (lactose, total protein, sodium, chloride, potassium)
	Kulski and Hartman⁷³	Serial changes of milk biomarkers during initiation of lactationLactoseNaKClProteins	22 Mothers of 23 term infants22 vaginal1 set of twinsMean gestational age: not indicated18 mothers breastfed4 mothers did not breastfeed	Not applicable	Milk biomarkers:0.5–5.0 mL samples collected by manual expression at variable time pointsSome mothers collected samples before birthBreastfeeding mothers (N = 18) collected samples between day 1 and ≥ day 6 postpartumNonbreastfeeding mothers (N = 4) collected samples between days 1–9 postpartumNot all biomarkers were measured for all subjects	Milk biomarkers:Patterns of biomarker change reported:Abrupt increase in lactose and KAbrupt decrease in Na and ClCorrelations for breastfeeding vs. nonbreastfeeding mothersNa −0.93 vs. −0.83 (p = 0.01)Cl −0.93 vs. −0.81 (p = 0.01)K 0.76 vs. 0.68 (p = 0.05)Proteins decreased to normal milk levels by day 3 postpartum in both breastfeeding and nonbreastfeeding mothersConclusion:Based on biomarker data, breastfeeding is not necessary for the initiation of lactation but is necessary for the continuation of full lactation
	Cregan et al.⁴⁰	Combinations of milk biomarkers on day 5 postpartum were compared for mothers of preterm and term infantsLactoseCitrateSodiumTotal protein	Mothers of 22 preterm infantsGestational age = 31–35 weeksMothers of 16 vaginally-delivered term infantsGestational age: >38 weeks	Not applicable	Milk biomarkers:Data collection occurred on day 5 postpartum in hospital or at homePreterm mothers1 mL of milk representing a 24-hour pooled specimen collected for analysisPumped milk volume was calculated by weighing with an electronic scaleTerm mothersMilk samples collected in the morning and evening were pooled, analyzed, and served as normal concentrations to which preterm mothers' milk was comparedDefinitions for impaired initiation of lactationBiomarker values >3SD outside the mean values for term mothers were defined as compromised lactationNumber of biomarkers ±3SD from the mean values for term mothers during the first 24 hours were summed and correlated with milk volume	Milk biomarkers:18 (82%) of preterm mothers had at least 1 biomarker >3SD outside normal values vs 0% of term mothersCoefficients of variation were greater for preterm mothers vs. term mothers:Lactose 13% vs. 7%Citrate 40% vs. 17%Total Protein 17% vs. 11%Sodium 42% vs. 33%Increases in milk volume:Preterm mothersMean 24-hour milk volume = 180 ± 175 mL; (range: 20–550 mL)Increases in milk volume and biomarkers:Preterm mothersGreater 24-hour pumped milk volume was associated with fewer number of biomarkers ≥3SD of the mean for term mother0 biomarkers >3SD: mean day 5 volume = 400 mL1 biomarker >3SD: mean day 5 milk volume = 180 mL2 biomarkers >3SD: mean day 5 milk volume = 86 mL3 biomarkers >3SD: mean day 5 milk volume = 37 mLAll 4 biomarkers >3SD = 0 pumped milk volume
						Conclusion:Preterm mothers are at greater risk for compromised secretory activationPositive correlation between number of biomarkers >3SD of normal values for term mothers and compromised secretory activation
	Hoban et al.⁴¹	Determine concentrations of milk biomarkers during first 14 days postpartum in breast pump dependent mothers of premature infantsLactoseCitrateSodiumProtein	16 pump-dependent mothers of preterm infants11 vaginal5 cesarean8 primiparous8 multiparousMean gestational age = 30.2 weeks	Not applicable	Data collection occurred between birth and day 14 postpartumMothers began pumping within 24 hours postpartum unless precluded by illness and recorded the start and stop times and total milk volume for each pumping sessionAll pumped milk was stored in preweighed containers, which were weighed after filling to determine milk volume1.8 mL samples collected twice daily for biomarker analysis, unless maternal milk volume was insufficient for infant feedingBlinding between clinical and basic science researchers	Patterns of milk biomarkers similar to those reported for mothers of healthy breastfeeding infantsCitrateIncreasedFirst biomarker to normalize (median [IQR] 3 [2.75–4] days)LactoseIncreasedSecond biomarker to normalize (3 [3–4] days)SodiumDecreasedThird biomarker to normalize (3.5 [2.75–5] days)Total proteinDecreasedLast biomarker to normalize (4 [4–9] days)All 8 mothers who achieved CTV (≥ 500 mL/d) by postpartum day 14 had all 4 biomarkers normalized by 5.4 days and reported more cumulative pumping sessionsDose–response relationship between number of normal biomarkers and pumped milk volume for postpartum days 3 and 5Only 40% of postpartum day 5 samples had all 4 biomarkers within normal range, but not all mothers maintained normal biomarkers after day 5Conclusion:Secretory activation is delayed in mothers who deliver prematurelyMilk biomarkers hold promise as an objective outcome measure and possibly point-of-care testing to identify mothers at risk for insufficient milk volume

Maternal perception of milk coming in

Maternal perception of milk coming in (MP) has been used as a measure of secretory activation for centuries, but has received limited rigorous investigation.³ Although this measure was originally described as a sudden sensation of breast fullness and leaking of milk, a myriad of indicators have since been reported and used in research and practice.³² These indicators have included both breast changes and infant behaviors such as audible swallowing during breastfeeding. Seven studies^32–38 examined the timing of MP, with three^32–34 of these seven measuring the time from birth until mothers reported MP. The remaining studies measured MP based on varied indicators such as maternal feeling of overfullness of breasts,³³ time postpartum that mother first felt breast fullness,^36,37,39 sensation of hard breasts, fullness, swelling, or leakage of milk,³² sudden feeling of breast fullness,^34,35 and a breast fullness score.³⁸ Although the average time postpartum for MP is 60 hours, this time varies significantly among mothers (12–128 hours) and is influenced by factors such as mode of birth and maternal health characteristics.²⁸

No previous research has established the concurrent validity of MP using other validated measures of secretory activation for individual mothers. Nonetheless several researchers have used MP for predictive and comparison studies. Chapman and Perez-Escamilla³⁶ established the predictive validity of the timing of MP as a marker for subsequent delayed onset of lactogenesis. Similarly, Arthur et al.³³ demonstrated that diabetic mothers reported MP later than nondiabetic mothers. Kulski et al.³² reported no difference between the timing of MP for cesarean versus vaginal birth. In separate studies, primigravidas reported MP later than multiparous mothers.^34,35 These studies also reveal variability in the precision with which mothers report the timing of MP, with some reporting an exact time and others reporting an interval such as “the morning” or “overnight.”³⁹ Although this cluster of studies used MP as a predictor or dependent variable, both the indicators and methods of assessment varied considerably among investigators, highlighting a research gap. Thus, to date it is unknown whether MP accurately measures secretory activation and, if it does, which specific indicators of MP should be used for research and practice.

Patterns of increase in milk volume

Multiple researchers have described patterns of increase in maternal milk volume during the first 2 weeks postpartum.^{2,33,37,39–44} This measure has been validated concurrently with serial milk biomarkers in individual mothers^{33,40,41,44,45} and has been used to predict delayed or impaired secretory activation in healthy and at-risk breastfeeding dyads.^{5,16,17,28,42,43} However, patterns of increase in maternal milk volume are not a direct measure of secretory activation, but rather a combination of milk synthesis and the effectiveness and efficiency of milk removal by the infant, hand, or breast pump.

Research with healthy breastfeeding dyads has established normal values for milk volume during the first 2 weeks postpartum by calculating the amount of milk removed from the breast by the infant during feeding, referred to as “milk intake” or “milk transfer.”⁴⁴ This measurement is done using test weights, in which the infant is weighed pre- and postfeed under the same conditions with a highly accurate digital (not a rotary balance) scale, with 1 g increase in weight = 1 mL of milk removed.^46,47 No significant differences in the accuracy of 24-hour test-weighing procedures have been reported between measures performed in the hospital by research staff and/or mothers and in the home by mothers.^{33,45,48–52} Furthermore, recognizing that in-home test weights during this vulnerable postpartum period may be incomplete, Neville et al. published an algorithm for estimating 24-hour milk volume when only intermittent test weights were performed.⁵³

Five studies used test weights to measure milk volume during the first 2 weeks in healthy term breastfeeding dyads and incorporated both prospective longitudinal^33,34,44,45 and cross-sectional⁵⁴ designs. Both milliliters (mL) and grams (g) of milk volume have been reported in these studies, so for the purpose of this review, we report the unit used by the investigators in published studies. Mean milk volumes reported during the first 24 hours postpartum were 15 g,⁵⁴ 37 g,⁵¹ 37.1 g,⁴⁵ and 44 g,⁴⁴ but these small volumes increased rapidly between days 2 and 7 postpartum.⁴⁴ In Neville's classic longitudinal study of 13 multiparous, exclusively breastfeeding mothers, milk volume patterns revealed a gradual increase between birth and 36 hours postpartum, followed by an abrupt increase between 49 and 96 hours, with a mean milk volume on day 7 of 610 g (range = 421–1008).⁴⁴ Chen et al. reported mean milk volume on day 5 postpartum for 24 primigravidas who gave birth vaginally (556 g) or by cesarean section (617 g) and for 16 multiparous mothers who gave birth vaginally (750 g).³⁴ Arthur et al. reported a mean milk volume of 82 g for day 2 and 556 g for day 6 postpartum in 13 exclusively breastfeeding mothers.³³

However, mean values do not reflect the marked variability for individual mothers and infants. For example, Kent et al.⁵⁵ reported 24-hour milk volumes ranging from 338 to 722 mL between days 6 and 13 for 29 healthy dyads who either did not perceive (N = 3) or did perceive (N = 26) breastfeeding problems. Similarly, Neville et al.⁴⁴ reported on a subset of mothers for whom milk volume peaked on day 4 postpartum but decreased thereafter.⁴⁴

Most, but not all, studies that measured hand expressed or pumped milk volume instead of infant milk intake were conducted with mothers of preterm infants hospitalized in the NICU.^37,40,41 While eight studies reported milk volume during the first 2 weeks postpartum, only three specifically validated patterns of increase in maternal milk volume with milk biomarkers of secretory activation in term⁴⁴ and preterm^40,41 populations. Remaining studies enrolled mothers of preterm infants into randomized^37,56,57 and nonrandomized^58,59 intervention studies for which patterns of increase in milk volume during the first 2 weeks postpartum were dependent variables and may have been reported in combination with another measure of secretory activation.³⁷

Similar to findings in term infants, these studies reveal minimal milk volumes during the first 24 hours postpartum. In Parker's randomized trial of early versus late pumping in mothers of very low birth weight (VLBW; < 1500 g birth weight) infants, mean milk volume during the first 24 hours postpartum was 19.2 mL and 0.7 mL for the early and late pumping groups, respectively.³⁷ Lussier's comparison of hand expression versus electric breast pump use revealed median (IQR) milk volumes of 0.1 mL (0, 2.6) and 3.7 mL (2, 22), respectively, for the first 24-hours postpartum.⁵⁷ A number of studies have reported a marked increase in milk volume starting on day 3 or 4 postpartum.^{2,17,39,41,45,55–57,60} Parker reported mean milk volumes on days 3 and 4, respectively, of 142 mL and 186 mL for the early pumping group and 45 mL and 70 mL for the late pumping group.³⁷ Lussier reported day 4 median milk volumes of 119 mL and 265 mL for hand expression and electric breast pump groups, respectively.⁵⁷ At the end of the first postpartum week, Parker reported mean cumulative milk volume of 1,374 mL and 608 mL in the early and late pumping groups,³⁷ and Lussier reported median cumulative volume of 456 mL and 1,371 mL in the hand expression and electric breast pump groups, respectively.⁵⁷ Marked individual maternal variability was reported in all studies.^37,41,57,59 Furthermore, maternal milk volume differed significantly as a function of type and timing of breast pump use, as well as hand expression versus pump for milk removal. These findings highlight the influence of the effectiveness and efficiency of milk removal when maternal milk volume is used as a measure of secretory activation.

Serial urinary lactose concentration measures

The use of serial maternal urinary lactose concentration (urinary lactose) as a measure of biosynthetic activity in the mammary gland was first described in the 19th century⁶¹ and refined by Watkins in 1928, who described an extreme sudden increase in urinary lactose immediately before birth.⁶² This measure is based upon both the upregulation of lactose production and secretion in the mammary gland, as well as the patency of paracellular pathways. Thus, serial changes in urinary lactose concentrations provide an indirect measure of paracellular pathway patency.⁶³ When the paracellular pathways are open, as is the case during secretory differentiation, lactose passes readily into the maternal blood and is excreted in the urine. When paracellular pathways close as occurs with secretory activation, urinary lactose concentrations decrease.²²

Although no study has focused specifically on the validation or use of serial urinary lactose measures during secretory activation, this measure has been correlated with patterns of increase in milk volume in mothers of term^64,65 and preterm infants.⁶³ It has also been used to predict milk volume as measured by test weights⁶⁴ and to diagnose subclinical mastitis,⁶⁶ which is accompanied by reopening of paracellular pathways during established lactation.^66–68 Serial urinary lactose concentration measures were originally conceptualized as an alternative to more invasive or disruptive measures of secretory activation such as test weights and maternal milk biomarkers.^63,64,67,68 However, the measurement of urinary lactose over a 24-hour period versus a one-time spot check is preferred because analytes can vary depending on the time of day collected and will yield variable results. Thus, this measure is seldom used in current research and practice due to the inconvenience of collecting and analyzing 24-hour urine samples.

Serial measures of maternal milk biomarkers

Predictable changes in serial maternal milk biomarker concentrations (milk biomarker) occur between birth and secretory activation,⁶⁹ forming the basis for a measurement technique that was developed over three decades ago.⁴⁴ These biomarkers, which include lactose, citrate, sodium (Na), and total protein, are secreted through distinct transcellular and paracellular pathways during secretory activation (Fig. 2) and currently serve as the accurate standard to which other measures are compared. Fat and potassium (K) have also been used as biomarkers, with fat representing a specific transcellular pathway and potassium used primarily in the Na/K ratio to standardize Na fluctuations.^32,45 Potassium concentrations increase rapidly after birth, stabilizing ≤96 hours postpartum.^71,72

FIG. 2.

Origins of secretory activation.

Four transcellular pathways are involved in milk synthesis and secretion and enable the transfer of milk components across the cellular membrane.⁷⁰ In contrast, a single paracellular pathway bypasses the epithelial cell itself, allowing direct communication between maternal blood and milk.⁷¹ This pathway is open at the time of birth and gradually closes during secretory activation, a prerequisite for continued milk secretion so that lactose, the primary osmotic driver of milk volume, remains in the mammary gland.²⁹ The paracellular pathway reopens only during inflammation (mastitis) and involution (weaning).⁷² Thus, the predictable changes in milk biomarker concentrations during the early postpartum period reflect both upregulated milk synthesis and gradual paracellular pathway closure (Table 2). These biomarker changes have been described in uncomplicated lactation scenarios, and aberrations in biomarker changes coincide with and/or predict impaired secretory activation.^5,17,40

Table 2.

Serial Changes in Milk Components as Biomarkers of Secretory Activation in Mothers of Term and Preterm Infants

Biomarker	Pathway(s)	Reference range	Direction of change during secretory activation	Investigators	Sampling frequency		Postpartum day(s) sample(s) collected	Population
Biomarker	Pathway(s)	Reference range	Direction of change during secretory activation	Investigators	Daily	Twice daily	Postpartum day(s) sample(s) collected	Term	Preterm
Lactose (g/L)	Transcellular IParacellular	3 days postpartum >43.46 days postpartum >53.6⁶⁹	abrupt increase day 1 postpartumpeaks ≤ day 5 postpartum	Kulski and Hartmann⁷³Kulski et al.³²Saint et al.⁴⁵Neville et al.⁴⁴Arthur et al.³³Chen et al.³⁴Cregan et al.⁴⁰Hoban et al.⁴¹	XX X X	XXX XX	1–7^a1–71–51–14^a1–10551–14	XXXXXXX	XX
Citrate (g/L)	Transcellular I	3 days postpartum >0.246 days postpartum >0.92⁶⁹	Increases immediately before copious milk secretion, and in proportion to increases in milk volume	Neville et al.⁴⁴Arthur et al.³³Cregan et al.⁴⁰Hoban et al.⁴¹	XX	XXXX	1–14^a1–1051–14	XXX	XX
Sodium (mM)	Transcellular IVParacellular	Days 1–5 decreases from 60 to 10⁵³	Decreases rapidly in the first 3 days postpartum	Kulski and Hartmann⁷³Neville et al.⁴⁴Morton⁵⁹Humenick et al.⁷⁴Cregan et al.⁴⁰Hoban et al.⁴¹	XXXX	X XXX	1–7^a1–14^a3–8651–14	XXXXX	XX
Potassium (mM)	Transcellular IVParacellular	45.3⁷⁶	IncreasesSecreted by lactocyteConcentrations diluted with open paracellular pathways from mixing of extracellular fluids	Kulski and Hartmann⁷³Neville et al.⁴⁴Cregan et al.⁴⁰Hoban et al.⁴¹	X X	XXX	1–7^a1–14^a51–14	XXX	X
Na/K	Transcellular IVParacellular	1.1–7.8Categorized:<0.6 = Normal≥0.6 and ≤1 elevated>1 = very high⁷⁶	Decreases	Murase et al.⁷⁵Lai et al. ⁷⁶	X		71^b	XX	X
Total Protein g/L	Transcellular I, IIIParacellular	3 days postpartum <34.16 days postpartum <24.3⁶⁹	Decreases	Kulski and Hartmann⁷³Saint et al.⁴⁵Neville et al.⁴⁴Cregan et al.⁴⁰Hoban et al.⁴¹	X XX	XXXX	1–7^a1–51–14^a51–14	XXX	XX
Fat g/L	Transcellular II	41.1 ± 7.8⁷⁹	Increases, but with high variability	Saint et al.⁴⁵Neville et al.⁴⁴	X	XX	1–51–14^a	XX

Sample collected once or twice daily over the interval, not each day over the interval.

One 24-hour sample collected at different lactation stages ranging from week 1 postpartum to week 27.

Milk biomarker changes have been used to measure the timing and characteristics of secretory activation in 10 studies.^{32,33,40,41,45,52,59,73–75} Six of these studies included both milk biomarkers and at least one other measure of secretory activation, including MP and patterns of increase in milk volume.^{32,39,40,45,52,71} In some studies, a single milk specimen was collected between postpartum days 3–8 to measure Na or the Na/K ratio to predict breastfeeding duration.^59,74,75 These studies revealed that a rapid decrease in Na was highly predictive of successful lactation, whereas a protracted elevation in Na or Na/K ratio predicted impaired secretory activation.^59,74 For example, Murase et al. concluded that the Na/K ratio on postpartum day seven might predict breastfeeding outcomes for mothers of term infants who perceive insufficient milk supply.⁷⁵

Although milk biomarkers enjoy high concurrent and predictive validity (Table 2), having been validated simultaneously in the same mother using patterns of increase in milk volume, it is still unknown whether all or just some biomarkers should be used in research and practice.⁴¹ It is also unknown which parameters should be used to interpret biomarker findings. For example, in three studies, only Na or Na/K ratios were measured and reported.^35,59,75 In contrast, research with breast pump-dependent mothers of preterm infants has incorporated all four primary biomarkers and examined the number of hours or days postpartum that different combinations of biomarkers achieved values considered normal for mothers of term infants.^40,41 Hoban et al., who measured 12-hourly milk samples over the first 14 days postpartum, reported a dose–response relationship between the number of biomarkers within normal range and pumped milk volume on days 3 and 5 postpartum.⁴¹

Thus, the use of milk biomarkers as a measure of secretory activation holds promise for research and practice, but additional studies are needed to establish normal values and to determine which biomarkers are most predictive of lactation problems in low- and high-risk populations. Milk biomarkers may have limited feasibility for use in low-risk populations due to laboratory analyses, costs, and need for frequent milk sampling during the early postpartum period.

Discussion

To our knowledge, this is the first article to review measures of secretory activation for use in research and practice with a primary emphasis on accuracy and feasibility. Although MP is the most feasible measure with respect to availability and cost, its accuracy has not been established using another measure of secretory activation concurrently for individual mothers. In contrast, patterns of increase in maternal milk volume have been validated with milk biomarkers in both breastfeeding and breast pump-dependent mothers and normal ranges have been established. However, it is not a direct measure of secretory activation because it is influenced by the effectiveness and efficiency of milk removal. The accuracy of serial urinary lactose concentrations has not been established for secretory activation, and this measure lacks feasibility due to the 24-hour urine sampling required to establish patterns of change. Milk biomarkers have been studied singly and in combination and are more accurate but less feasible than are either MP or patterns of increase in maternal milk volume. Although normal postpartum patterns for milk biomarkers have been established, additional research is needed to adapt these measures to routine clinical use.

The findings from this integrative review reveal an inverse relationship between the accuracy of a measure and its feasibility, with the more accurate measures currently being the least feasible. Thus, a priority for research, as well as personalized lactation practice, is to determine which secretory activation measure is appropriately used for which population of mothers, based on maternal risk for impaired secretory activation (Fig. 3). However, this conceptualization should include an updated definition of maternal lactation risk, which has traditionally been based upon whether the infant is in the NICU and/or the mother is breast pump dependent. This approach misses many mothers who are at a significant risk for delayed or impaired secretory activation and subsequent suboptimal lactation outcomes, such as otherwise healthy mothers who are overweight or obese.^{11,12,16,18,20,21}

FIG. 3.

Matching measure of secretory activation to maternal infant risk model.

Of particular urgency is the need to establish the accuracy of MP. This measure has the highest feasibility for use as a population-based screening tool for early detection of delayed or impaired secretory activation in healthy populations. Top research priority must be given to determining which indicators (e.g., full breasts, leaky breasts, and infant swallowing) to include and whether these indicators require adaptation for different populations. For example, no data affirm that overweight or obese mothers with larger breasts and greater tissue adiposity can accurately assess the same indicators of MP as normal weight mothers or whether breast pump-dependent mothers should use the same indicators as healthy breastfeeding dyads. Studies should target the concurrent validation of MP using milk biomarkers as the accurate standard in individual mothers.

Of the secretory activation measures, patterns of increase in milk volume measure has been studied the most, has acceptable accuracy and feasibility, has established normal ranges through to the first 2 weeks postpartum, and is limited only by being an indirect measure as described. Thus, there is sufficient evidence for the clinical use of in-home test weights in at-risk populations such as mothers with a previous experience of early unplanned weaning or those with risk factors such as obesity, diabetes, polycystic ovarian syndrome, and cesarean delivery. Similarly, intervention research that targets the prevention, diagnosis, and management of impaired secretory activation should incorporate this objective, accurate, and feasible measure rather than the unvalidated measure of MP. However, when the milk removal entity is ineffective or inefficient such as with hand expression or in the case of late preterm/early term infants with suboptimal intraoral suction pressures, test weights may not distinguish between problems with secretory activation versus those related to milk removal.

Finally, the development of clinical science to support the use of milk biomarkers with mothers at the greatest risk for delayed or impaired secretory activation is an important research priority. At highest risk are breast pump-dependent mothers of preterm infants with multiple antepartum and intrapartum risk factors, such as excessive blood loss or pregnancy-induced hypertension and its resultant pharmacotherapy. Two separate studies with milk biomarkers in this population have revealed high rates of impaired secretory activation, as well as the feasibility of collecting sequential milk samples from mothers with hospitalized infants.^37,40 Furthermore, innovative research by Hoban et al.⁴¹ has demonstrated the potential clinical utility of milk biomarkers in breast pump-dependent mothers.

Research in this area should define normal ranges for specific biomarkers, determine which biomarker or combination of biomarkers should be measured, and inform the frequency and duration of testing. For example, Hoban et al. demonstrated that achievement of secretory activation, as measured by milk biomarkers, was not permanent in all mothers and was easily reversed during the first 2 weeks postpartum with suboptimal pumping behaviors.⁴¹ As a minimum standard, intervention studies in this population should measure secretory activation with milk biomarkers rather than only with pumped milk volumes. Similarly, there is a need to increase the feasibility of measuring milk biomarkers with respect to cost and ease of use. Hoban et al. used LAQUA Twin Sodium and Potassium Meters (Horiba, Ltd, Kyoto, Japan) in a laboratory setting, but these instruments enjoy high feasibility for potential adaptation in the clinical setting for point-of-care measurement of Na or Na/K ratio.⁴¹ This conclusion was supported in a recent report by Lai et al.⁷⁶ who established the accuracy of these instruments and concluded that these ion selective probes hold promise for the diagnosis of low milk supply and/or mastitis.

A strength of this article is the integration of original studies, in-depth search strategies, and the review of all studies by a minimum of two authors. Our review was limited by the relatively few studies that met inclusion criteria, but this reflects the current underdeveloped state of the research in this field. An additional limitation is that we chose not to include measurement of secretory activation using RNA-sequencing analysis of the human milk fat layer transcriptome that identifies gene expression profiles during the different stages of lactation as detailed by Lemay et al.⁷⁷ because these technologies are still under development and refinement.

Summary

The biologic changes in milk synthesis and secretion that characterize the first 2 weeks postpartum have been well delineated, but this science has not been integrated into clinical practice and research with the intent of identifying and managing delayed or impaired secretory activation. As increasing numbers of mothers have health conditions that elevate the risk of lactation problems originating in the first 2 weeks postpartum, these clinical and research gaps must be addressed. Research should target establishing the accuracy of MP for heterogeneous populations using already-validated measures of patterns of increase in maternal milk volume in intervention studies. In addition, developing the translational science for the use of milk biomarkers in populations at the highest risk for delayed or impaired secretory activation must be a priority.

Footnotes

Authors' Contributions

All authors made substantial contributions to and approved the systematic review.

Disclosure Statement

No competing financial interests exist.

Funding Information

2017 Trainee Expansion Program, supported jointly by the International Society for Research in Human Milk and Lactation (ISRHML) and Family Larsson Rosenquist Foundation; 2018 Golden Lamp Society Dissertation Award, Rush University College of Nursing.

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